A Randomized Phase II/III Study of Conventional Chemotherapy +/- Uproleselan (GMI-1271) in Older Adults With Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: National Cancer Institute (NCI)

1 
Update #04 
 
 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
 
PROTOCOL UPDATE TO ALLIANCE A041701 
 
 
A RANDOMIZED PHASE II/III STUDY OF CONVENTIONAL CHEMOTHERAPY +/- UPROLESELAN (GMI-
1271) IN OLDER ADULTS WITH ACUTE MYELOID LEUKEMIA RECEIVING INTENSIVE INDUCTION 
CHEMOTHERAPY 
NCI-supplied agent: Uproleselan (GMI-1271) (NSC #801708, IND #
 IND holder: DCTD  
Commercial agent(s): Daunorubicin (NSC #82151), Cytarabine (NSC #63878) 
 
This is an FDA Registration Study. 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
X Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
X Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other: Updated CTSU Boilerplate Language  
 
 
 
 
If your site utilizes the CIRB as your IRB of record: No recommended IRB level of review is provided 
by the Alliance since the CIRB is the IRB of record for this trial. The site has 30 days after the posting 
of this amendment to implement it at their site. Please refer to the amendment application and CIRB 
guidelines for further instructions.  
 
If your site utilizes a local IRB as your IRB of record: IRB approval (or disapproval) is required within 
90 days. Please follow your local IRB guidelines. Expedited IRB Approval is allowed. The proposed 
changes in this amendment are minor and do not affect the overall risk/benefit ratio. 
 
As of Amendment #04, there will be no additional accrual to the Phase III component of the trial 
regardless of the outcome of the Phase II analysis and the study will be permanently closed to accrual.  

2 
UPDATES TO THE PROTOCOL: 
Cover Page 
• 
Drs. Wendy Stock and Geoffrey L. Uy have replaced Dr. Richard M. Stone as the Leukemia 
Committee Co-Chairs. All contact information has been updated accordingly.  
• 
Dr. Marina Konopleva has replaced Dr. John C. Byrd as the Correlative Study Co-Chair. All contact 
information has been updated accordingly.  
• 
Dr. Ken Byrd has replaced Dr. Stephen Strickland as the ECOG-ACRIN Study Champion. All 
contact information has been updated accordingly. 
• 
Dr. Jun (Vivien) Yin’s email address has been updated.  
• 
Per the updated Alliance protocol template, the institution names associated with the co-chairs and 
study champions have been removed.  
 
Study Resources (Page 2) 
• 
Per the updated Alliance protocol template, Ilene Galinsky’s institution name and phone number 
have been removed.    
• 
Caroline Harvey has replaced Ryan Daley has the A041701 Pharmacy Contact. All contact 
information has been updated accordingly. 
• 
The telephone number for the Alliance Hematologic Malignancy Biorepository (HEME) has been 
updated.  
 
CTSU Address and Contact Information (Page 3) 
This section has been changed to reflect the updated boilerplate language.  
 
Section 4.1 (Investigator and Research Associate Registration with CTEP) 
This section has been changed to reflect the updated boilerplate language. 
 
Section 4.2 (Cancer Trials Support Unit Registration Procedures) 
This section has been changed to reflect the updated boilerplate language.  
 
Section 4.5 (Patient Registration/Randomization Procedures) 
This section has been changed to reflect the updated boilerplate language.  
 
Section 6.1 (Data Collection and Submission) 
• 
This section has been changed to reflect the updated boilerplate language.  
• 
Section 6.1.3 (Data Quality Portal) has been changed to reflect the updated boilerplate language. 
• 
Section 6.1.4 (Rave-CTEP-AERS integration) has been added to reflect the Alliance protocol 
template 
 
Section 9.1.1 (Rave-CTEP-AERS integration) 
This section has been changed to reflect the updated boilerplate language. 
 
Section 13.1.1 (Primary Endpoint) 
The following information has been added to the end of the section: “As of Amendment 04, there will be 
no additional accrual to the Phase III component of the trial regardless of the outcome of the Phase II 
analysis.” 
 

3 
Section 13.1.2 (Sample Size and Power Justification) 
The following information has been added to the end of the section: “As of Amendment 04, there will be 
no additional accrual to the Phase III component of the trial regardless of the outcome of the Phase II 
analysis.” 
 
Section 13.2.1 (Primary Endpoint) 
• 
The first sentence of the Phase II component’s final analysis paragraph has been updated to the 
following: “The Phase II decision-making will be conducted when at least 191 events are observed 
(approximately expected 37 months after the first patient enrolled). If less than 191 events are 
observed 2 years after Phase II accrual ends, then the Phase II decision will occur at the target data 
lock.” 
• 
The second sentence of the Phase II component’s final analysis paragraph has been moved to be its 
own paragraph in the “Phase II component” subsection.  
• 
The second paragraph in the “Phase II component” subsection has been updated to the following: 
“At the final analysis of the Phase II, it will be concluded that the experimental arm regimen is 
promising and suggest proceeding to the Phase III component of the trial, if we a one-sided p-value 
< 0.10 from the log-rank test observe an HR <= 0.831 favoring the experimental arm.” 
• 
The following information has been added as a third paragraph in the “Phase II component” 
subsection: “As of Amendment 04, there will be no additional accrual to the Phase III component 
of the trial regardless of the outcome of the Phase II analysis. Given the maturity of follow-up on 
the current patients and no additional accrual to the trial, the final Phase III OS analysis will also 
be performed at the time of final Phase II EFS analysis. All Phase III alpha (one-sided 2.5%) will 
be spent at this analysis. The target data lock date is August 12, 2024.”  
• 
The first sentence of the Phase II component’s interim analysis paragraph has been updated to the 
following: “We will conduct a futility interim analysis which will take place after 50% of the total 
events are have occurred (approximately 25 months after the first patient enrolled).” 
• 
The following information has been added after the table as a second paragraph in the “Phase III 
component” subsection: “As of Amendment 04, there will be no additional accrual to the Phase III 
component of the trial regardless of the outcome of the Phase II analysis. Given the maturity of 
follow-up on the current patients and no additional accrual to the trial, the final Phase III OS 
analysis will also be performed at the time of final Phase II EFS analysis. The final Phase III of 
analysis of OS will conclude that the novel regimen significantly improves the OS compared to the 
daunorubicin and cytarabine arm if the one-sided p-value from the stratified log-rank test is < 0.025. 
The target data lock date is August 12, 2024.” 
 
Section 13.3 (Accrual Time and Study Duration) 
The following information has been added to the end of the section: “As of Amendment 04, there will be 
no additional accrual to the Phase III component of the trial regardless of the outcome of the Phase II 
analysis.” 
 
Section 13.5 (Study Monitoring) 
The following information has been added to the end of the section: “All EFS and OS outcome data will be 
requested for release after DSMB review at the time of the final Phase II EFS analysis, with patient follow-
up continuing per protocol.” 
 
Section 13.7 (Inclusion of Women and Minorities) 
This section has been changed to reflect the updated boilerplate language. 
 

4 
Section 14.1.3 (Methods) 
• 
The fifth sentence of the first paragraph has been moved to the second paragraph of the section.  
• 
The second paragraph has been completely revised to list of time points of the samples in a bullet 
list format.  
• 
The second sentence of the first bullet point under the “Submission of Cytogenetic Samples” 
subsection to be the following: “Include the karyotype description or clone number in the bottom 
of the high resolution electronic image (.jpeg or .tiff files) with arrows placed indicating 
abnormalities.” 
• 
After the second sentence of the first bullet point under the “Submission of Cytogenetic Samples” 
subsection, the following information has been added: “Images (karyotype, metaphase, and FISH) 
are preferred to be submitted together in one PowerPoint (PPT) file. If this is not possible, 
individual .jpeg or .tiff files are accepted.” 
• 
Under the “Submission of Cytogenetic Samples” subsection, the fourth bullet point has been 
updated to the following: “If case is abnormal, non-clonal (has one or more of the characteristic 
abnormalities specified on the list), enter the ISCN of each cell and provide a karyotype and 
corresponding metaphase representing each type of abnormality present.” 
• 
After the first sentence of the seventh bullet point under the “Optional Additional Procedures” 
subsection, the following information has been added: “Abnormal FISH results are encouraged to 
be submitted.” 
• 
Under the “Optional Additional Procedures” subsection, the third sentence of the seventh bullet 
point has been updated to the following: “Provide FISH information and two images (in the 
PowerPoint file with karyotypes and metaphases (preferred) or as individual .jpeg or .tiff files) for 
each assay performed.” 
• 
The heading of the third subsection has been updated to the following: “Questions regarding 
karyotype submission can be directed to Lisa Sterling, Cytogenetic Data Manager, at” 
• 
Under the “Questions regarding karyotype submission can be directed to Lisa Sterling, Cytogenetic 
Data Manager, at” subsection, the address for the Alliance Cytogenetics Committee Office has been 
completely removed.  
 
Section 14.1.4 (Analyses) 
The first sentence has been completely removed.  
 
Section 15.0 (Monitoring Plan and Regulatory Considerations) 
• 
The section heading has been updated to the following: “Monitoring Plan and Regulatory 
Considerations.” 
• 
Section 15.3 (Early Study Closure at Sites) has been added to provide guidance regarding early 
study closure at sites.  
____________________________________________________________________________________ 
UPDATES TO THE MODEL CONSENT: 
No 
changes 
have 
been 
made 
to 
the 
model 
consent. 
 
Replacement protocol and model consent documents have been issued. 
________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 

 
Version Date: 08/12/2024 
1 
Update #04 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A041701 
A RANDOMIZED PHASE II/III STUDY OF CONVENTIONAL CHEMOTHERAPY +/- UPROLESELAN (GMI-
1271) IN OLDER ADULTS WITH ACUTE MYELOID LEUKEMIA RECEIVING INTENSIVE INDUCTION 
CHEMOTHERAPY 
NCI-supplied agent: Uproleselan (GMI-1271) (NSC #801708, IND #
 IND holder: DCTD  
Commercial agent(s): Daunorubicin (NSC #82151), Cytarabine (NSC #63878) 
This is an FDA Registration Study. 
ClinicalTrials.gov Identifier: NCT03701308 
Study Chair & Leukemia Committee Co-Chair 
Geoffrey L. Uy, MD 
Washington University School of Medicine 
660 S Euclid Ave, CB 8007 
St. Louis, MO 63110 
Tel: 314-454-8304  Fax: 314-454-7551 
guy@wustl.edu 
 
Correlative Study Co-Chair 
Leukemia Committee Co-Chair 
Marina Konopleva, MD 
Wendy Stock, MD 
Tel: 718-430-4068 
Tel: 773-834-8982 
Marina.Konopleva@einsteinmed.edu 
wstock@medicine.bsd.uchicago.edu 
 
Cancer in the Older Adult & Health 
Outcomes Co-Chair 
Community Oncology Co-chair 
Cytogenetics Co-Chair 
Heidi Klepin, MD 
Anthony Jaslowski, MD 
Andrew Carroll, PhD 
Tel: 336-716-5772   
Tel: 920-433-8889 
Tel: 205-934-9555 
hklepin@wakehealth.edu 
tony.jaslowski@gboncology.com 
acarroll@uab.edu 
 
SWOG Study Champion 
ECOG-ACRIN Study Champion 
Primary Statistician 
Jane Liesveld, MD 
 
Ken Byrd, MD 
 
Jun (Vivien) Yin, PhD 
Tel: 585-275-5823   
Tel: 913-588-6030 
Tel: 507-538-6252 
jane_liesveld@urmc.rochester.edu 
kbyrd3@kumc.edu 
Vivien.Yin@moffitt.org 
 
Secondary Statistician 
Protocol Coordinator 
Data Manager 
Oudom Kour, MS  
Diane Feldman 
Korrie Skogen 
Tel: 507-422-6934 
Tel: 773-702-4236 
Tel: 507-293-7170 
Kour.Oudom@mayo.edu 
dfeldman3@bsd.uchicago.edu 
skogen.korrie@mayo.edu 
 
Participating NCTN Groups: Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-
ACRIN Cancer Research Group, SWOG / SWOG 

Alliance A041701 
Version Date: 08/12/2024 
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Update #04 
Study Resources: 
Expedited Adverse Event Reporting 
http://eapps-ctep.nci.nih.gov/ctepaers/ 
Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
A041701 Nursing Contact 
Ilene Galinsky, MSN, ANP-C 
igalinsky@partners.org 
A041701 Pharmacy Contact 
Caroline Harvey, RPh. 
Tel: 617-632-3786   
caroline_harvey@dfci.harvard.edu 
Alliance Hematologic Malignancy 
Biorepository (HEME) 
The Arthur G. James Cancer Hospital  
& Research Institute 
300 West 10th Avenue, Lobby 
Columbus, OH 43210 
Tel: 614-366-6295 
AllianceLTB@osumc.edu 
Drug Distribution Contact 
NCI Pharmaceutical Management Branch 
Tel: 240-276-6575 
PMBAfterHours@mail.nih.gov 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
regulatory@allianceNCTN.org 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
pharmacovigilance@allianceNCTN.org 
Questions regarding specimens/specimen 
submissions: 
appropriate Alliance Biorepository  
Questions regarding drug supply 
PMB  
Questions regarding drug administration 
Pharmacy Contact 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
CONTACT INFORMATION 

Alliance A041701 
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Update #04 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
https://www.ctsu.org, and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to 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 page located on the CTSU members’ website (https://www.ctsu.org).  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU members’ 
website. 
 
For clinical questions (i.e., patient eligibility or treatment-related)  
Study Chair, Nursing Contact, Protocol Coordinator, and (where applicable) Data Manager 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 
 

Alliance A041701 
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Update #04 
A RANDOMIZED PHASE II/III STUDY OF CONVENTIONAL CHEMOTHERAPY +/- UPROLESELAN (GMI-1271) IN 
OLDER ADULTS WITH ACUTE MYELOID LEUKEMIA RECEIVING INTENSIVE INDUCTION CHEMOTHERAPY 
 
Eligibility Criteria (see Section 3.0) 
• 
Diagnosis of AML based on 2017 WHO criteria excluding acute promyelocytic leukemia with PML-
RARA 
• 
No activating mutation in Fms-like tyrosine kinase-3 (FLT3) 
• 
No evidence of CNS involvement of AML 
• 
No prior chemotherapy for MDS, MPN or AML including hypomethylating agents or lenalidomide 
(see Section 3.3.2 for exceptions) 
• 
Age ≥ 60 years 
• 
Total Bilirubin ≤ 3 x upper limit of normal (ULN) 
• 
Creatinine ≤ 3 x upper limit of normal (ULN) 
OR Creatinine Clearance ≥ 30 mL/min/1.73m2 
 

Alliance A041701 
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Update #04 
Table of Contents 
 
1.0 
Background ....................................................................................................................................... 9 
1.1 
Treatment of Older Adults with AML .......................................................................................... 9 
1.2 
Role of E-selectin AML .............................................................................................................. 10 
1.3 
Clinical Data of uproleselan in AML .......................................................................................... 11 
1.4 
Selection of uproleselan dose ...................................................................................................... 13 
1.5 
Rationale ..................................................................................................................................... 14 
2.0 
Objectives ....................................................................................................................................... 15 
2.1 
Primary objectives ...................................................................................................................... 15 
2.2 
Secondary objectives................................................................................................................... 15 
2.3 
Correlative science objective(s) .................................................................................................. 15 
3.0 
Patient Selection .............................................................................................................................. 16 
3.1 
On-Study Guidelines ................................................................................................................... 16 
3.2 
Pre-Registration Eligibility Criteria (Step 0) .............................................................................. 16 
3.3 
Registration Eligibility Criteria (Step 1) ..................................................................................... 16 
4.0 
Patient Registration ......................................................................................................................... 18 
4.1 
Investigator and Research Associate Registration with CTEP ................................................... 18 
4.2 
Cancer Trials Support Unit Registration Procedures .................................................................. 19 
4.3 
Patient Pre-Registration Requirements ....................................................................................... 21 
4.4 
Patient Registration Requirements .............................................................................................. 21 
4.5 
Patient Registration/Randomization Procedures ......................................................................... 21 
4.6 
Registration to Correlative and Companion Studies ................................................................... 22 
4.7 
Stratification Factors, Grouping Factors, and Treatment Assignments ...................................... 22 
5.0 
Study Calendar ................................................................................................................................ 23 
6.0 
Data and Specimen Submission ...................................................................................................... 25 
6.1 
Data Collection and Submission ................................................................................................. 25 
6.2 
Specimen collection and submission .......................................................................................... 27 
7.0 
Treatment Plan/Intervention ........................................................................................................... 28 
7.1 
Arm 1 Treatment: 7+3 ................................................................................................................ 28 
7.2 
Arm 2 Treatment: 7+3 + Uproleselan ......................................................................................... 29 
8.0 
Dose and Treatment Modifications ................................................................................................. 30 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ......................................... 30 
8.2 
Dose Modifications ..................................................................................................................... 31 
9.0 
Adverse Events ............................................................................................................................... 32 
9.1 
Routine Adverse Event Reporting .............................................................................................. 32 

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Update #04 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 34 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 34 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Uproleselan (GMI-1271, 
NSC 801708) .......................................................................................................................................... 37 
10.0 
Drug Information ............................................................................................................................ 39 
10.1 
General Considerations: .............................................................................................................. 39 
10.2 
Uproleselan (GMI-1271) (NSC #801708) (IND 
, IND holder: DCTD) ....................... 39 
10.3 
Daunorubicin (Cerubidine®, Daunomycin, DNM) (NSC #82151) ............................................ 42 
10.4 
Cytarabine Intravenous (Cytosar, Ara-C) (NSC #63878) ........................................................... 44 
11.0 
Measurement of Effect .................................................................................................................... 46 
11.1 
Morphologic complete remission (CR) ....................................................................................... 46 
11.2 
Cytogenetic complete remission (CCyR) .................................................................................... 46 
11.3 
Morphologic complete remission with incomplete blood count recovery (CRi) ........................ 46 
11.4 
Treatment failure (TF) ................................................................................................................ 46 
11.5 
Recurrence/morphologic relapse ................................................................................................. 46 
12.0 
End of Treatment/Intervention ........................................................................................................ 47 
12.1 
Duration of Protocol Treatment .................................................................................................. 47 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention ............................................... 47 
12.3 
Follow-up .................................................................................................................................... 47 
12.4 
Extraordinary Medical Circumstances ........................................................................................ 48 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention . 48 
13.0 
Statistical Considerations ................................................................................................................ 48 
13.1 
Study Design ............................................................................................................................... 48 
13.2 
Analysis Plan .............................................................................................................................. 50 
13.3 
Accrual Time and Study Duration .............................................................................................. 52 
13.4 
Adverse Event Stopping Rule ..................................................................................................... 53 
13.5 
Study Monitoring ........................................................................................................................ 53 
13.6 
Clinical Data Update System (CDUS) Reporting ....................................................................... 53 
13.7 
Inclusion of Women and Minorities ........................................................................................... 54 
14.0 
Correlative And Companion Studies .............................................................................................. 54 
14.1 
Cytogenetic Correlative Science (Alliance A041701) ................................................................ 55 
14.2 
Molecular Genetic Analysis ........................................................................................................ 58 
14.3 
E-selectin studies (Alliance A041701-LC1) ............................................................................... 59 
15.0 
Monitoring Plan and Regulatory Considerations ............................................................................ 63 
15.1 
Central Data Monitoring and Source Data Verification.............................................................. 63 
15.2 
On-site Monitoring ...................................................................................................................... 64 
15.3 
Early Study Closure at Sites ........................................................................................................ 65 

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16.0 
References ....................................................................................................................................... 66 
Appendix I 
List of specific abnormalities for which karyotypes must be provided for single cells ...... 68 
Appendix II 
Collaborative agreements language .................................................................................... 69 
Appendix III 
Patient drug information handout and wallet card .......................................................... 71 
 
 
 

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Update #04 
1.0 
BACKGROUND 
1.1 
Treatment of Older Adults with AML 
For more than 40 years, “7+3” regimens (ie, cytarabine infused for 7 days with 3 days of an 
anthracycline) have been a standard for AML induction therapy [1]. Despite widespread use in 
older adults, 7+3 induction in these patients is associated with lower complete remission rates 
(50-60%), increased early mortality (up to 20%), and higher relapse rates compared with 
younger adults [2, 3]. Attempts at improving 7+3 through the addition of novel agents or 
intensification of post-remission therapy has largely failed to improve outcomes [4-6]. 
The reasons for the poor outcome of older adults with AML are poorly understood and include 
both unfavorable tumor biology as well as patient-specific characteristics such as increased 
comorbidity. Furthermore, within this patient population, there is significant heterogeneity in 
physical and psychological functioning and little consensus on optimal assessment strategies for 
determining which individuals are candidates for intensive remission and post-remission 
therapies. Currently, the choice of intensive versus nonintensive therapy is largely based on 
physician perceptions of patient tolerability and probability of success with little empirical data. 
In 2017, the landscape of AML treatment changed with the regulatory approval of new agents 
midostaurin, CPX-351, gemtuzumab ozogamicin (GO) and enasidenib for AML. Midostaurin 
was approved by the FDA based on the results of a randomized Phase III study performed in 
adults ages 18-60 years with AML harboring a mutation in the FLT3 tyrosine kinase. With a 
median follow-up of 59 months, the median overall survival was 74.7 months (95% confidence 
interval [CI], 31.5 to not reached) in the midostaurin group compared to 25.6 months (95% CI, 
18.6 to 42.9) in the placebo group (one-sided P=0.009) [7]. 
CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin at a fixed 5:1 drug ratio. 
In an open-label, phase III trial, 309 patients aged 60-75 years with untreated secondary AML 
and de novo AML with MDS related cytogenetic changes were randomized to receive 1-2 
induction cycles of CPX-351 or conventional 7+3, followed by consolidation therapy. CPX-351 
significantly improved median overall survival compared with 7+3 (9.56 vs 5.95 months; hazard 
ratio=0.69 [95% confidence interval, 0.52-0.90]; 1-sided P=0.003). Response rate was also 
significantly higher with CPX-351 versus 7+3 (47.7% vs 33.3%; 1-sided P=0.008). 
The approval of GO was based primarily on the ALFA-0701 study which was a randomized 
trial comparing daunorubicin and cytarabine with or without GO 3 mg/m2 days 1, 4 and 7 for 
treatment of patients 50-70 years old with newly-diagnosed AML. The primary endpoint was 
event-free survival (EFS). There were 271 patients randomized. The analysis of EFS showed a 
statistically significant improvement with a hazard ratio (HR) of 0.56 (95% CI 0.42, 0.76; 
p<0.001), but analysis of the secondary endpoint OS did not show statistically significant 
improvement (HR 0.81; 95% CI, 0.60, 1.09; p=0.16). 
A series of meetings between leukemia experts in the United States and Canada were convened 
to address the issues of improving the treatment of older adults with AML and to design the next 
series of studies within the NCTN. Two separate studies were proposed, one using intensive 
therapies in older adults comparing novel regimens to a 7+3 control arm and a study of non-
intensive therapy which would utilize a hypomethylating agent as the control. These studies 
would share a similar phase II/III design with an intermediate endpoint which would facilitate a 
more rapid screening of regimens that should be tested in larger phase III comparisons. The 
SWOG 1612 Intergroup Less Intense AML Platform (LEAP) trial which will study less 
intensive therapies for this older adult population against an azacitidine control arm. The current 
proposed study is designed to be complementary to SWOG 1612. Both SWOG1612 and this 
study contain a common comprehensive geriatric assessment platform to identify patient 

Alliance A041701 
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Update #04 
characteristics which may predict excess toxicity and suitability for intensive chemotherapy vs. 
non-intensive chemotherapy.  
1.2 
Role of E-selectin AML 
The small molecule uproleselan is a glycomimetic specific E-selectin antagonist that binds to 
the adhesion molecule E-selectin that is expressed on endothelial cells. E-selectin expression is 
transient in the normal vasculature during an inflammatory response and constitutive in the bone 
marrow resulting in sequestration of AML cells. It binds a trisaccharide domain common to both 
sialyl Lewisa (sLea) and its isomer, sialyl Lewisx (sLex) on cells. E-selectin binding ligands that 
include CD15, CD44, and CD65 have been defined on histologically diverse normal and 
malignant cells, including AML.  
E-selectin inhibition is hypothesized to disrupt the adhesion of AML cells in bone marrow. In a 
murine model of AML generated by retroviral transduction of the MLL-AF9 fusion oncogene 
into human HSCs, leukemic blasts were found to upregulate E-selectin on the bone marrow 
vasculature 5- to 10-fold [8]. Targeted disruption of potential E-selectin-mediated interactions 
by uproleselan was sufficient to mobilize leukemic blasts into the peripheral circulation. Studies 
in which wild-type or E-selectin knock-out mice engrafted with MLL-AF9 leukemic cells were 
treated with high dose cytarabine demonstrated that although the absence of E-selectin had no 
effect on total LSC numbers per femur, the absence of E-selectin increased chemosensitivity of 
LSCs by 20-fold. Uproleselan was also evaluated in combination with cytarabine and 
daunorubicin in an orthotopic model of human AML for its ability to eliminate patient-derived 
AML tumor cells from bone marrow and spleen and affect survival [9]. Mice treated with 40 
mg/kg uproleselan in combination with cytarabine and daunorubicin had fewer numbers of 
AML blasts than mice treated with cytarabine and daunorubicin alone. In uproleselan and 
chemotherapy treated animals, the number of blasts were significantly lower in the combined 
compartments of the spleen and bone marrow.  
Adhesion of AML blasts to E-selectin initiated up-regulation of pathways critical to leukemia 
progression that include members of Wnt signaling [10]. The magnitude of this response 
correlated with expression of E-selectin ligands on blasts. The Wnt pathway is associated with 
the regulation of cell proliferation, differentiation, and apoptosis in AML and has been identified 
as a target for therapy. uproleselan inhibits the E-selectin-mediated activation of the Wnt 
pathway and may improve response in treatment of AML. Similarly, E-selectin is unique among 
vascular adhesion molecules in being able to directly activate NF-κB. Upstream blockade of E-
selectin by uproleselan has been shown to inhibit NF-κB activation [11]. NF-κB signaling was 
identified as a pathway potentially dampened in AML blasts following uproleselan 
administration, suggesting that adhesion to E-selectin activates pro-survival NF-κB signaling in 
AML cells leading to enhanced chemoresistance. Collectively, these results suggest that E-
selectin is a key vascular niche component in the bone marrow mediating LSC resistance to 
chemotherapy.  
Expression of E-selectin or its binding epitope (sialyl Lea/x) may predict the clinical course and 
patient outcomes in AML [12-16]. Soluble E-selectin (sE-selectin) may be shed from the cell 
membrane and detected by enzyme-linked immunosorbent assay (ELISA) in the peripheral 
blood. AML is associated with increased vessel density, and sE-selectin release by 
activated/proliferating endothelial cells in the bone marrow may contribute to increased 
E-selectin levels in patients with untreated AML [13, 17]. sE-selectin levels were increased in 
the serum of patients with newly diagnosed AML compared with that in the serum of healthy 
subjects [12-14]. sE-selectin levels have also been correlated with the extramedullary infiltration 
of AML cells (P<0.001) and predicted the occurrence of relapse of AML (P=0.01); sE-selectin 

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levels at diagnosis of AML predicted low survival (P<0.001); and decrease in sE-selectin levels 
correlated with durable remission of AML [12, 15]. 
Data also suggest an important role for E-selectin in chemotherapy-induced mucositis through 
the regulation macrophage trafficking to the site of injury in the gut lining. Chemotherapy causes 
initial cell damage, and through a series of inflammatory and adhesion-molecule-mediated 
stages, the damage is propagated with resulting loss of mucosal integrity. E-selectin knockout 
mice are protected against chemotherapy-induced mucositis using 5-fluorouracil (5-FU). 
Similar results were demonstrated where mice administered uproleselan with 5-FU had 
enhanced neutrophil recovery [18], less mucositis and improved weight loss [19] as compared 
with mice treated with 5-FU alone. Furthermore, E-selectin was up-regulated in the intestines 
following chemotherapy or radiation damage. Both genetic deletion of E-selectin and 
pharmacologic inhibition using uproleselan effectively blocked secondary migration of 
inflammatory F4/80+ Ly-6C+ macrophages to intestines of mice following chemotherapy or 
irradiation. 
1.3 
Clinical Data of uproleselan in AML 
A Phase I/II, open-label, multicenter trial evaluating the safety, PK, PD, and efficacy of 
uproleselan as an adjunct to standard chemotherapy in 91 subjects with acute myeloid leukemia 
(AML). The Phase I of GMI-1271-201 was a repeat dose-escalation study of 3 doses (5 mg/kg, 
10 mg/kg, and 20 mg/kg) in adult subjects with relapsed/refractory (R/R) AML treated with 
mitoxantrone, etoposide and cytarabine (MEC) chemotherapy No dose-limiting toxicity was 
observed at any dose level. Pharmacodynamic analysis demonstrated on-target activity as 
measured by reduction in shed E-selectin (sE-sel) in the plasma at all 3 dose levels and no dose-
response was observed, suggesting that the dose levels assessed were all above a plateau level 
for PD effect. 
The Phase II consisted of two patient populations. Arm A dose expanded this population at the 
RP2D level of 10 mg/kg. Phase II Arm B evaluated uproleselan in older adult patients ≥ 60 years 
of age with newly diagnosed AML in combination with 7+3, cytarabine and idarubicin.   
Enrollment and dosing in this trial is complete. Sixty-six (66) R/R subjects and 25 older adult 
newly diagnosed subjects were administered uproleselan with cytotoxic chemotherapy. 
Clinically relevant improvements in remission and overall response rates were observed. 
Preliminary data as of the December 2017 data cut-off are shown in Table 1 and Table 2.  
Table 1 
GMI-1271-201 Baseline Demographics 
Sub-group 
Phase I 
R/R 
(MEC) 
N (%) 
Phase II 
R/R 
(MEC) 
N (%) 
Total 
R/R 
(MEC) 
N (%) 
Phase II 
Older Adult 
Newly 
Diagnosed 
(7+3) 
N (%) 
Subjects with available data 
19 
47 
66 
25 
Age, median (range) 
51 (26-77) 
61 (27-84) 
59 (26-84) 
67 (60-79) 
Primary Refractory, n (%) 
7 (37) 
15 (32) 
22 (33) 
- 
Relapsed, All, n (%) 
12 (63) 
32 (68) 
44 (67) 
- 
Relapsed <6 months 5 (26) 
17 (36) 
22 (33) 
- 
Frontline, All, n(%) 
- 
- 
- 
25 (100) 
de novo - 
- 
- 
12 (48) 

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Sub-group 
Phase I 
R/R 
(MEC) 
N (%) 
Phase II 
R/R 
(MEC) 
N (%) 
Total 
R/R 
(MEC) 
N (%) 
Phase II 
Older Adult 
Newly 
Diagnosed 
(7+3) 
N (%) 
Secondary AML - 
- 
- 
13 (52) 
Prior Therapies, n (%) 
 
 
 
 
HSCT 4 (21) 
7 (15) 
11 (17) 
- 
≥2 Induction Regimens 6 (32) 
16 (34) 
22 (33) 
- 
Risk Category (ELN), n (%) 
 
 
 
 
Intermediate 2 (11) 
9 (19) 
11 (17) 
7 (28) 
Adverse 11 (58) 
22 (47) 
33 (50) 
12 (48) 
Unknown 4 (21) 
11 (23) 
15 (23) 
3 (12) 
Mutations 
 
 
 
 
FLT3-ITD 0 
3 (6) 
3 (5) 
- 
TP53 mutation; del (17p) 1 (5) 
3 (6) 
4 (6) 
- 
AML = acute myeloid leukemia; ECOG = Eastern Cooperative Oncology Group; ELN = European Leukemia Net;  
HSCT = hematopoietic stem cell transplantation; MEC = mitoxantrone + etoposide + cytarabine; R/R = 
relapsed/refractory; 7+3 = cytarabine + idarubicin 
Table 2 
Summary of Outcomes Observed in GMI-1271-201 
Outcome 
Phase I 
R/R 
(MEC) 
Phase II 
R/R 
(MEC) 
Total 
R/R 
(MEC) 
RP2D 
R/R 
(MEC) 
Older 
Adult 
Newly 
Diagnosed 
(7+3) 
N Completing Induction Period 
19 
47 
66 
54 
25 
BONE MARROW RESPONSE,  
n (%) 
 
 
 
 
 
CR 
8 (42) 
14 (30) 
22 (33) 
19 (35) 
13 (52) 
CR/CRi 
9 (47) 
18 (38) 
27 (41) 
23 (43) 
17 (68) 
ORR (CR/CRi/MLFS/PR) 
10 (53) 
22 (47) 
32 (48) 
27 (50) 
20 (80) 
All-Cause Mortality 0-30 days, n 
(%) 
0 
1 (2) 
1 (2) 
1 (2) 
2 (8) 
All-Cause Mortality 0-60 days, n 
(%) 
2 (11) 
4 (9) 
6 (9) 
5 (9) 
3 (12) 
Outcomes by Subgroup (CR/CRi 
Rate and %) 
 
 
 
 
 
Primary Refractory 
4/7 (57) 
4/15 (27) 
8/22 (36) 
5/17 (29) 
- 
Relapsed (all) 
5/12 (42) 
14/32 (44) 
19/44 
(43) 
18/37 (49) 
- 
Duration, prior remission <6 mos 1/5 (20) 
5/17 (29) 
6/22 (27) 
6/19 (32) 
- 
Duration, prior remission ≥24 mos 3/3 (100) 
3/4 (75) 
6/7 (86) 
6/7 (86) 
- 
AML Type 
 
 
 
 
 

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Outcome 
Phase I 
R/R 
(MEC) 
Phase II 
R/R 
(MEC) 
Total 
R/R 
(MEC) 
RP2D 
R/R 
(MEC) 
Older 
Adult 
Newly 
Diagnosed 
(7+3) 
De novo - 
- 
- 
- 
9/12 (75) 
Secondary AML - 
- 
- 
- 
8/13 (62) 
ELN Risk Category 
 
 
 
 
 
Favorable risk - 
- 
- 
- 
3/3 (100) 
Intermediate risk - 
- 
- 
- 
4/7 (57) 
Adverse risk - 
- 
- 
- 
8/12 (67) 
MEC = mitoxantrone + etoposide + cytarabine; R/R = relapsed/refractory; 7+3 = cytarabine + idarubicin 
The subjects enrolled are representative of the high-risk, poor prognosis populations expected 
to be seen at tertiary academic cancer research centers participating in this trial. In the phase I/II 
study overall complete response rates (CR/CRi) of 43% were observed in the R/R AML 
population and 68% in older adult AML population. The 30- and 60-day all-cause mortality was 
extremely low. These data compare favorably with published data where higher induction 
mortality rates are expected in the older population, with rates of 15-20% commonly reported.  
The adverse events (AEs) observed in these AML patient populations were typical for induction 
chemotherapy and no specific uproleselan-related concerns have been identified. While most 
events were reported at similar rates as reported in the literature for MEC and 7+3, the incidence 
and severity of mucositis was low overall with only 2 Grade 3/4 events reported in 2 R/R subject 
treated with MEC (3%). These data suggest that uproleselan may reduce the incidence and 
severity of chemotherapy-induced mucositis, thereby providing an important safety advantage 
over chemotherapy alone 
Table 3 
Oral Mucositis Adverse Events Reported During Induction in GMI-1271-201, N (%) 
Oral Mucositis Adverse Event 
Phase I 
R/R 
(MEC) 
Phase II 
R/R 
(MEC) 
Total 
R/R 
(MEC) 
RP2D 
R/R 
(MEC) 
Older 
Adult 
Newly 
Diagnosed 
(7+3) 
Evaluable Patients 
19 
47 
66 
54 
25 
Grades 1/2* 
5 (26) 
9 (19) 
14 (21) 
9 (17) 
5 (20) 
Grades 3/4* 
1 (5) 
1 (2) 
2 (3) 
2 (3) 
0 
*AE grade definitions follow CTCAE v4.03. 
1.4 
Selection of uproleselan dose 
In the phase I clinical trial of uproleselan, three dose levels of uproleselan (5, 10, and 20 mg/kg 
BID) were assessed. Clinical outcomes (bone marrow response to uproleselan with induction 
chemotherapy) were similar across the dose levels. The concentration for IC50 and IC90 in the 
binding assay for E-selectin has been established for uproleselan. A comparison of plasma 
concentrations achieved with uproleselan and IC50 and IC90 levels was performed, using area 
under the curve (AUC), time above IC50 (T>IC50), and time above IC90 (T> IC90). Target 
exposure levels for efficacy in terms of AUC, T>IC50 or T> IC90, were established based on in 
vitro data and preclinical efficacy data. Population PK analysis on the Phase 1 was conducted 

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to understand the pharmacokinetics of uproleselan in AML patients. Clearance of uproleselan 
varies with renal function and exhibits dose-linear PK with no accumulation of uproleselan at 
any dose was observed, as expected from the short half-life. Clearance did not vary with body 
size or weight in AML patients. The target exposure levels in terms of AUC and time above 
IC50 and IC90 were attained at all doses in the Phase 1 portion of the study. However, the daily 
AUC nonclinical no-observed-adverse-effect level (NOAEL) limits for mouse were exceeded 
in a majority of patients at the 20 mg/kg dose level. Based on these observations in the Phase 1, 
the Recommended Phase 2 Dose was 10 mg/kg which provided the highest levels of exposure 
that do not exceed the nonclinical safety limits for a majority of patients. Simulation of flat-
fixed dosing was performed and compared to a weight-based dose of 10 mg/kg.  The simulation 
suggests that the flat-fixed dose of 800 mg will provide less variability in PK metrics while 
achieving the target exposure levels necessary for efficacy. Further, in an exposure-response 
analysis of patients with AML administered uproleselan with cytotoxic chemotherapy in the 
Phase 1/2 trial, no exposure-response relationships for efficacy and safety were identified. While 
exposure was found to vary with renal function, simulations of the 800 mg dose over a wide 
range of renal function demonstrated that exposure remains within the range attained in the 
Phase 1/2 trial. Therefore, the flat, fixed dose of 800 mg is expected to provide exposure 
consistent with that already evaluated at the RP2D of 10 mg/kg in the Phase 1/2 trial and will 
be used in this and other trials of uproleselan in AML. 
1.5 
Rationale 
We will conduct a randomized study testing the addition of uproleselan to a standard 
daunorubicin/cytarabine regimen in older adults with previously untreated AML. E-selectin 
inhibition with uproleselan in AML is attractive in that it targets both disease biology 
(adherence/activation of AML blasts) and a host response contributing to treatment morbidity 
(macrophage trafficking to the site of chemotherapy injury in the gut mucosa). The 
administration of uproleselan with chemotherapy in the initial Phase I/II study resulted in 1) 
higher than expected CR/CRi rates, 2) low induction-related mortality rates, and 3) low Grade 
3/4 events of mucositis and warrants further investigation in a randomized study. 
We propose a randomized phase II/III trial using EFS as the phase II endpoint and OS as the 
phase III endpoint. Although we are ultimately interested in agents that provide an overall 
survival benefit to patients, a shorter, intermediate endpoint is desirable to screen potential novel 
agents more quickly for phase III testing. In AML, the lack of surrogate endpoints that predict 
OS remains a major barrier for clinical development.  There are several reasons for this including 
the availability of potentially effective salvage regimens including allogeneic HCT (alloHCT). 
The most common endpoint used in phase II AML studies are rates of morphologic CR. A 
drawback of the use of CR as a phase II endpoint in an upfront study is that it does not take into 
consideration the potential beneficial effects of the study agent in consolidation therapy. 
Another drawback to CR as an endpoint is that promising improvements in CR have later been 
demonstrated to show no benefit to overall survival as a result of increased toxicity and non-
relapse mortality.  
The choice of EFS has several benefits in that it incorporates measures of efficacy such as CR 
and remission duration as well as toxicity including nonrelapse mortality. Like CR, EFS has a 
modest correlation with overall survival due to the potential for patients to be salvaged by 
nonprotocol therapy including alloHCT [20]. For older adults with AML, the median remission 
duration and the effectiveness of salvage chemotherapy and alloHCT is less of a consideration 
than in a younger patient population. Furthermore, EFS may be considered a desirable endpoint 
as patients in CR may have an improved quality of life from normalization of their blood counts 
because of transfusion independence and decreased risk of infection. Recently, the FDA has 

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accepted EFS as evidence of clinical efficacy in older patients with newly diagnosed AML 
supportive of the full approval of Mylotarg [21]. 
2.0 
OBJECTIVES 
2.1 
Primary objectives 
2.1.1 
Phase II 
Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus 
daunorubicin and cytarabine in subjects ≥ age 60 with previously untreated acute myeloid 
leukemia 
2.1.2 
Phase III 
Compare the overall survival (OS) of the daunorubicin, cytarabine plus uproleselan to 
daunorubicin and cytarabine in this patient population.  
2.2 
Secondary objectives 
2.2.1 
Determine the rates of complete remission (CR), complete remission with incomplete 
count recovery (CRi), complete remission with incomplete hematopoietic recovery (CRh) 
and cytogenetic complete remission (CCyR) for each chemotherapy regimen. 
2.2.2 
Determine the overall survival (OS), and remission duration of patients for each 
chemotherapy regimen. 
2.2.3 
Describe the frequency and severity of adverse events for patients for each chemotherapy 
regimen 
2.2.4 
Describe the interaction of pretreatment disease and patient characteristics including 
morphology, cytogenetics, molecular genetic features, WBC count and hemogram, and 
performance status on clinical outcomes. 
• 
Note: Analysis of cohort with performance status of 4 will be done separately from 
patients with an ECOG performance status of 0-3, as most phase III trials only include 
patients with a performance score of 0-3. 
2.3 
Correlative science objective(s) 
2.3.1 
Assessment of Cytogenetics and ELN Risk Categories 
• 
Correlate specific karyotype groups (normal or various primary and secondary 
chromosomal abnormalities) with clinical and laboratory parameters and with response 
rates, response duration, survival and cure in patients treated with various induction 
and post-induction regimens. 
• 
Correlate specific karyotype groups with selected molecular abnormalities and with 
measurable residual disease. 
• 
To determine karyotype changes at end of consolidation and the influence of the type 
of change (or no change) in karyotype at the end of consolidation on subsequent 
clinical course. 
• 
To determine karyotype changes at relapse and the influence of the type of change (or 
no change) in karyotype at relapse on subsequent clinical course. 
 
 

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3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled 
diabetes mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. HIV infected patients 
on effective antiretroviral therapy with undetectable viral load within 6 months are 
eligible for this trial. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥ 3 years. 
3.2 
Pre-Registration Eligibility Criteria (Step 0) 
___ 
3.2.1 
Bone Marrow and Peripheral Blood Submission 
All patients must be pre-registered in order to submit the required bone marrow 
and peripheral blood specimens to the Alliance HEME Biobank (see Section 6.2). 
Note: Bone marrow aspirate and peripheral blood for patients who consent to 
A041701-LC1 and/or banking should also be submitted at this time as outlined in 
Section 6.2.  
Please ensure patient has suspected diagnosis of AML and meets on study 
guidelines per Section 3.1 prior to informed consent and biospecimen collection. 
3.3 
Registration Eligibility Criteria (Step 1) 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
___ 
3.3.1 
Documentation of Disease 
• 
Diagnosis of AML based on 2017 WHO criteria [22] excluding acute 
promyelocytic leukemia with PML-RARA. 
Note: Patients with myeloid sarcoma without bone marrow involvement, acute 
leukemia of ambiguous lineage or blast transformation of CML are not 
eligible.  
• 
No activating mutation in the Fms-like tyrosine kinase-3 (FLT3) defined as a 
ratio of mutant to wild-type allele ≥ 0.05 by capillary electrophoresis or a 

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Update #04 
variant allele fraction of ≥ 5% by next generation sequencing from either bone 
marrow or peripheral blood. 
• 
No evidence of CNS involvement of AML 
___ 
3.3.2 
Prior Treatment  
• 
No prior chemotherapy for MDS, MPN or AML including hypomethylating 
agents (e.g. azacitidine and decitabine), ruxolitinib or lenalidomide with the 
following exceptions: 
o Emergency leukapheresis 
o Hydroxyurea 
o Growth factor/cytokine support 
o All-trans retinoic acid (ATRA) 
o Single dose of intrathecal cytarabine and/or methotrexate for patients 
undergoing lumbar puncture to evaluate for CNS involvement 
___ 
3.3.3 
Age ≥ 60 years 
___ 
3.3.4 
Required Initial Laboratory Values 
Total Bilirubin 
≤ 3 x upper limit of normal (ULN) 
Creatinine 
OR 
≤ 3 x upper limit of normal (ULN) 
Creatinine Clearance 
≥ 30 mL/min/1.73m2 
 
 

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Refer to the NCI RCR page on the CTEP website for additional information. For questions, 
please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on the person and site roster assignment housed in the Roster Maintenance application 
and in most cases viewable and manageable via the Roster Update Management System 
(RUMS) on the Cancer Trials Support Unit (CTSU) members’ website. 
This study is supported by the NCI CTSU. 
IRB Approval   
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(CTEP) and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases. 
In addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies that are not 
reviewed by the CIRB, or if the study was previously open at the site under the local IRB. 
International sites should continue to submit Research Ethics Board (REB) approval to the 
CTSU Regulatory Office following country-specific regulations.  
Sites participating through the NCI CIRB must submit the Study Specific Worksheet (SSW) for 
Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email (CTSURegPref@ctsu.coccg.org) or by calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status 
following processing of the IRB/REB approval record: 
• 
Have an active CTEP status; 
• 
Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  

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Update #04 
• 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Have the appropriate CTEP registration type for the protocol.  
4.2.1 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• 
Compliance with all applicable protocol-specific requirements (PSRs). 
4.2.2 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and their associated investigators and staff on a 
participating roster. To view/download site registration forms:   
• 
Log in to the CTSU members’ website (https://www.ctsu.org); 
• 
Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select Alliance, 
and protocol number A041701. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.)  
4.2.3 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
4.2.4 
Checking Site’s Registration Status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go: 

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Update #04 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.2.5 
Delegation of Tasks Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application which is accessible via the Delegation Log link on the CTSU members’ website 
or directly at https://dtl.ctsu.org.  The Clinical Investigator (CI) is required to review and 
electronically sign the DTL prior to the site receiving an approved site registration status 
and enrolling patients to the study. To maintain an approved site registration status the CI 
must re-sign the DTL at least annually and when a new version of the DTL is released; and 
to activate new task assignments requiring CI sign-off. Any individual at the enrolling site 
on a participating roster may initiate the site DTL. Once the DTL is submitted for CI 
approval, only the designated DTL Administrators or the CI may update the DTL. 
Instructions on completing the DTL are available in the Help Topics button in the DTL 
application and describe DTL task assignments, CI signature, and CTEP registration 
requirements, as well as include a Master Task List.  
4.3 
Patient Pre-Registration Requirements 
• 
Informed consent: The patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, 
and discomforts. Current human protection committee approval of this protocol and a 
consent form is required prior to patient consent and registration. 
• 
Bone marrow and peripheral blood submission: All patients are required to be pre-
registered to A041701 in order to submit bone marrow aspirate and peripheral blood 
samples to the HEME Biobank for the required banking for molecular genetic analysis 
(see Section 6.2).  
4.4 
Patient Registration Requirements 
• 
Pre-registration (Step 0) Completed: After patient pre-registration, specimens must 
be submitted as outlined in Section 6.2. Pre-registration (Step 0) must be completed in 
order to complete patient registration (Step 1). Once patient registration eligibility is 
confirmed (see Section 3.3), the patient may be registered (Step 1). 
4.5 
Patient Registration/Randomization Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs’ 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 

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• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, or receiving investigator for a patient transfer in OPEN, the IVR or 
NPIVR must list the Institutional Review Board (IRB) number used on the site’s IRB approval 
on their Form Food and Drug Administration (FDA) 1572 in the Registration and Credential 
Repository (RCR). If a DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.6 
Registration to Correlative and Companion Studies 
4.6.1 
Registration to Substudies described in Section 14.0  
There are two substudies within Alliance A041701. These substudies do not require 
separate IRB approval. The substudies included within Alliance A041701 are: 
• 
E-selectin studies (Section 14.3), Alliance A041701-LC1 
If a patient answers “yes” to “I agree that my samples and related information may be used 
for the laboratory study described above,” Question #1 in the model consent, they have 
consented to participate in the substudy described in Section 14.3. The patient should be 
registered to Alliance A041701-LC1 at the same time they are registered to the treatment 
trial (A041701). Samples should be submitted per Section 6.2. 
4.7 
Stratification Factors, Grouping Factors, and Treatment Assignments 
Stratification factors: age (60-69 vs. 70 and older), performance status (0-1 vs. 2-4), de novo vs. 
secondary/therapy related AML 
Grouping factors: phase II vs. phase III 
The randomization routine is found in Section 13.0 (Statistical Considerations). 
 
 

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5.0 
STUDY CALENDAR 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday one week later would be considered 
Day 7. 
 
Baseline* 
Induction 
End of 
Induction 
Consolidation 
End of 
Treatment 
Follow-
up** 
Tests & Observations 
 
 
History and physical 
X 
X 
 
X 
X 
X 
Performance Status 
X 
 
 
 
 
 
Height and weight 
X 
X 
 
X 
 
 
MUGA or ECHO 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
 
Laboratory Studies 
 
 
FLT3 Mutation analysis 
X 
 
 
 
 
 
CBC with differential 
X 
X(2) 
X 
X(2) 
 
X 
Serum Creatinine 
X 
X(3) 
 
X(3) 
 
 
Bilirubin, AST, ALT, 
Alk. Phos. 
X 
X(3) 
 
X(3) 
 
 
INR, PTT, fibrinogen 
X 
 
 
 
 
 
Uric Acid 
X 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
Molecular genetic 
testing 
X(1) 
 
 
 
 
 
Cytogenetics 
X 
 
B 
 
B 
B 
Staging 
 
 
BM biopsy/aspirate 
X(4) 
A 
X 
 
X 
C 
Correlative studies: For patients who consent to participate 
Bone marrow and blood 
samples 
Prior to treatment, end of induction, end of consolidation, and relapse. See 
Section 6.2. 
* 
Baseline studies are to be completed ≤ 14 days prior to registration. 

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** Follow-up should occur at least every 2 months (+/- 14 days) in year 1, every 3 months (+/- 14 days) 
in year 2, then every 6 months (+/- 30 days) until 5 years from registration (See Section 12.3). 
Cytogenetics reports for applicable time points should be submitted until 15 years following 
registration. 
1 
Molecular testing is to be performed according institutional standards but should include testing for 
mutations in FLT3, NPM1, CEBPA, RUNX1, ASXL1, IDH1, IDH2 and TP53 to allow classification of 
patients by 2017 WHO criteria and stratification by 2017 ELN genetic risk classification [23]. 
2 
CBC should be performed daily while inpatient and at least twice weekly until hematopoietic recovery. 
Please submit induction lab tests and results in Rave from either the labs drawn at the end of the cycle, 
or the lab that that will correspond to the disease response.  
3 
Monitoring of serum creatinine, bilirubin, AST/ALT/Alk Phos should be performed prior to the start 
of each cycle of treatment and then as clinically indicated. 
4 
Baseline bone marrow biopsy/aspirate should be obtained at the time of pre-registration and specimens 
should be submitted as outlined in Section 6.2 (see also Sections 3.2 and 4.4).   
A Day 14 of first course (+3 days) 
B Cytogenetics are required prior to initiation of therapy, at achievement of first complete remission (if 
diagnostic specimen is abnormal), at the end of consolidation (if CR cytogenetics are abnormal), and 
at first relapse. After local review is complete, the designated local cytogeneticist will submit electronic 
karyotypes, metaphases, karyotype processing information, and FISH information (if applicable). See 
Section 14.1. 
C Bone marrow assessments post-treatment are only required if clinical or laboratory signs of relapse are 
present. 
 
 

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6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 
• 
and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• 
Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to 
Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata. No action will be required; each study invitation will be automatically accepted and 
study access in Rave will be automatically granted. Site staff will not be able to access the study 
in Rave until all required Medidata and study-specific trainings are completed. Trainings will 
be in the form of electronic learnings (eLearnings) and can be accessed by clicking on the 
eLearning link in the Tasks pane located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link to the eLearning will appear 
under the study name in the Studies pane located in the center of the iMedidata screen; once the 
successful completion of the eLearning has been recorded, access to the study in Rave will be 
granted, and a Rave EDC link will replace the eLearning link under the study name.  
No action will be required by site staff (to activate their account) who have not previously 
activated their iMedidata/Rave account at the time of initial site registration approval for the 
study in the Regulatory application. Pending study invitations (previously sent but not accepted 
or declined by a site user) will be automatically accepted and study access in Rave will be 
automatically granted for the site user. Account activation instructions are located on the CTSU 
website in the Data Management section under the Data Management Help Topics > Rave 
resource materials (Medidata Account Activation and Study Invitation). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com.   

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6.1.1 
Data submission schedule 
A Schedule of Forms is available on the Alliance study webpage, within the Case Report 
Forms section. The Schedule of Forms is also available on the CTSU site within the study-
specific Education and Promotion folder, and is named Time & Events. 
6.1.2 
Supporting Documentation to be Submitted to the Alliance 
This study requires supporting documentation for diagnosis, response, and relapse. 
Supporting documentation will include CBC, bone marrow pathology, molecular genetic 
testing, cytogenetics, and FISH reports (if applicable) which must be submitted at the 
following time points: 
Diagnosis: CBC, bone marrow pathology, molecular genetic testing, cytogenetics, and 
FISH reports (if applicable) 
Day 14: Bone marrow pathology 
End of induction: CBC, bone marrow pathology, cytogenetics, and FISH reports (if 
applicable) 
End of treatment: CBC, bone marrow pathology, cytogenetics, and FISH reports (if 
applicable) 
Time of relapse: CBC, bone marrow pathology, cytogenetics, and FISH reports (if 
applicable) 
Supporting documentation is to be submitted via Rave. 
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent 
forms, forms with current status, and timeliness reports. Site staff should review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the CTSU 
website. Staff who have Rave study access can access the Rave study data via direct links 
available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a month. 
These notifications serve as alerts that queries and/or delinquent forms require site review, 
providing a summary count of queries and delinquent forms for each Rave study that a site 
is participating in. Additional site staff can subscribe and unsubscribe to these notifications 
using the CTSU Report and Information Subscription Portal on the CTSU members’ 
website. 
To learn more about DQP use and access, click on the Help Topics button displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 

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Update #04 
6.1.4 
Rave-CTEP-AERS integration 
See Section 9.1.1 for information regarding submission of adverse event information 
utilizing the Rave-CTEP-AERS integration. 
6.2 
Specimen collection and submission  
The Alliance A041701 Correlative Science Manual (CSM) contains instructions for specimen 
collection, processing and shipping. The manual can be found on the BioMS and CTSU 
websites. Questions regarding the CSM should be address to the contacts specified in the 
manual. 
For all patients registered to Alliance A041701: Bone marrow and peripheral blood will be 
collected and banked for molecular genetic analysis described in Section 14.2. 
For patients registered to substudy A041701-LC1 and/or patients who consent to banking: All 
participating institutions must ask patients for their consent to participate in Alliance A041701-
LC1 and the banking of their specimens for future studies, although patient participation is 
optional. Rationale and methods for the scientific components of these studies are described in 
Section 14.0. For patients who consent to participate, bone marrow and blood samples will be 
collected at the following time points for these studies: 
 
 
At Pre-
registration 
End of 
Induction 
End of 
Consolidation 
Relapse 
Storage/ 
Shipping 
conditions 
Submit to: 
 
For all patients registered to A041701, submit the following 
Bone marrow 
aspirate1 
(EDTA/lavender 
top) 
5 mL 
 
 
 
Ambient 
HEME 
Peripheral 
blood 
(EDTA/lavender 
top) 
10 mL 
 
 
 
Ambient 
HEME 
 
For patients registered to A041701-LC1A, submit the following 
Bone marrow 
aspirate 
(heparin/green 
top) 
2 mL 
2 mL 
2 mL 
 
Ambient 
Hematologics 
Peripheral 
blood 
(Na citrate/light 
blue top) 
2.7 mL 
2.7 mL 
 
 
Frozen/dry 
ice 
HEME 

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Update #04 
 
For patients who consent to bankingB, submit the following 
Bone marrow 
aspirate1 
(EDTA/lavender 
top) 
5 mL 
5 mL 
5 mL 
5 mL 
Ambient 
HEME 
Peripheral 
blood 
(EDTA/lavender 
top) 
10 mL 
10 mL 
10 mL 
10 mL 
Ambient 
HEME 
1 
Or submit 30 mL peripheral blood (EDTA/lavender top) if marrow inaspirable or if the patient has had a 
bone marrow aspiration prior to pre-registration and refuses to have another one performed. This 
peripheral blood is in addition to the 10 mL required prior to treatment. 
A 
Collect and submit only from patients who consent to model consent question #2. No additional specimen 
will be required for RNA testing. The sample collected for E-selectin ligand testing will provide 
sufficient material for RNA aliquoting. If marrow inaspirable or if the patient has had a bone marrow 
aspiration prior to pre-registration and refuses to have another one performed, then the submitted 30 mL 
peripheral blood (EDTA/lavender top) used for all patients registered to A041701 will be used.    
B 
Collect and submit only from patients who consent to model consent question #4. 
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 7 days of registration.  
For questions regarding treatment, please see the study contacts page.  
Patients may be removed from protocol treatment at any time post-induction to undergo allogeneic 
hematopoietic cell transplantation. In rare cases where a subject is discovered to have acute 
promyelocytic leukemia with PML-RARA or AML with BCR-ABL only after starting protocol 
treatment, these patients should be removed from protocol therapy in order to receive targeted agents. 
7.1 
Arm 1 Treatment: 7+3 
7.1.1 
Remission Induction 
• Daunorubicin 60 mg m2/day IV Days 1-3 (total dose 180 mg/m2) 
• Cytarabine 100 mg/m2/day CIVI Days 1-7 (168 hour infusion, total dose 700 mg/m2) 
During the Remission Induction, a bone marrow examination (aspirate and biopsy) on Day 
14 (+3 days) is required in all patients. Recommendations regarding the need for second 
induction are provided in the table below. Consult with the study chair if there are questions 
about the need for reinduction,  
Bone Marrow 
Cellularity 
Bone Marrow 
Leukemic Blasts 
Action 
≥ 20% 
≥ 5% 
Second remission induction  
< 5% 
Do not start second remission induction therapy. Repeat 
bone marrow biopsy upon count recovery or by Day 42  
< 20% 
≥ 5% 
Repeat bone marrow biopsy in one week, and follow 
guidelines in table. 

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Update #04 
< 5% 
Do not start second remission induction therapy. Repeat 
bone marrow biopsy upon count recovery or by Day 42  
Patients with residual disease as indicated above on Day 14 or subsequent biopsy following 
the first course of induction chemotherapy are eligible to receive a second remission 
induction course. It is recommended that a second induction course start within 7 days of 
bone marrow documentation of residual disease but may be delayed based on the clinical 
status of the patient. Removal of a patient following a single cycle of induction 
chemotherapy to receive non-protocol therapy is highly discouraged as the results of the 
day 14 bone marrow (i.e. high cellularity, blast percentage) do not predict the outcome of 
second remission induction course.  
7.1.2 
Second Remission Induction (if required) 
• Daunorubicin 60 mg/m2/day IV Days 1-2 (total dose 120 mg/m2) 
• Cytarabine 100 mg/m2/day CIVI Days 1-5 (120 hour infusion, total dose 500 mg/m2) 
7.1.3 
Consolidation (up to 3 cycles) 
Patients who achieve either a CR or CRi are eligible to receive up to 3 cycles of 
Consolidation. Each Consolidation cycle is four weeks (28 days) in duration, and should 
begin within two weeks following hematologic recovery (ANC ≥ 1000/µL +/- platelet 
count ≥ 100,000/µL), but not sooner than four weeks from the beginning of the previous 
cycle.  
• Cytarabine 2000 mg/m2/day by IV infusion over 3 hours on Days 1-5 (total dose 10000 
mg/m2) 
7.2 
Arm 2 Treatment: 7+3 + Uproleselan 
7.2.1 
Remission Induction 
• Uproleselan 800 mg IV, once a day on Day 1, and q12 hours on Days 2-10 (total of 19 
doses) 
• Daunorubicin 60 mg m2/day IV Days 2-4 (total dose 180 mg/m2) 
• Cytarabine 100 mg/m2/day CIVI Days 2-8 (168 hour infusion, total dose 700 mg/m2) 
The first dose of uproleselan will be given 24 hours (+/- 2 hours) prior to the first dose of 
chemotherapy as a single sentinel dose. On days 2-10, uproleselan will be administered 
every 12 hours (+/- 1 hour). On days in which both uproleselan and daunorubicin are 
administered, administer uproleselan approximately 2 hours (+/- 15 minutes) prior to 
daunorubicin. 
During the Remission Induction, a bone marrow examination (aspirate and biopsy) on Day 
14 (+3 days) is required in all patients. Recommendations regarding the need for second 
induction are provided in the table below. Consult with the study chair if there are questions 
about the need for reinduction. 
Bone Marrow 
Cellularity 
Bone Marrow 
Leukemic Blasts 
Action 
≥ 20% 
≥ 5% 
Second remission induction  
< 5% 
Do not start second remission induction therapy. Repeat 
bone marrow biopsy upon count recovery or by Day 42  

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Update #04 
< 20% 
≥ 5% 
Repeat bone marrow biopsy in one week, and follow 
guidelines in table. 
< 5% 
Do not start second remission induction therapy. Repeat 
bone marrow biopsy upon count recovery or by Day 42  
Patients with residual disease as indicated above on Day 14 or subsequent biopsy following 
the first course of induction chemotherapy are eligible to receive a second remission 
induction course. It is recommended that a second induction course start within 7 days of 
bone marrow documentation of residual disease but may be delayed based on the clinical 
status of the patient. Removal of a patient following a single cycle of induction 
chemotherapy to receive non-protocol therapy is highly discouraged as the results of the 
day 14 bone marrow (i.e. high cellularity, blast percentage) do not predict the outcome of 
second remission induction course.  
7.2.2 
Second Remission Induction (if required) 
• Uproleselan 800 mg IV, once on Day 1, and q12 hours on Days 2-8 (total of 15 doses) 
• Daunorubicin 60 mg/m2/day IV Days 2-3 (total dose 120 mg/m2) 
• Cytarabine 100 mg/m2/day CIVI Days 2-6 (120 hour infusion, total dose 500 mg/m2) 
The first dose of uproleselan will be given 24 hours (+/- 2 hours) prior to the first dose of 
chemotherapy as a single sentinel dose. On days 2-8, uproleselan will be administered 
every 12 hours (+/- 1 hour). On days in which both uproleselan and daunorubicin are 
administered, administer uproleselan approximately 2 hours (+/- 15 minutes) prior to 
daunorubicin. 
7.2.3 
Consolidation (up to 3 cycles) 
Patients who achieve either a CR or CRi are eligible to receive up to 3 cycles of 
Consolidation. Each Consolidation cycle is four weeks (28 days) in duration, and should 
begin within two weeks following hematologic recovery (ANC ≥ 1000/µL +/- platelet 
count ≥ 100,000/µL), but not sooner than four weeks from the beginning of the previous 
cycle.  
• Uproleselan 800 mg IV, once on Day 1, and q12 hours on Days 2-8 (total of 15 doses) 
• Cytarabine 2000 mg/m2/day by IV infusion over 3 hours on Days 2-6 (total dose 10000 
mg/m2) 
Uproleselan is to be administered 24 hours (+/- 2 hours) prior to the first dose of cytarabine. 
On days 2-8, uproleselan will be administered every 12 hours (+/- 1 hour). On days in 
which both uproleselan and cytarabine are administered, administer uproleselan 
approximately 2 hours (+/- 15 minutes) prior to cytarabine. 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Ancillary Therapy 
Patients should not receive any other therapy which would be considered treatment for 
their AML while on protocol treatment. Per the FDA approved indication, oral azacitidine 
(Onureg) may be administered at the discretion of the treating physician for the continued 
treatment of patients who achieve CR or CRi and are not able to complete consolidation 
therapy. Patients who receive oral azacitidine in this manner should remain on study and 

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Update #04 
in clinical follow up with the administration of oral azacitidine recorded in the case report 
forms. Additional guidance on the use of oral azacitidine for patients enrolled in this study 
will be provided as an amendment prior to the opening of the phase 3 portion of the study 
after consultation with the company sponsor and the FDA 
8.1.2 
Supportive Care 
Patients should receive full supportive care while on this study according to institutional 
practices including the use of blood products, antibiotics, and antiemetics. 
Tumor lysis prophylaxis including hydration, allopurinol, or rasburicase should be 
administered during induction chemotherapy. 
Steroid eye drops are recommended for patients during consolidation with cytarabine. 
8.1.3 
Myeloid Growth Factors 
The routine administration of Myeloid Growth Factors (e.g. filgrastim (G-CSF), 
pegfilgrastim, or sargramostim (GM-CSF)) is prohibited during remission induction 
chemotherapy. Myeloid Growth Factors are permitted as part of the supportive care during 
consolidation therapy per institutional practice. 
8.2 
Dose Modifications 
8.2.1 
Dose Modifications for Hepatotoxicity 
Daunorubicin doses during both remission induction and second remission induction (if 
required) should be modified as follows: 
Total Bilirubin (mg/dL) 
% Daunorubicin Dose  
≤ 2 
60 mg/m2 (100%) 
> 2 – ≤ 3 
45 mg/m2 (25% dose reduction) 
> 3 
30 mg/m2 (50% dose reduction) 
 
 

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8.2.2 
Dose Modifications for Impaired Renal Function 
Daunorubicin doses during both remission induction and second remission induction (if 
required) should be modified as follows: 
Serum Creatinine (mg/dL) 
% Daunorubicin Dose  
> 3 
30 mg/m2 (50% dose reduction) 
During consolidation, cytarabine should be modified as follows: 
Serum Creatinine(mg/dL) 
Cytarabine Dose  
≤ 2 
2000 mg/m2 (100%) 
> 2 – ≤ 3 
1000 mg/m2 (50% dose reduction) 
> 3 
Do not administer cytarabine 
8.2.3 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing 
is performed according to actual body weight. Therefore, all dosing is to be determined 
solely by actual weight without any modification. Failure to use actual body weight in the 
calculation of drug dosages will be considered a major protocol deviation. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Form, “Adverse Events” 
is used for routine AE reporting in Rave. 
9.1.1 
Rave-CTEP-AERS integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting. Sites must initiate all AEs for this study in 
Medidata Rave.  
Pre-treatment AEs: AEs that occur after informed consent is signed and prior to start of 
treatment are collected in Medidata Rave using the Pre-treatment Adverse Event form.  
Pre-existing medical conditions (formerly referred to as baseline AEs) identified during 
baseline assessment are not considered AEs and therefore should not be reported on the 
Pre-treatment Adverse Event form. If these pre-existing conditions worsen in severity, the 

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Update #04 
investigator must reassess the event to determine if an expedited report is required. 
Whether or not an expedited report is required, the worsened condition should be reported 
in Rave as a routine AE. 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each treatment 
course or reporting period and is used to collect AEs that start during the period or persist 
from the previous reporting period. AEs that occur 30 days after the last administration of 
the investigational study agent/intervention are collected using the Late Adverse Event 
form. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query-free.  
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form (i.e., checking the box 
Send All AEs for Evaluation and save the form). Both NCI and protocol-specific reporting 
rules evaluate the AEs submitted for expedited reporting. A report is initiated in CTEP-
AERS using information entered in Medidata Rave for AEs that meet reporting 
requirements. The CRA completes the report by accessing CTEP-AERS via a direct link 
on the Medidata Rave Expedited Reporting Evaluation form. Contact the CTSU Help Desk 
at 1-888-823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the 
direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
• 
Study specific documents: Protocols > Documents> Protocol Related Documents> 
Adverse Event Reporting; and   
• 
Additional resources: Resources > CTSU Operations Information> User Guides & 
Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
9.1.2 
Solicited Adverse Events: The following adverse events are considered "expected" and 
their presence/absence should be solicited, and severity graded, at baseline and for each 
cycle of treatment by CTCAE, PRO-CTCAE, or both. 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ Class (SOC) 

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Febrile neutropenia 
Blood and lymphatic system disorders 
Nausea 
Gastrointestinal disorders 
Diarrhea 
Gastrointestinal disorders 
Oral mucositis 
Gastrointestinal disorders 
Alanine aminotransferase increased 
Investigations 
Aspartate aminotransferase increased 
Investigations 
Blood bilirubin increased 
Investigations 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) 
Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) 
Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Study Chair, and their 
Institutional Review Board if a patient has a reportable serious adverse event. The descriptions 
and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5 will be utilized for AE reporting. The CTCAE is identified and located on 
the CTEP website at: ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTCAE.  
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note: All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 

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• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
9.3.2 
Expedited AE reporting timelines defined 
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 
calendar days of the initial 24-hour report. 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
Alliance A041701 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (any arm) in 
this trial. 
Grade ≤4 cytopenias (anemia, decreased white blood cell, lymphocyte, neutrophil, or 
platelet counts) and hospitalization resulting from such do not require CTEP-AERS, but 
should be submitted as part of study results. All other grade 3, 4, or 5 adverse events that 
precipitate hospitalization or prolong an existing hospitalization must be reported via 
CTEP-AERS. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions. 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, and in situ tumors.  

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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:  
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
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 unless otherwise specified. Whenever possible, the CTEP-AERS reports for new 
malignancies should include tumor pathology, history or prior tumors, prior 
treatment/current treatment including duration, any associated risk factors or evidence 
regarding how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor, and new malignancy treatment and outcome, if 
available. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
CTEP-AERS reports should be submitted electronically. 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and submitted, along with any 
additional medical information (form is available on the CTEP website at 
http://ctep.cancer.gov/). The potential risk of exposure of the fetus to the investigational 
agent(s) or chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
9.4 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Uproleselan 
(GMI-1271, NSC 801708) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that 
are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification.  Frequency is provided based on 184 patients. Below is the CAEPR for 
GMI-1271. 

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RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Dyspnea; Hypoxia; Nasal congestion; Pulmonary edema 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Rash maculo-papular 
 
Note: Uproleselan (GMI-1271) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
10.0 DRUG INFORMATION 
10.1 
General Considerations: 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% 
of the actual calculated dose. 
It is not necessary to change the doses of chemotherapy due to changes in weight unless the 
calculated dose changes by ≥10%. 
All study agents are to be administered at the registering institution.  
10.2 
Uproleselan (GMI-1271) (NSC #801708) (IND #
 IND holder: DCTD) 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP-supplied investigational agents for the 
study should be ordered under the name of one lead participating investigator at that 
institution. 
Sites may request a maximum of 10 vials when a patient is being screened. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, a “current” password, and 
active person registration status.  For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time.  Refer to the PMB’s website for specific policies 
and guidelines related to agent management.   
Agent Inventory Records  
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from the 
PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, formulation and ordering investigator 
on this protocol. 
Investigator Brochure Availability 
The current version of the Uproleselan IB will be accessible to site investigators and research 
staff through the PMB OAOP application. Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, and a “current” 

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password and active person registration status.  Questions about IB access may be directed 
to the PMB IB Coordinator via email. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP  
• 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account: 
https://ctepcore.nci.nih.gov/iam/   
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov   
• 
IB Coordinator:  IBCoordinator@mail.nih.gov   
• 
PMB email:  PMBAfterHours@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
Characteristics 
Chemical 
Name: 
Sodium 
(1R,3R,4R,5S)-3-({2-N-acetylamino-2-deoxy-3-O-[(1S)-1-
carboxylato-2-cyclohexylethyl]-β-D-galactopyranosyl}oxy)-4-({6-deoxy-α-L-
alactopyranosyl}oxy)-5-ethyl-cyclohexan-1-yl-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-
dodecaoxa-39-azahentetracontan-41-yl) carboxamide 
Other Names: GMI-1271 
Chemical Formula: C60H108N3NaO27  
Molecular Weight: 1326.5 
Classification: Uproleselan is a specific E-selectin antagonist 
Mode of Action: The proposed mechanism of action is by competitive inhibition of E-
selectin, thereby interrupting E-selectin-mediated interactions. Pre-clinical data collectively 
suggest that Uproleselan-mediated disruption of E-selectin interactions between the 
endothelium and various tumor cells, such as those in leukemia and myeloma, confers 
increased sensitivity to cytotoxic agents by preventing these cancerous cells from remaining 
in the bone marrow niche and attenuating stroma-induced resistance to chemotherapy. 
Description: White to off white solid 
Formulation 
Uproleselan is supplied by GlycoMimetics, Inc. and distributed by PMB, CTEP, DCTD, 
NCI. Uproleselan Injection is a sterile, isotonic solution for IV administration, supplied in 
single-use vials at a concentration of 50 mg/mL.  Each 16 mL, single dose vial contains 800 
mg of Uproleselan. The solution contains sodium chloride, water, and TRIS buffer to 
stabilize the pH at 7.4 (6.4 to 8.4). 
Storage and Stability 
Uproleselan Injection 50 mg/mL is stored refrigerated (2°C to 8°C), prior to administration.  

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If a storage temperature excursion is identified, promptly return uproleselan to 2°C to 8°C 
and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability studies are ongoing. 
Preparation 
Uproleselan solution should be clear, colorless to slightly yellow, and free from visible 
particulates. Uproleselan can be administered undiluted or diluted. If dilution is preferred, 
use only normal saline and dilute to a concentration of not less than 5 mg/mL.  
Uproleselan may be prepared prior to administration and stored in syringes or IV bags for 24 
hours at room temperature or 72 hours at refrigerated conditions, except when using 
administration sets composed of PVC with DEHP where the storage time is limited to 2 hours 
(see Administration section below). While it is highly recommended that uproleselan prepared 
prior to administration be refrigerated until one hour prior to dosing, solutions kept at room 
temperature can be administered within 24 hours of preparation 
Administration 
Uproleselan Injection should be administered through a peripheral line, a central catheter, or 
a peripherally inserted central line catheter (PICC). Infusion should take place at a steady 
rate over a period of 20 minutes using a syringe pump or IV pump. Microbore tubing is 
preferred. In-line filtration with a 0.2-micron filter is highly recommended.  
The storage time for an IV line primed with uproleselan solution is dependent on the tubing 
composition. Tubing composed of PVC with DEHP has a maximum storage time of 2 hours 
prior to administration. The storage time for administration sets composed of PVC without 
DEHP is 24 hours at room temperature or 72 hours at refrigerated conditions, including 
administration.  
Uproleselan is compatible with IV bags composed of PVC (with or without DEHP), 
polyolefin, or ethylene vinyl acetate, glass bottles, and syringes. IV administration sets 
composed of PVC without DEHP or lined with polyethylene are compatible with 
uproleselan. IV admin sets composed of PVC with DEHP should not exceed 2 hours of 
contact with uproleselan. 
Compatibility with other therapeutic agents has not been determined, therefore uproleselan 
should not be administered concurrently with anything other than saline. If a flush is used, 
saline flush is preferred. 
Pharmacokinetics 
PK evaluations in healthy volunteers showed a dose-linear relationship in mean PK 
parameters after IV infusion of 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg 
uproleselan. Uproleselan is characterized by a half-life of 1.4-2.5 hours and does not 
accumulate after doses up to 20 mg/kg BID. Population PK analysis in healthy volunteers 
and patients with AML demonstrate similar PK profiles, PK parameters, and dose-
proportionality. Clearance was found to depend on renal function and have a similar 
magnitude in both healthy volunteers and in patients with AML. The PK of uproleselan does 
not appear to be affected when co-administered with chemotherapy. 
Adverse Events 
Uproleselan continues to be evaluated in clinical trials. In AML and MM trials, the AE profile 
at the doses and regimens tested to date does not indicate concerns about safety or tolerability 

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of uproleselan when administered alone or with MEC, cytarabine/idarubicin (7+3 or 5+2), or 
cytarabine alone in patients undergoing induction or consolidation chemotherapy for AML, 
or bortezomib-based chemotherapy for MM. No anticipated toxicities, or target organ for 
toxicity, have been identified thus far in nonclinical studies or in clinical trials. 
Potential Drug Interactions 
Uproleselan is not expected to undergo extensive hepatic metabolism in humans. Uproleselan 
does not cause direct or time-dependent inhibition of CYP1A, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 or CYP3A4.  Uproleselan also showed no evidence of induction of 
CYP1A2, CYP2B6 or CYP3A4. Active transporter substrate analysis revealed that 
uproleselan is a substrate for the efflux transporters P-gp and MRP2, may be a weak substrate 
for BCRP, and is not a substrate of the efflux transporter BSEP. In addition, uproleselan is 
not a substrate for the following uptake transporters: OATP1B1, OATP1B3, OAT1, OAT3, 
OCT1, OCT2, MATE1 and MATE2-K. Uproleselan is not an inhibitor of the efflux 
transporters P-gp, BCRP, or BSEP, and is not an inhibitor of the following substrate 
transporters: OATP1B1, OATP1B3, OAT1, OAT3, OCT2 and OCT1. 
Patient Care Implications 
Women of childbearing potential and men must use highly effective methods of 
contraception during the study and for 3 months after the last dose of study drug.  Do not 
administer uproleselan to pregnant or lactating women. 
See CAEPR in 9.4. 
10.3 
Daunorubicin (Cerubidine®, Daunomycin, DNM) (NSC #82151) 
Procurement  
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection as:  
Injection, powder for reconstitution: 20 mg 
Injection, solution: 5 mg/mL (4 mL, 10 mL) 
Preparation, Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store intact 
vials of powder for injection at room temperature of 15°C to 30°C (59°F to 86°F); intact vials 
of solution for injection should be refrigerated at 2°C to 8°C (36°F to 46°F). Protect from 
light. Dilute vials of powder for injection with 4 mL SWFI for a final concentration of 5 
mg/mL.  May further dilute in 100 mL D5W or NS. Reconstituted solution is stable for 4 days 
at 15°C to 25°C. Further dilution in D5W, LR, or NS is stable at room temperature (25°C) 
for up to 4 weeks protected from light. 
Administration 
Daunorubicin is not for I.M. or SubQ administration. Administer as a slow I.V. push over 1-
5 minutes into the tubing of a rapidly infusion I.V. solution of D5W or NS or dilute in 100 
mL of D5W or NS and infuse over 15-30 minutes.  Daunorubicin is a potent vesicant; it is 
best to administer IV infusion doses through a central venous access device. 

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Drug Interactions 
Avoid Concomitant Use of Daunorubicin with any of the following: BCG; Natalizumab; 
Pimecrolimus; Tacrolimus (Topical); Vaccines (Live). 
Increased Effect: Daunorubicin may increase the levels/effects of: Leflunomide; 
Natalizumab; Vaccines (Live).  
The levels/effects of Daunorubicin may be increased by: Bevacizumab; Denosumab; P-
Glycoprotein inhibitors; Pimecrolimus; Tacrolimus (Topical); Taxane Derivatives; 
Trastuzumab 
Decreased Effect: Daunorubicin may decrease the levels/effects of: BCG; Cardiac 
Glycosides; Sipuleucel-T; Vaccines (Inactivated); Vaccines (Live) 
The levels/effects of Daunorubicin may be decreased by: Cardiac Glycosides; Echinacea; P-
Glycoprotein Inducers 
Ethanol/Herb/Nutraceutical Interactions: Avoid ethanol (Due to GI irritation). 
Pharmacokinetics 
Distribution: Vd: 40 L/kg; to many body tissues, particularly liver, spleen, kidney, lung, 
heart; does not distribute into the CNS; crosses placenta 
Protein binding, plasma: 70% to 76% 
Metabolism: Primarily hepatic to Daunorubicinol (active), then to inactive aglycones, 
conjugated sulfates, and glucuronides 
Half-life elimination:  
Distribution: 2 minutes 
Elimination: 14-20 hours 
Terminal: 18.5 hours 
Daunorubicinol plasma half-life: 24-48 hours 
Excretion: Feces (~40%); urine (~25% as unchanged drug and metabolites) 
Nursing Guidelines 
• Drug is a potent vesicant. Establish patency of IV before and frequently during administration 
as to avoid extravasation. If drug is being administered IV push administer through side port 
of rapidly running IV solution. If suitable vein cannot be used, central venous access may 
become necessary. Discuss with treating MD. If extravasation occurs treat per your 
institution’s policy. 
• Drug is not compatible with heparin. Be sure to flush heparin locked IV’s or central lines 
before administering agent. 
• Moderate to severe nausea occurs in up to 50% of patient within first 24 hours. Administer 
antiemetics as ordered and assess for their effectiveness. 
• Inform patient about alopecia 
• Potent myelosuppressive agent. Monitor CBC closely. Inform patient to report any signs or 
symptoms of infection, or unusual bruising or bleeding. 
• Drug is cardiotoxic. Maximum lifetime dose limit is 550 mg/m2. Monitor for signs of acute 
cardiac toxicity, which is possible within hours after administration. This is unrelated to 
cumulative dose and may manifest symptoms of pump or conduction dysfunction. Watch for 
signs or symptoms of CHF, pericardial effusion, and transient ECG abnormalities. 
• Monitor liver function tests. Dose reduction is necessary in patients with impaired liver 
function. 
• Radiation recall is a possibility with this drug. Monitor patient’s skin at site of previous 
irradiation for damage. 
• Inform patient that urine may be pink or red for up to 48 hours after administration. 
Adverse Events 

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The most common adverse reactions associated with daunorubicin include hematologic, 
gastrointestinal, and cardiovascular. Leukopenia and thrombocytopenia are often dose-
limiting. Daunorubicin causes nausea and vomiting, but is generally considered moderately 
emetogenic. Stomatitis is also common. Acute cardiovascular reactions include EKG 
abnormalities which are usually asymptomatic and self-limiting. Chronic cardiomyopathy 
manifests as congestive heart failure. Risk factors include age (> 70 years), mediastinal 
irradiation and cumulative lifetime dose (e.g., > 450 mg/m2). Dermatologic reactions 
(alopecia, “radiation recall”) are also common. Less common are red/orange urine (more 
alarming than of notable consequence to patients) and skin “flare.” The flare consists of 
redness and itching along the distribution of the vessel through which daunorubicin was 
administered. It is usually self-limiting and of short duration, but should be distinguished 
from an extravasation reaction. Extravasation of daunorubicin does not occur very often, but 
can result in severe skin and tissue necrosis. Cold should be applied to the site of a suspected 
or actual extravasation of daunorubicin. 
Please refer to the package insert for the comprehensive list of adverse events. 
10.4 
Cytarabine Intravenous (Cytosar, Ara-C) (NSC #63878) 
Procurement 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection, powder for reconstitution: 100 mg, 500 mg, 1 gram, 2 
gram. Commercially available solution for injection in concentrations of 20 mg/mL and 100 
mg/mL. Commercially available preparations may be preservative-free or preservative-
containing. 
Preparation, Storage and Stability 
Store intact vials of powder at room temperature 15ºC to 30ºC (59ºF to 86ºF). Reconstitute 
with bacteriostatic water for injection. Reconstituted solutions are stable for up to 8 days at 
room temperature, although the manufacturer recommends use within 48 hours. Further 
dilution in 250-1000 mL of D5W or 0.9% NaCL is stable for 8 days at room temperature 
(25°C). Note: Solutions containing bacteriostatic agents should not be used for the 
preparation of either high doses or intrathecal doses of cytarabine. 
Administration 
Refer to the drug treatment section of the protocol for specific administration directions and 
infusion rates. May be given IV or subcutaneously. 
Drug Interactions 
Cytochrome P450 Effect: None known  
Increased Effect/Toxicity: Cytarabine may increase the levels/effects of: Clozapine, 
Leflunomide, Natalizumab, Vaccines (Live).   The levels of Cytarabine may be increased by:  
Denosumab, Pimecrolimus, Roflumilast, Tacrolimus (Topical); Trastuzumab 
Decreased Effect: Cytarabine may decrease the levels/effects of:  BCG, Cardiac Glycosides, 
Coccidiodin Skin Test, Flucytosine, Sipuleucel-T, Vaccines (inactivated); Vaccines (live).   
Herb/Nutraceutical Interactions: Avoid Echinacea.  
Pharmacokinetics 
Distribution: Vd: Total body water; widely and rapidly since it enters the cells readily; high-
dose cytarabine crosses the blood-brain barrier with CSF levels of 40% to 50% of plasma 
level 

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Update #04 
Metabolism: Primarily hepatic; metabolized by deoxycytidine kinase and other nucleotide 
kinases to aracytidine triphosphate (active); about 86% to 96% of dose is metabolized to 
inactive uracil arabinoside. 
Half-life elimination: I.V.: Initial: 7-20 minutes; Terminal: 1-3 hours. 
Excretion: Urine (~80%) within 24 hours 
Nursing Guidelines 
• Can be a potent myelosuppressive agent. Monitor CBC closely. Anemia, leukopenia, and 
thrombocytopenia are expected. Nadir within 5-7 days with recovery expected in 2-3 weeks. 
Hematological toxicity is more intense if ARA-C is given as a continuous IV infusion versus 
an IV bolus. 
• Nausea and vomiting is dose-related, common, and often preventable with antiemetic drugs. 
Administer as ordered and assess for their effectiveness. 
• Instruct patient of possibility of metallic taste.  The use of sugarless hard candies may lessen 
this effect. 
• Stomatitis is possible. 
• May cause pancreatitis or peritonitis. Instruct patient to report any severe or worsening 
abdominal pain immediately. 
• Monitor LFT’s-elevations of LFT’s may occur. 
• Cerebellar toxicity can occur in 16-40% of patients with more severe symptoms at higher 
doses. Monitor for these toxicities with each dose of ARA-C. Signs and symptoms of 
cerebellar toxicity can include: lethargy with progressive confusion, ataxia, nystagmus, 
slurred speech. Report any of these or other neurological changes to the MD immediately. 
• Instruct patient to report any shortness of breath or difficulty breathing as this may be a sign 
of a rare but life threatening pulmonary complication. 
• Monitor for signs of conjunctivitis and/or keratitis. This is usually prevented with 
prophylactic glucocorticoid eye drops. 
• Assess for skin rash. This may present itself as an erythema without exfoliation, or a 
generalized rash. Report to MD.  
• Monitor for “ARA-C” syndrome. This is characterized by bone and muscle pain, chest pain, 
fever, general weakness, reddened eyes, and skin rash. Report these to the MD, as patient 
may need to be treated with corticosteroids. 
Adverse Events 
The most common adverse reactions reported with cytarabine (“usual dosage” e.g., ≤ 200 
mg/m2/day) 
include 
hematologic, 
gastrointestinal, 
dermatologic, 
and 
hepatic. 
Myelosuppression includes neutropenia, thrombocytopenia and anemia. Cytarabine is 
considered highly emetogenic. In addition to nausea and vomiting, diarrhea and mucositis are 
reported in > 10% of patients receiving cytarabine. Alopecia is common. Rash, including 
hand-foot syndrome, is reported also. Mild jaundice, and elevated transaminase levels also 
are reported in > 10% of patients. Fever (non-infectious) is also reported among the most 
common adverse reactions associated with cytarabine. Less commonly, a “cytarabine 
syndrome” or “ara-C syndrome” has been reported. The syndrome may be characterized by 
fever, myalgia, bone pain, rash, malaise, and chest pain. 
In addition to the above, the following adverse reactions have been described with high dose 
(≥ 1 gm/m2/day) cytarabine. Neurologic toxicity is primarily cerebellar (nystagmus, 
dysarthria, dysdiadochokinesia, ataxia, abnormal gait) but cerebral toxicity (somnolence, 
confusion, psychosis, seizures) may also be seen. Ocular toxicity including photophobia and 
conjunctivitis are described with high dose cytarabine. Steroid ophthalmic solution should be 
administered, beginning 6-12 hours before cytarabine and continuing for 24 hours after the 

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last “high dose”, to prevent conjunctivitis. Pulmonary edema has been rarely reported in 
association with high dose cytarabine. 
Please refer to the package insert for the comprehensive list of adverse events. 
11.0 MEASUREMENT OF EFFECT 
Response to treatment will be assessed according to the 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 [24]. 
11.1 
Morphologic complete remission (CR) 
Defined as morphologic leukemia-free state, including < 5% blasts in BM aspirate, no blasts 
with Auer rods, no persistent extramedullary disease, ANC ≥ 1,000/µl and platelet count ≥ 
100,000/µl. The patient must be free of the need for RBC transfusions. 
11.2 
Cytogenetic complete remission (CCyR) 
Only patients with an identified cytogenetic abnormality pretreatment may receive this 
designation. Defined as a morphologic complete remission plus reversion to a normal karyotype 
(no clonal abnormalities detected in a minimum of 20 metaphase cells). 
11.3 
Morphologic complete remission with incomplete blood count recovery (CRi) 
Defined as CR with the exception of neutropenia <1,000/µl or thrombocytopenia <100,000/µl.  
11.4 
Treatment failure (TF) 
Treatment failure includes those patients for whom treatment has failed to achieve a CR or CRi 
and will be classified as follows: 
• 
Treatment failure due to resistant disease includes patients who survive at least 7 days after 
completion of the final dose of the initial course of treatment but whose last posttreatment 
peripheral blood smear and/or bone marrow sample showed persistent AML. 
• 
Treatment failure due to complications from aplasia includes patients who survive at least 
7 days after the final dose of the initial course of treatment and die while cytopenic, but 
whose last posttreatment bone marrow was aplastic or hypoplastic, as determined by the 
institutional morphologist or pathologist, without evidence of leukemia, provided that 
marrow was obtained within 7 days of death.  
• 
Treatment failure of indeterminate cause includes three categories of patients:  
- 
Patients who die less than 7 days after conclusion of the initial course of treatment, 
and  
- 
Patients who die 7 or more days after the conclusion of treatment whose most recent 
peripheral blood smear did not show persistent leukemia and who did not have a 
bone marrow examination subsequent to therapy 
- 
Patients who die without completing the first course of therapy.  
11.5 
Recurrence/morphologic relapse 
Defined as reappearance of blasts in the blood or the finding of ≥ 5% blasts in the BM, not 
attributable to any other cause. 

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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Patients will continue with the therapy specified in this protocol until one of the following 
occurs: 
• 
Completion of all protocol-specific treatments. 
• 
Unacceptable toxicity. 
• 
Treatment failure due to resistant disease or death. 
• 
Recurrence / morphologic relapse. 
• 
Withdrawal of consent by the patient to continue on study. 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Completion of all protocol-specified therapy 
• 
Recurrence/morphologic relapse 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Termination of the study by sponsor 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 
Follow-up  
12.3.1 Duration of Follow-up  
Patients who complete protocol therapy will go to clinical follow-up, followed every 2 
months until 1 year after completion of therapy, every 3 months between 1 and 2 years 
after completion of therapy, then every 6 months for up to 5 years from study registration 
or until relapse.  
12.3.2 Follow-up for Patients who Stop Study Treatment/Intervention Early  
Patients who end treatment for reasons other than relapse and subsequent treatment other 
than oral azacitidine per Section 8.1.1 will go to clinical follow-up, followed every 2 
months until 1 year from the date of discontinuation, then every 3 months until 2 years 
from the date of discontinuation, then every 6 months for up to 5 years from registration or 
until relapse.  
Patients who relapse or receive a subsequent treatment other than transplantation or 
azacitidine per Section 8.1.1 will go to survival follow-up, followed every 6 months from 
the date of discontinuation for 5 years from registration.  

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Patients who receive transplantation will be removed from this protocol and go to clinical 
follow-up, followed every 3 months for 2 years and then every 6 months up to 5 years from 
registration.  
Patients who withdraw prior to starting any protocol treatment will go to survival follow-
up, followed every 6 months for up to 5 years in observation from registration. 
12.2.3 Follow-up for Specimen Submission 
Specimen submission must continue during all treatment stages, observation and clinical 
follow-up. Specimen submission are not required if patient is in survival follow-up.   
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below.  
Baseline, off treatment, and post-treatment follow up (i.e., relapse, progression, and survival) 
data submission required. See the Data Submission Schedule accompanying the All Forms 
Packet. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This is an open-label, randomized phase II/III study. 

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The primary objective of the Phase II study is to determine based on the event-free survival 
(EFS) whether the combination of uproleselan plus daunorubicin/cytarabine should be tested 
further against standard of care: daunorubicin/cytarabine in the phase III component of this trial.  
The primary objective of the Phase III study is to compare the OS between uproleselan plus 
daunorubicin/cytarabine versus the control arm (daunorubicin/cytarabine). Patients accrued 
during the Phase II portion of the trial will be used in the Phase III analysis.  
Randomization: Randomization will be stratified on the following stratification factors: age (60-
69 vs. 70 and older), performance status (0-1 vs. 2-4), de novo vs. secondary/therapy related 
AML. Patients will be randomized to receive one of the two treatment regimens with equal 
allocation using a permutated block method to balance the stratification factors. 
13.1.1 Primary Endpoint 
• 
Phase II component: Event-free survival (EFS). EFS is defined as the time from 
the date of randomization to the first of failure to achieve a CR/CRi during 
induction, relapse, or death due to any cause, with patients last known to be alive 
and event-free censored at the date of last contact. Patients who are removed from 
protocol treatment for allogeneic HCT or azacitidine per Section 8.1.1 will not be 
censored for EFS, and will be continued to be followed for relapse or death. 
Patients who receive other non-protocol therapy without relapse or CR/CRi during 
induction will be censored at the time they discontinue the treatment. All 
randomized patients meeting the eligibility criteria will be evaluable for the 
primary endpoint (EFS) analysis based on an intention to treat. 
• 
Phase III component: Overall survival (OS) – measured from the date of 
randomization to death from any cause, with patients last known to be alive censored 
at the date of last contact. All randomized patients will be evaluable for this endpoint. 
As of Amendment 04, there will be no additional accrual to the Phase III component 
of the trial regardless of the outcome of the Phase II analysis. 
13.1.2 Sample Size and Power Justification 
Phase II component 
Patients will be randomized to receive daunorubicin and cytarabine or the novel regimen 
with equal allocation using a permutated block method. E2906 study6 reported a 1-year 
EFS of 29%. Therefore, we estimate that the 1-year EFS in the daunorubicin and cytarabine 
arm will be 30%. We are interested in testing the alternative hypothesis that the 1-year EFS 
in the novel experimental arm will be at least 47% (a 17% improvement in the 1-year EFS). 
This translates to an improvement in the median EFS from 7 to 11 months (HR = 0.64), 
assuming exponential distributions of EFS in both control and experimental arm. A sample 
size of 131 evaluable patients per arm (262 total) provides 96% power to detect an 
improvement in median EFS from 7 months to 11 months (a hazard ratio of 0.64), using a 
one-sided log-rank test at a significance level of 10%. 
Phase III component 
A median OS of 12 months is anticipated on the control arm.6 We are interested in testing 
the alternative hypothesis that the median OS in the novel experimental arm will be at least 
16 months (a 33% improvement in the median OS, for a HR of 0.75). This translates into 
an improvement in the 1-year OS from 50% to 60%, assuming exponential survival. A 
randomized trial comparing the novel agents passing the Phase II component against the 
standard arm (daunorubicin and cytarabine) will be conducted using a 1:1 randomization 

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scheme. A sample size of 335 evaluable patients per arm (670 total) provides 90% power 
to detect an improvement in median OS from 12 months to 16 months (a hazard ratio of 
0.75), using a one-sided log-rank test at a significance level of 2.5%. The overall power for 
the phase II/III design is 86% (=0.96*0.9). The total sample size for the Phase III 
component will include the patients rolled over from the Phase II component. 
As of Amendment 04, there will be no additional accrual to the Phase III component of the 
trial regardless of the outcome of the Phase II analysis. 
13.2 
Analysis Plan 
13.2.1 Primary Endpoint 
The analysis for both phase II and III component would be intention-to-treat (ITT), which 
means that all patients who signed a consent form and are randomized are included in the 
analysis and will be analyzed in the arms to which they are randomized. 
Phase II component 
Final analysis: The Phase II decision-making will be conducted when at least 191 events 
are observed (approximately expected 37 months after the first patient enrolled). If less 
than 191 events are observed 2 years after Phase II accrual ends, then the Phase II decision 
will occur at the target data lock. 
At the final analysis of the Phase II, it will be concluded that the experimental arm regimen 
is promising, if we a one-sided p-value < 0.10 from the log-rank test favoring the 
experimental arm. 
As of Amendment 04, there will be no additional accrual to the Phase III component of the 
trial regardless of the outcome of the Phase II analysis. Given the maturity of follow-up on 
the current patients and no additional accrual to the trial, the final Phase III OS analysis 
will also be performed at the time of final Phase II EFS analysis. All Phase III alpha (one-
sided 2.5%) will be spent at this analysis. The target data lock date is August 12, 2024. 
Interim analysis: We will conduct a futility interim analysis which will take place after 
50% of the total events have occurred (approximately 25 months after the first patient 
enrolled). If at the planned interim analysis the hazard ratio is >1.0 in favor of the control 
arm, the recommendation will be to stop further accrual to the experimental arm and 
conclude that the novel regimen does not have improved EFS. 
We will suspend accrual between phase II and III. In order to protect the phase III 
comparison, the results of the phase II portion will only be released to the FDA and/or 
industry sponsors for regulatory purposes, contingent upon the approval and 
recommendation from the Alliance Data Monitoring Committee. Other than that, the 
Alliance DMC will only release whether the criteria for continuation to Phase III have been 
satisfied and not any of the actual results. 
Phase III component  
The final analysis will be conducted after 521 deaths have been observed. In addition, we 
will conduct 2 interim analyses which will take place after approximately 50% and 75% of 
the total events have occurred. The first interim analysis is for futility only, and the second 
interim for both futility and efficacy. If in the second interim evaluation, sufficient evidence 
(per criteria outlined below) is observed that the experimental arm is superior to the control 
arm in terms of OS, then accrual to the control arm may be suspended and terminated. To 
preserve the Type I error rate control on superiority, the Lan-DeMets error spending 
function with the O’Brien-Fleming stopping boundaries is utilized. Futility boundaries 

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have also been developed for the comparison against control, where if at any of the planned 
interim analyses the hazard ratio is >1 in favor of the control arm, the recommendation will 
be to stop further accrual to the experimental arm (if the trial is still accruing) and conclude 
that the novel regimen does not have improved OS. At the final analysis, if we observe a 
p-value <= 0.022 from the log-rank test (equivalently, HR <= 0.838 favoring the 
experimental regimen, assuming the exponential distribution) we will conclude that the 
novel regimen significantly improves the OS, compared to the daunorubicin and cytarabine 
arm. The interim and final analysis boundaries and characteristics were generated using the 
East clinical trial software program (version 6.3, Cytel Inc).  
Information 
Fraction 
Cum. 
events 
Cum. 
alpha 
spent 
Cum. 
beta 
spent 
Efficacy Boundaries 
Futility 
Boundaries 
HR 
P-
value 
Z score HR 
p-value 
50% 
261 
0 
0.01 
NA 
NA 
NA 
1 
0.5 
75% 
391 
0.010 
0.011 
0.789 
0.010 
-2.339 
1 
0.5 
100% 
521 
0.025 
0.1 
0.838 
0.022 
-2.012 
0.838 
0.022 
As of Amendment 04, there will be no additional accrual to the Phase III component of the 
trial regardless of the outcome of the Phase II analysis. Given the maturity of follow-up on 
the current patients and no additional accrual to the trial, the final Phase III OS analysis 
will also be performed at the time of final Phase II EFS analysis. The final Phase III of 
analysis of OS will conclude that the novel regimen significantly improves the OS 
compared to the daunorubicin and cytarabine arm if the one-sided p-value from the 
stratified log-rank test is < 0.025. The target data lock date is August 12, 2024. 
13.2.2 Secondary Endpoints 
• 
1-year EFS rate: The 1-year EFS rate is the proportion of efficacy evaluable patients 
event-free 1 year from registration. Patients who fail to achieve a CR/CRi during the 
induction, relapse, or die prior to 1 year after randomization/registration will be 
considered as a failure for this endpoint. Patients who are removed from protocol 
treatment for allogeneic HCT will continue to be followed for relapse or death at 1 
year. Patients who are removed from study for other non-protocol therapy without 
relapse or CR/CRi during induction are also considered as a failure for the 1-year EFS 
endpoint.  
• 
Disease-free survival (DFS): DFS will be calculated as the time from achieving a 
CR/CRi to the time of relapse and/or death. Any patients who have not achieved the 
event of interest will be censored at the time of their last evaluation. 
• 
Complete Remission (CR) and overall response rates: Response to treatment will 
be assessed according to the 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.  
• 
Toxicity and tolerability: As per NCI CTCAE v5.0, the term toxicity is defined as 
adverse events that are classified as either possibly, probably, or definitely related to 
the study treatment. The maximum grade for each type of toxicity will be recorded for 
each patient, and frequency tables will be reviewed to determine toxicity patterns. In 
addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified 
as either “unrelated” or “unlikely to be related” to study treatment in the event of an 

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actual relationship developing. The incidence of severe (grade 3+) adverse events or 
toxicities will be described for each treatment arm, but will also be compared between 
the arms. Fisher’s exact tests will be used to quantitatively compare the incidence of 
severe as well as specific toxicities of interest between the treatment arms and we will 
graphically assess differences in maximum grades observed for toxicities between the 
arms.  Toxicity and tolerability will be monitored regularly. The study will be 
reviewable by the Alliance DSMB every 6 months to identify any toxicity or 
tolerability issues in either of the treatment arms.  
• 
Association of clinical outcomes with pretreatment disease and patient characteristics. 
We will examine whether CR, EFS, DFS, and OS are predicted by pretreatment 
characteristics such as age, morphology, cytogenetics, immunophenotype, molecular 
genetic features, WBC count and hemogram, and performance status with clinical 
outcomes. The associations between these baseline factors and CR, EFS, DFS, and OS 
will be analyzed using Kaplan-Meier curves, log-rank test, contigency table and chi-
square test whenever appropriate. Multivariable analysis including Cox proportional 
hazards models and logistic regression models will be used as well to evaluate the 
associations.  
13.2.3 Primary Analysis of the Key Secondary Endpoint of EFS 
In the event that the primary endpoint OS for phase III is significant as determined by the 
primary analysis, then the key secondary endpoint of EFS will be formally tested 
hierarchically in a confirmatory setting at an overall one sided alpha of 0.025 level at the 
same time as the primary endpoint. Both hazard ratio and p-value for EFS will be presented. 
13.2.4 Sensitivity Analysis 
To evaluate the impact of off-protocol transplantation, sensitivity analyses will be 
conducted. Approaches will include but not limited to: 1) considering transplantation as a 
competing risk, 2) censoring patients who go off study for transplant without relapse at the 
time they discontinue the treatment, 3) multi-state model. In addition, the proportion of 
patients who received transplantation in the two arms will be summarized and compared 
using a chi-square test. We acknowledge that censoring patients at the time of HCT may 
potentially lead to informative censoring and biased efficacy results. Similar sensitivity 
analyses will be conducted for patients who take other off-protocol treatment due to MRD. 
13.2.5 Subgroup Analyses 
Subgroup analyses by potential prognostic factors at baseline will be conducted, to evaluate 
the consistency of the treatment effect among each subgroup. Non-parametric methods 
such as Kaplan-Meier and log-rank tests will be used within each subgroup. 
Univariate/multivariate Cox models will be fit within each subgroups; hazard ratios will 
be used to quantify the treatment effect within each subgroup, along with the 95% 
confidence intervals. 
13.3 
Accrual Time and Study Duration 
The anticipated accrual rate is approximately 5 pts/month in the first year, 10 pts/month second 
year, and 14 patients per month afterwards. The phase II component is expected to accrue in 30 
months after trial activation. Accrual will be suspended between the phase II and phase III 
component for primary endpoint analysis from phase II; the suspension between the Phase II 
and Phase III is expected to be 12 months to allow for follow-up on the last phase II patients 
and completion of the primary analysis for phase II. The phase III component is expected to 
accrue in approximately 59 months. Including the suspension between Phase II and III, the total 

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study duration is expected to be approximately 83 months, or until the last Phase III patient 
accrued has been observed for at least 12 months. 
As of Amendment 04, there will be no additional accrual to the Phase III component of the trial 
regardless of the outcome of the Phase II analysis. 
13.4 
Adverse Event Stopping Rule 
Early stopping rule will be based on 30-day mortality rate. If 3 or more of the first 20 Phase II 
patients enrolled or 15% or more of the Phase II patients enrolled thereafter die within 30 days 
after start of treatment, enrollment to the study will be suspended. The study team will review 
all adverse event data in light of the early deaths. A trial recommendation will be formulated 
and presented to the Alliance DSMB – the study may permanently close or may re-open to 
accrual after any needed modifications to the dose, the design etc., and after discussion with 
CTEP.  
13.5 
Study Monitoring 
As a randomized phase II/III trial this study will be monitored by the Alliance Data and Safety 
Monitoring Board (DSMB) twice per year. The DSMB follows the Alliance Policies and 
Procedures for all randomized phase II trials. The DSMB will review accrual, toxicity, and 
interim analyses results. All summary findings of the DSMB will be communicated to study 
investigators by the Alliance. In addition the Alliance Statistical Data Center will submit 
quarterly reports to CTEP by electronic means using the Clinical Data Update System.  
All EFS and OS outcome data will be requested for release after DSMB review at the time of 
the final Phase II EFS analysis, with patient follow-up continuing per protocol. 
13.6 
Clinical Data Update System (CDUS) Reporting 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 31, and 
October 31. Instructions for submitting data using the CDUS can be found on the CTEP Web 
site (http://ctep.cancer.gov/reporting/cdus.html). 
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS, but expedited adverse events are still required to be submitted 
via CTEP-AERS. 
 

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14.1 
Cytogenetic Correlative Science (Alliance A041701) 
14.1.1 Background 
Cytogenetic analyses in acute myeloid leukemia (AML) and acute lymphoblastic leukemia 
(ALL) have revealed a great number of non-random chromosome abnormalities. In many 
instances, molecular studies of these abnormalities identified specific genes implicated in 
the process of leukemogenesis. The more common chromosome aberrations have been 
associated with specific laboratory and clinical characteristics, and are now being used as 
diagnostic and prognostic markers guiding the clinician in selecting the most effective 
therapies. Specific chromosome aberrations and their molecular counterparts have been 
included in the World Health Organization classification of hematologic malignancies, and 
together with morphology, immunophenotype and clinical features are used to define 
distinct disease entities. The European Leukemia Net Classification also uses specific 
chromosome aberrations and molecular information to classify patients.   
Pretreatment cytogenetic findings have been repeatedly shown to be among the most 
important, independent prognostic factors in AML Consequently, cytogenetic analyses are 
considered mandatory for analyzing outcome of many clinical trials and are currently used 
to stratify patients for different types of therapy. For instance, based on the European 
Leukemia Net (ELN) 2017 risk categories (Döhner et al, Blood, 2017; 129:424-47), 
patients with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) and t(8;21)(q22;q22.1) are 
associated with a better risk and survival. Patients with t(6;9)(p23;q34.1), t(v;11q23.3), 
t(9;22)(q34.1;q11.2), inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2), −5 or del(5q), −7, 
−17/abn(17p) and complex or monosomal karyotype are associated with adverse risk and 
poor survival. The remaining patients, those with t(9;11)(p21.3;q23.3) or cytogenetic 
abnormalities not classified as favorable or adverse are associated with intermediate risk 
and survival. 
Clonal chromosome abnormalities, that is, an identical structural aberration or gain of the 
same, structurally intact chromosome detected in at least two metaphase cells or the same 
chromosome missing from a minimum of three cells, are consistently found in the majority 
of AML patients at diagnosis. However, in contrast to patients diagnosed with CML, who 
are invariably positive for t(9;22) or its variants, the cytogenetic picture of AML is much 
more complex. To date, approximately 200 different structural and numerical aberrations 
such as reciprocal translocations, inversions, insertions, deletions, unbalanced 
translocations, isochromosomes, isodicentric chromosomes, isolated trisomies and 
monosomies have been found to be recurring chromosome changes in AML. Many of these 
aberrations are very rare, being so far detected in a few patients worldwide, whereas others 
occur more frequently [25]. 
14.1.2 Objectives 
• 
Correlate specific karyotype groups (normal or various primary and secondary 
chromosomal abnormalities) with clinical and laboratory parameters. 
• 
Correlate specific karyotype groups with response rates, response duration, survival 
and cure in patients treated with various induction and post-induction regimens. 
• 
Correlate specific karyotype groups with selected molecular abnormalities. 
• 
To correlate specific karyotype groups with measurable residual disease. 
• 
To correlate CR karyotype with outcome. 

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• 
To determine karyotype changes at end of consolidation and the influence of the type 
of change (or no change) in karyotype at end of consolidation on subsequent clinical 
course. 
• 
To determine karyotype changes at relapse and the influence of the type of change (or 
no change) in karyotype at relapse on subsequent clinical course. 
14.1.3 Methods 
Specimens for cytogenetic and FISH analysis must be performed for the required time 
points at each institution’s preferred CLIA-approved cytogenetic and FISH laboratory.1 A 
copy of the Cytogenetic Form from the Case Report Forms in Medidata Rave® should be 
printed and submitted to the institution’s preferred cytogenetic lab along with the contact 
information for the CRP and the specimen; the Cytogenetic Form can be found in the 
A041701 All Forms Packet on the Alliance and CTSU websites.2 An editable PDF of the 
forms can also be obtained by contacting the Alliance Cytogenetics Committee Office (see 
below). 3Use of an Alliance approved cytogeneticist is encouraged but not required; a list 
of Alliance-approved cytogeneticists can be found on the study-specific webpage on the 
Alliance and CTSU websites.4  
Cytogenetics samples obtainedare required to be submitted at the following timepoints: 
• 
Prior to initiation of therapy  
• 
1st complete remission (if diagnostic specimen is abnormal)  
• 
End of consolidation (if cytogenetics are abnormal at CR) 
• 
Relapse. 
Required processing of specimen includes 24 or 48 hour culture of bone marrow specimen 
(unstimulated blood culture required if marrow tap is dry), G-banding, and analysis of first 
20 analyzable metaphase spreads. 
Submission of Cytogenetic Samples  
After local review has been performed, the designated local cytogeneticist will complete 
the Cytogenetic Form and provide the required karyotype, metaphase images, and FISH 
information (if applicable) to the institution. The responses provided by the local 
cytogeneticist on the Cytogenetic Form will be entered in Medidata Rave® by site staff, 
and the required supporting documentation will be uploaded in Medidata Rave® for the 
use of the Alliance Cytogenetic Committee Office. The cytogenetic data from the prior to 
registration time point should be entered in Medidata Rave® within 28 days of patient 
registration; data for all other time points should be entered within 14 days of institution’s 
receipt of local review results. 
• 
Karyotypes and metaphases must be submitted via Medidata Rave®. Include the 
karyotype description or clone number in the bottom of the high resolution 
electronic image with arrows placed indicating abnormalities. Images (karyotype, 
metaphase, and FISH) are preferred to be submitted together in one PowerPoint 
(PPT) file. If this is not possible, individual .jpeg or .tiff files are accepted. 
Photocopies, faxes, and low-resolution PDF scans of karyotypes and metaphases 
will not be accepted. Write "Random Loss" next to the homologue when 
appropriate. If one copy (or both copies) of a given chromosome is overlapped or 
distorted, please submit a partial karyotype from another cell from the same clone 
showing both homologues of this chromosome intact, so that the reviewers are able 

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to evaluate each chromosome pair without distortion or overlap in at least two cells 
from the same clone. 
• 
For any abnormal, non-clonal cell not on the "List of Specific Abnormalities" 
(Appendix I), submit the International System for Human Cytogenetics 
Nomenclature (ISCN), karyotype is not required. 
• 
Two karyotypes of each abnormal clone and the corresponding metaphase spreads 
are required for submission. For any abnormal, non-clonal cell related to a clone, or 
for any abnormal, non-clonal cell not related to a clone and not on the "List of 
Specific Abnormalities" (Appendix I), submit the ISCN, but do not submit 
karyotype. 
• 
If case is abnormal, non-clonal (has one or more of the characteristic abnormalities 
specified on the list), enter the ISCN of each cell and provide a karyotype and 
corresponding metaphase representing each type of abnormality present. 
• 
If case is normal, submit two karyotypes and corresponding metaphase spreads for 
the normal clone. Submit karyotypes and associated metaphases for any abnormal 
non-clonal cell present in a normal case if it contains an abnormality on the “List of 
Specific Abnormalities” (Appendix I). 
• 
If the presence of a constitutional abnormality is suspected, the laboratory should 
perform analysis necessary to confirm or refute such suspicion (e.g., PHA-
stimulated cultures of peripheral blood) and submit the results. 
• 
Unsuccessful cytogenetic studies at the required time points are still required to be 
submitted. 
• 
For samples of peripheral blood only abnormal outcome will be accepted.  
• 
Follow-up will continue for required cytogenetic samples until relapse, withdrawal 
of consent, or death for up to 15 years. 
Optional Additional Procedures:  
• 
Direct preparations of AML specimens are acceptable only if the case is abnormal. 
• 
Unstimulated 24-48 hour cultures of peripheral blood. 
• 
Standard PHA-stimulated cultures of peripheral blood. 
• 
Other banding procedures. 
• 
Counting and/or analysis of additional metaphase spreads. 
• 
Submission of additional karyotypes. 
• 
Appropriate metaphase or interphase fluorescence in situ hybridization (FISH) 
analyses. Abnormal FISH results are encouraged to be submitted. Provide FISH 
information and two images (in the PowerPoint file with karyotypes and metaphases 
(preferred) or as individual .jpeg or .tiff files) for each assay performed. 
Questions regarding karyotype submission can be directed to Lisa Sterling, 
Cytogenetic Data Manager, at:  
Alliance Cytogenetics Committee Office 
Tel: 614-688-9750 
Lisa.sterling@osumc.edu 

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Central Karyotype Review 
Karyotypes will be sent to the Central Karyotype Review Committee if the material is 
adequate in terms of numbers of metaphases and required numbers of karyotypes. 
14.1.4 Analyses 
Analyses will be conducted using the analysis dataset used for the analysis of the clinical 
endpoints to ensure consistent data is reported for the primary and secondary endpoints 
(e.g. data associated with censoring, proper inclusion of crossover data, and data to be 
excluded in cases of consent withdrawals for follow-up and correlative studies). In this 
study, we plan to group the patients into ELN 2017 risk categories using centrally reviewed 
cytogenetics, see Section 14.1.3: Central Karyotype Review.  We will then use that data as 
a factor in analyses as it is well known that cytogenetics play a role in outcome of patients. 
Since we are focusing on these ELN 2017 risk categories, we will be able to avoid making 
false conclusions due to multiple testing.  For correlative studies, we will use per family 
error rate by setting the expected false discovery rate to 1. Using this we will be able to 
determine the multiplier needed to adjust for various hypotheses contained in the objectives 
of the study. 
14.2 
Molecular Genetic Analysis 
An amendment for the molecular genetic testing will be submitted to CTEP, NCI for review and 
approval according to NCTN guidelines. Amendments to the protocol and/or proposals for use 
of banked bone marrow or blood samples will include the appropriate background, experimental 
plans with assay details, and a detailed statistical section. Samples for testing will not be released 
for testing until the appropriate NCI approvals have been obtained. 
14.2.1 Background 
Large scale DNA sequencing studies have identified over 250 recurring somatic mutations 
in AML and have defined the genomic landscape of the disease [26]. Understanding the 
genetics of AML has led to refinements in disease classification, informs prognosis, and 
has identified potential targets for therapeutic intervention. 
Molecular genetic testing using either single gene or next generation sequencing assays has 
become a routine and essential part of the clinical care of patients with AML.  As a 
corollary, interpretation of clinical trial data in AML requires and understanding of the 
genetic context of the patient population.  In clinical practice, however, heterogeneity exists 
in commercially available next generation sequencing assays for AML due to differences 
including sequencing platform, library generation, sequencing platform, sequencing 
coverage, read depth and variant interpretation.  Furthermore, because the field of 
molecular genetics is a rapidly evolving area in AML with constant refinements in gene 
panels and sequencing technology.  Genetic information that would be considered 
clinically meaningful and relevant in the future at the time of study analysis may not be 
currently available through routine clinical testing for patients enrolled earlier in the course 
of the study. 
For these reasons, a baseline, pretreatment bone marrow and blood sample will be required 
from all patients to allow for centralized genetic molecular profiling. The information 
obtained will complement cytogenetic analysis to refine prognostic groups and response to 
treatment. 

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14.2.2 Objectives 
• 
To prospectively obtain specimens required for a baseline molecular 
characterization of patients treated on study. 
• 
To determine the frequency of specific gene alterations. 
• 
To determine the association of specific gene alterations with pretreatment 
characteristics and clinical outcomes.  
14.2.3 Methods 
The specific details of the molecular genetic testing for the samples will be determined 
after all patients are enrolled and will reflect the best available information about the 
molecular genetics of AML and sequencing technology at the time of analysis. 
14.2.4 Analysis 
The objectives are to examine three types of associations: (1) association of molecular 
features with pretreatment characteristics, (2) association among molecular markers, and 
(3) the association of molecular markers with clinical endpoints, such as CR, DFS, EFS, 
CIR, and OS. The type of analysis will be determined based on the nature of the variables 
analyzed. Fisher’s exact and Wilcoxon rank-sum tests will compare categorical and 
continuous variables, respectively. To analyze multiple factors related to the probability of 
achieving CR, logistic regression models will be constructed. For DFS, EFS, and OS, 
Kaplan-Meier curves will be constructed and the log-rank test will be used to examine the 
impact of single molecular markers on outcome. In addition, combinations of molecular 
markers along with other potentially important variables will be examined in multivariable 
analyses, using Cox regression. 
14.3 
E-selectin studies (Alliance A041701-LC1) 
14.3.1 Background 
E-selectin mediated interactions may play a role in AML and the expression of E-selectin 
or its binding epitope (sialyl Lea/x) may predict the clinical course and patient outcomes in 
AML. Increased expression of E-selectin, as seen in inflammatory conditions, malignant 
states such as leukemia, and during chemotherapy, is also associated with increased 
shedding of E-selectin from the cell surface resulting in higher levels of sE-selectin in the 
circulation. 
We will measure the levels of E-selectin ligand on pretreatment bone marrow blasts in 
patients treated with or without uproleselan to describe the cell-surface expression pattern 
of E-selectin ligand on AML blasts and to determine the effect on clinical outcomes. We 
will also examine plasma sE-selectin at baseline and after treatment with chemotherapy 
with or without uproleselan to determine if E-selectin inhibition affects sE-selectin levels 
and to correlate plasma levels with clinical outcomes. 
E-selectin (E-sel) is a cell adhesion glycoprotein that is expressed on endothelial cells and 
has been implicated in therapeutic resistance. In most myeloid leukemias, leukemic blasts 
express E-selectin ligands, which contain the glycan epitope of the carbohydrate sialyl Lex 
(sLex). This sequestration in the bone marrow vascular niche, leading to cell adhesion-
mediated drug resistance and resultant poor clinical outcome.  Uproleselan is an E-selectin 
antagonist which interrupts leukemic cell homing to the vascular niche, increases 
susceptibility to cytotoxic and targeted therapies and can be a potent adjunct to 
therapeutics. In deed data has demonstrated a correlation between leukemic cell surface 

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levels of E-selectin ligands using multiparameter flow cytometry and response to 
uproleselan. 
Recently, transciptome profiling of E-selectin ligand-forming glycosylation genes have 
been explored from public data sets to identify elevated E-selectin ligand expression in 
patients with AML.  RNA-seq data from patients treated in COG AAML1031 (N = 1,074) 
was available for evaluation.  Of 24 genes examined, Fucosyltransferase 7 (FUT7) and ST3 
beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) were significantly associated 
with adverse outcome (HR = 1.013, p < 0.0001, and HR = 1.023, p < 0.0001, respectively). 
and directly synthesize sLex.  Patients highly expressing FUT7 (highest quartile of 
expression) had significantly worse outcome than lower expressors (lowest 3 quartiles of 
expression), with a 5-year OS of 50.3% vs. 68.3% (p < 0.0001). Similarly, those with high 
ST3GAL4 expression had a 5-year OS of 51.3%, compared to 68.1% for low expressors (p 
< 0.0001).  High expression of these genes was shown to be associated with cell surface E-
selectin ligand expression.  Taken together these data suggest a strong correlation between 
transcriptome measurements of E-selectin ligand-forming glycosylation genes and cell 
surface glycosylation levels of E-selectin ligands, and lend support for the use of E-selectin 
ligand glycosylation genes as predictive biomarkers.  
We will measure the expression of E-selectin ligand-forming glycosylation genes from 
pretreatment bone marrow blasts treated with or without uproleselan to describe the RNA 
expression levels of these genes on AML blasts and to determine the effect on clinical 
outcomes. 
Traditional measures of response in AML rely on the morphological characterization of 
blasts after therapy with complete remissions requiring less than 5% blasts to be present in 
the bone marrow.  The morphological determination of blasts lacks sensitivity to identify 
low levels of residual disease and is subject to both sampling and interpretation error.  
Measurable residual disease (MRD) denotes the presence of leukemia cells down to levels 
of 1:104 to 1:106 white blood cells (WBCs), compared with 1:20 in morphology-based 
assessments. Multiple studies have demonstrated that the achievement of a negative MRD 
status is associated with improved clinical outcomes. In this study, we will utilize a flow 
cytometry-based MRD assessment at the end of induction and consolidation to explore 
potential differences in the experimental and control arms and correlate these results with 
clinical outcomes. 
14.3.2 Exploratory Objectives 
• 
To examine the correlation of E-selectin ligand expression of leukemic blasts with 
clinical outcome. 
• 
To examine the correlation of plasma soluble E-selectin concentrations with clinical 
outcomes. 
• 
To examine the correlation of MRD after induction and consolidation chemotherapy 
with clinical outcomes. 
• 
To examine the correlation of E-selectin ligand-forming glycosylation genes of 
leukemic blasts with clinical outcome. 
14.3.3 Methods 
E-selectin ligand will be measured on bone marrow blasts using multiparameter flow 
cytometry using a standardized panel of monoclonal antibodies designed to identify the 
blast population. The percentage of cells and mean fluorescence intensity will be used to 
quantify the extent of E-selectin ligand in this population. 

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sE-Selectin will be measured from plasma samples obtained at baseline and after induction 
using a commercially available enzyme-linked immunosorbent assay (ELISA) to human 
E-selectin. 
Expression levels of the E-selectin ligand-forming glycosylation genes, Fucosyltransferase 
7 (FUT7) and ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 4 (ST3GAL4), in RNA 
extracted from residual bone marrow aspirates of patients diagnosed with AML will be 
determined by reverse transcription quantitative PCR (RT-qPCR). 
To determine whether the E-selectin ligand expression is associated with clinical outcomes, 
descriptive statistics (i.e. mean, median, standard deviation, and range) and graphical 
methods (i.e. boxplots, jitter plots) will be used to summarize both pre- and post-treatment 
E-selection level to understand its distribution in each treatment arm.  To evaluate its 
association to clinical outcomes, two-sample t-tests or Wilcoxon rank-sum tests will be 
conducted to compared the E-selection level between those who achieve remission versus 
not.  
Suppose 80% of patients (n=536) enrolled will have a bone marrow sample available for 
E-selectin analysis. Assuming 375 patients (out of 536 patients) achieving a remission, we 
will have 88% power to detect an effect size of 0.3 (effect size defined as the difference in 
mean divided by the standard deviation, 𝛿= |𝜇1 −𝜇1|/𝜎) in baseline E-selectin 
expression levels between the responders and non-responders at the 0.05 two-sided alpha 
level; this assumes a remission rate of 70%. Furthermore, to analyze multiple factors 
related to the probability of achieving CR, logistic regression models will be constructed. 
For DFS, EFS, and OS, E-selection level along with other potentially prognostic factors 
will be examined in multivariable analyses, using Cox regression model, stratified by 
treatment arm. Similar analyses will be conducted for sE-selection. Secondary analysis will 
evaluate the sE-selectin expression level pre- vs. post-induction will be compared using 
two-sample t-tests or Wilcoxon rank-sum tests, as well as descriptive statistics and 
graphical methods. Exploratory analysis will be conducted to investigate the optimal cut-
point of baseline E-selectin expression level through ROC analysis. 
Flow cytometry will be used to assess for MRD by discriminating between normal 
regenerating hematopoietic cells in the bone marrow and any remaining acute myeloid 
leukemia (AML) which abnormally expresses cell surface antigens [27]. This technique, 
termed “Difference from Normal” is based on correlating the quantitative expression of 
multiple cell surface antigens (gene products) in the specimens using standardized antibody 
panels. The Difference from Normal approach identifies all the normal regenerating cells 
within the specimen first, subtracts them away and then detects clusters of abnormal cells 
within the remaining data set.  Using this technique, it is possible to define the precise 
composition of the specimen, identifying cells of all lineages and maturational stages as 
well as assessing specimen quality in addition to detecting and quantifying any abnormal 
cell population [28].   
Bone marrow specimens will be obtained at the end of induction and the end of 
consolidation. The quality of each specimen will be defined based on total cellularity, 
hemodilution, and viability. Collection of fewer than 100,000 cells in each of 8 tubes, 
significant hemodilution of >50%, lymphoid predominance of >50%, or significant cell 
death resulted in a specimen quality classification of suboptimal or inadequate [29]. 
14.3.4 Statistical Analysis Plan 
A041701 is a randomized Phase II/III study. The study will open with accrual open to two 
arms (one experimental arm and one control arm). The total Phase II sample size is 

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expected to be approximately 262 eligible patients (131 patients per arm). The total Phase 
III sample size is expected to be 670 (335 patients per arm). In the event that the Alliance 
Data Safety and Monitoring Board (DSMB) releases the requested Phase II data, the 
hypothesis-generating analyses described here will be performed based on Phase II accrual. 
Otherwise, this proposal is mainly based on Phase III accrual. Because this substudy is 
being newly incorporated in a protocol amendment post-study activation (54 patients 
accrued as of 11/22/2019), the current accrual rate suggests that approximately 600 
evaluable Phase III patients may participate in this substudy. 
We assume that 60% patients treated on A041701 will achieve a CR/CRi. Of those 
achieving CR/CRi, we expect to have end-of-induction marrow samples for MRD 
assessment on 90% of patients (n=324), and blood samples on 95% of patients (n=342).  
We note that the Cox regression models below will be stratified by treatment arm as 
appropriate. Multivariable analyses will be evaluated as a complement to each univariate 
analysis. Multivariable analyses will include baseline covariates age, gender, performance 
status, cytogenetic risk, white blood cell count, platelet count, bone marrow blast 
percentage, and number of induction courses (1 vs 2). 
1. Primary integrated objective (To evaluate whether the presence of MRD will be a strong 
predictor of relapse-free survival (RFS) in patients achieving a CR/CRi following 
induction chemotherapy): 
We expect that approximately 25% of patients who achieve a CR/CRi will have detectable 
MRD by flow cytometry using the current methodology. Log-rank test will be used to 
assess associations between MRD and RFS. And RFS will be estimated by the Kaplan-
Meier method.  
In the calculations below, the RFS is assumed to follow an exponential distribution with a 
median of 11.5 months (null hypothesis). For the RFS outcome (assuming 59 months of 
accrual and an additional one year of follow-up per protocol), the marrow results (n=324) 
will have 80% power to detect an absolute difference in median RFS of 5 months between 
MRD- and MRD+ patients (HR = 0.7), 13 months for MRD- versus 8 months for MRD+) 
with a two-sided alpha of 0.05, and the blood (n=342) results will have 83% power for the 
same effect size and alpha level. C-statistics will be calculated to quantify the model’s 
ability to predict outcomes. We will also fit multivariable Cox regression models with both 
end-of-induction MRD (present vs absent) plus the covariates listed above. 
In the event that the Alliance Data Safety and Monitoring Board (DSMB) releases the 
requested Phase II data, the hypothesis-generating analyses described here will be 
performed based on Phase II accrual. Similarly, because this substudy is being newly 
incorporated in a protocol amendment post-study activation (54 patients accrued as of 
11/22/2019), the current accrual rate suggests that approximately 200 evaluable Phase II 
patients may participate in this substudy. 
For the RFS outcome (assuming additional 18 months of accrual and an additional one year 
of follow-up per protocol), the marrow results (n=108) will have 63% power, and the blood 
(n=114) results will have 65% power for a HR of 0.6 and two-sided alpha of 0.05. C-
statistics will be calculated to quantify the model’s ability to predict outcomes. We will 
also fit multivariable Cox regression models with both end-of-induction MRD (present vs 
absent) plus the covariates listed above. 
To analyze the association of MRD with overall survival (OS), time-to-relapse (TTR, 
defined as the time from randomization to relapse, with death without relapse censored at 
time of death), and relapse risk: OS and TTR will be estimated using the Kaplan–Meier 

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method, and compared using log-rank tests.  Risk of relapse (RR) will be summarized using 
cumulative incidence estimates. Cox regression analyses will be used to assess the 
association between the outcomes of interest and the covariates listed above. 
To compare whether evaluate whether MRD from the peripheral blood provides similar 
prognostic information compared to bone marrow: We will fit multivariate marginal Cox 
regression models (Wei, Lin, Weissfeld 1989) including either blood and marrow MRD 
results with covariates for sample type (blood versus marrow), and a second model both 
blood and marrow MRD, and a third model with the interaction between the two covariates. 
We will calculate C-statistics for each of these models. 
To compare the presence of MRD at the end of induction versus end of consolidation time 
points to determine if either of these better predicts RFS: We will fit multivariate marginal 
Cox regression models (Wei, Lin, Weissfeld 1989) including either MRD results at the end 
of induction or at the end of consolidation. We will calculate C-statistics for each of these 
models. 
To compare the rates of MRD by treatment arm: Two-way table and chi-square tests will 
be used to compare the MRD rates by treatment arm. 
15.0 MONITORING PLAN AND REGULATORY CONSIDERATIONS 
15.1 
Central Data Monitoring and Source Data Verification  
Centralized data monitoring activities will be performed for all patient cases enrolled at each 
site (as identified by a unique CTEP Institution Code). The cases selected for central data 
monitoring will be reviewed for completeness and consistency via source data verification 
(SDV) with source documents compared to the data reported via the electronic Case Report 
Forms in Rave. Central data monitoring with SDV will be performed for all patients for key 
eligibility and response/disease outcomes. The first two treatment cycles will be reviewed for 
all patients. 
A source document is a document in which data collected for a clinical trial is first recorded. A 
subset of data is usually later entered in the Case Report Forms. The ICH-GCP guidelines define 
source documents as original documents, data, and records.  
The following data and documents will be reviewed via centralized data monitoring and source 
documents should be uploaded within the two weeks after registration:  
1) 
Informed Consent Document (ICD): De-identified last page of the signed and dated 
informed consent document as well as any pages with responses indicated by patient for 
optional studies.  Patient’s full signature should be redacted, but date should be retained.  
2) 
Key Eligibility Criteria:  
a. Diagnosis of AML based on 2017 WHO criteria excluding acute promyelocytic 
leukemia with PML-RARA 
b. No activating mutation in Fms-like tyrosine kinase-3 (FLT3) 
c. No evidence of CNS involvement of AML.  
d. No prior chemotherapy for MDS or AML including hypomethylating agents or 
lenalidomide (see section 3.3.2 for exceptions). 
e. Age ≥60 years 
3) 
Treatment Verification/IP Administration: Applicable drug administration and dosing 
records to document the first cycle of induction therapy and the first cycle of 
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4) 
Disease Outcome/Response:  Verify the claimed response for the primary endpoint based 
on source data containing assessment or response per the 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. 
See the Data Submission Schedule, available on the Alliance and CTSU websites, for 
additional details regarding source data verification requirements.  
Sites should ensure that patient identifiers have been removed from all pages that will be 
uploaded and add study-specific identifying information (i.e. Alliance Patient ID) and then 
scan and upload all source documents to Rave. Please ensure that all pages are legible and 
correct.  
In the event central monitoring or review of key performance indicators (KPIs) identify 
deficiencies, then additional central monitoring, an unscheduled on-site monitoring visit, 
or an audit visit may be triggered. Deficiencies or KPIs that may elicit one of these 
responses include, but are not limited to:  
• 
Accrual rate 
• 
Eligibility 
• 
Early Termination 
• 
Data submission timelines 
• 
Outstanding forms 
• 
Outstanding queries 
• 
Query responsiveness 
• 
Protocol deviations 
15.2 
On-site Monitoring 
Member networks that accrue five or more patients will be monitored approximately every 12 
months. Member networks that accrue 10 or more patients per year will be monitored 
approximately every 6 months. Member networks that accrue less than five patients will not be 
monitored on site, unless other deficiencies have been identified, and thus indicate the need for 
a monitoring visit. 
The first on-site monitoring visit will occur after the fifth patient has been enrolled and within 
6 months of the fifth enrollment. Thereafter, on-site monitoring visits will occur at 
approximately 12 month intervals during the treatment phase of the study. 
At the end of each on-site monitoring visit, the monitor will debrief the site study team and 
highlight areas that need improvement (if applicable). Any deficiencies and related actions will 
be documented in a visit follow-up letter, and on-site monitoring visit follow-up letters will be 
distributed to the site Principal Investigator (PI) and Lead Clinical Research Professional within 
30 days of the last day of the on-site monitoring visit.  
All affiliate/component sites will be monitored at the main member site during scheduled on-
site visits, unless a separate on-site visit is deemed necessary. All records from 
affiliate/component sites must be accessible to monitors. Institutions that utilize electronic 
medical records must provide monitors access to electronic records.  
Routine monitoring visits will be scheduled at approximately 6 – 12 month intervals, depending 
on accrual and other KPIs to ensure proper oversight of trial execution. Frequency of monitoring 
visits may be adjusted and will be determined based upon factors such as enrollment rate, data 

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quality, protocol compliance, site performance, and the available amount of data to be 
monitored.  
On-site monitoring visits will only be conducted during the treatment phase. Central data 
monitoring will continue during the follow-up phase. Institutions may also be audited per the 
Alliance auditing schedule.  
Deficiencies impacting the protection of rights and safety of human patients, unreported or 
underreported safety information, or other non-compliance may result in an increase in the 
percentage of patient data monitored or monitoring visit frequency.  
At selected sites, a minimum 25% of patients will be selected for on-site SDV of the following:  
• 
Eligibility 
• 
Primary endpoint 
At selected sites, 100% of patients will be selected for on-site SDV of the following:  
• 
Informed consent 
15.3 
Early Study Closure at Sites 
Institutions may not close this trial without discussion and approval by the Alliance Regulatory 
team (regulatory@alliancenctn.org). Before contacting the Alliance regulatory team please 
confirm this study does not appear on the list of trials terminated by the Alliance or on a study-
specific termination memo (located on the “Study Terminations of Patient Follow-up” page of 
the Alliance website or on the study specific page of the CTSU website). 
 
 

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Winkler, I.G., et al., Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self 
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Activating Pro-Survival NF-Kb Signalling - Therapeutic Blockade of E-Selectin Dampens NF-Kb 
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Glenjen, N., K.A. Mosevoll, and Ø. Bruserud, Serum levels of angiogenin, basic fibroblast growth 
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Horacek, J., et al., Biochip Array Technology and Evaluation of Serum Levels of Multiple Cytokines 
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Horacek, J.M., et al., Multi-analytical evaluation of serum levels of cytokines and adhesion 
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Noguchi, M., et al., A minor E-selectin ligand, CD65, is critical for extravascular infiltration of 
acute myeloid leukemia cells. Leukemia research, 2001. 25(10): p. 847-853. 
17. 
Song, Y., et al., Levels of bone marrow microvessel density are crucial for evaluating the status of 
acute myeloid leukemia. Oncology Letters, 2015. 10(1): p. 211-215. 
18. 
Winkler, I.G., et al., Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self 
renewal and chemoresistance. Nature medicine, 2012. 18(11): p. 1651-1657. 
19. 
Winkler, I.G., et al., Administration Of E-Selectin Antagonist GMI-1271 Improves Survival After 
High-Dose Chemotherapy By Alleviating Mucositis and Accelerating Neutrophil Recovery. Blood, 
2013. 122(21): p. 2266-2266. 
20. 
Othus, M., et al., Relationship between event-free survival and overall survival in acute myeloid 
leukemia: a report from SWOG, HOVON/SAKK, and MRC/NCRI. Haematologica, 2016. 101(7): 
p. e284-6. 

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21. 
FDA 
approves 
Mylotarg 
for 
treatment 
of 
acute 
myeloid 
leukemia. 
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574507.htm, 2017. 
22. 
Arber, D., et al., The 2016 revision to the World Health Organization classification of myeloid 
neoplasms and acute leukemia. Bloood, 2016. 127: p. 2391-2405. 
23. 
Döhner, H., et al., Diagnosis and management of AML in adults: 2017 ELN recommendations from 
an international expert panel. Blood, 2017. 129(4): p. 424-447. 
24. 
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. 
25. 
Mrozek, K., N. Heerema, and C. Bloomfield, Cytogenetics in acute leukemia. Blood Rev, 2004. 
18(2): p. 115-36. 
26. 
Ley, T., et al., Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. 
N Engl J Med, 2013. 368(22): p. 2059-74. 
27. 
Schuurhuis, G., et al., Minimal/measurable residual disease in AML: a consensus document from 
the European LeukemiaNet MRD Working Party. Blood, 2018. 131(12): p. 1275-91. 
28. 
Loken, M., L. Broderson, and D. Wells, Monitoring AML Response Using “Difference from 
Normal” Flow Cytometry; TE Druley MRD Testing, Current Innovations and Future Directions. 
2019, Springer International Publishing AG: Cham, Switzerland. p. 101-137. 
29. 
Loken, M., et al., Normalization of bone marrow aspirates for hemodilution in flow cytometric 
analyses. Cytometry B Clin Cytom, 2009. 76B(1): p. 27-36. 

 
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APPENDIX I 
LIST OF SPECIFIC ABNORMALITIES FOR WHICH KARYOTYPES MUST BE PROVIDED FOR 
SINGLE CELLS 
1. 
Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) 
a. any abnormality of 5q 
b. any abnormality of 7q 
c. any abnormality of 11q 
d. +8 
e. t(8;21)(q22;q22) + missing sex chromosomes 
f. t(15;17)(q22;q11-12) 
g. t(9;11)(p22;q23) 
h. t(6;9)(p23;q34) 
i. del(16)(q22), inv(16)(p13q22) or t(16;16)(p13;q22) 
j. Philadelphia chromosome 
k. ring chromosomes 
l. any abnormality involving 3q 
m. any abnormality of 12p 
n. der (1)t(1;7)(p11;p11) 
o. any abnormality of 9q 
p. any abnormality of 17p 
q. any abnormality of 20q 
r. any structural abnormality, other than the aforementioned, that is known to be recurrent in AML 
or MDS. 
2. 
Acute Lymphocytic Leukemia (ALL) 
a. hyperdiploid cells, especially > 50 chromosomes 
b. t(4;11)(q21;q23) 
c. t(8;14)(q24;q32) 
d. t(2;8)(p11-13;q24) 
e. t(8;22)(q24;q11) 
f. Philadelphia chromosome 
g. t(1;19)(q23;p13) or der(19)t(1;19)(q23;p13) 
h. t(11;14)(p13;q13) 
i. t(11;14)(q13-23;q32) 
j. near-haploid cells 
k. any deletion of 6q 
l. any abnormality of 14q 
m. any abnormality of 9p 
n. any abnormality of 12p 
o. any abnormality of 11q 
p. any structural abnormality, other than the aforementioned, that is known to be recurrent in ALL.

 
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APPENDIX II 
COLLABORATIVE AGREEMENTS LANGUAGE 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the 
following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of 
award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators.  The protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a copy of this protocol is 
requested by a patient or patient’s family member participating on the study, the individual should sign 
a confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by each 
Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred 
to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NCI, the design of the proposed combination 
protocol, and the existence of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing 
prior to the commencement of the trials that it will use the Multi-Party Data solely for development, 
regulatory approval, and commercialization of its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made 
available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is 
required 
by 
law 
or 
court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all Clinical 
Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable 
federal statutes and regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who 
will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for 
other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and 
policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 

 
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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group studies 
for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  Collaborator shall 
have the right to request that publication be delayed for up to an additional 30 days in order to ensure 
that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual 
property rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, manuscript or 
other form of public disclosure shall contain any of Collaborator’s confidential/ proprietary information. 
 
 

 
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APPENDIX III PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
Version #02 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, uproleselan.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others 
who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
 
• Uproleselan does not cause direct or time-dependent inhibition of CYP1A, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.  
• Uproleselan is a substrate for the efflux transporters P-gp and MRP2, may be a weak 
substrate for BCRP, and is not a substrate of the efflux transporter BSEP. These transport 
proteins may affect how much or how fast uproleselan is moved in and out of cells/organs.   
• Uproleselan is not an inhibitor of the efflux transporters P-gp, BCRP, or BSEP. 
• Uproleselan is not a substrate for or inhibitor of the following uptake transporters: 
OATP1B1, OATP1B3, OAT1, OAT3, OCT1 and OCT2.  
    
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Uproleselan may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this 
clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
Uproleselan must be used very carefully with other medicines that use certain transport proteins 
to be effective or to be cleared from your system.  Before you enroll onto the clinical trial, your 
study doctor will work with your regular health care providers to review any medicines and 
herbal supplements that are considered strong inducers/inhibitors or substrates] of P-gp, MRP2, 

 
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and BCRP. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 

 
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STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
uproleselan.  This clinical trial is sponsored by the NCI.  Uproleselan 
may interact with drugs that use certain transport proteins in your 
body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
Uproleselan interacts with the transport proteins P-gp, MRP2, and 
BCRP, and must be used very carefully with other medicines that 
interact with these transporters.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong 
inducers/inhibitors or substrates of P-gp, MRP2, or BCRP.  
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

 
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VOLANTE DE INFORMACIÓN SOBRE EL FÁRMACO PARA EL PACIENTE Y TARJETA PARA LA BILLETERA 
Versión #02 
 
Información para los pacientes, sus cuidadores y el equipo de atención médica ajeno al 
estudio sobre posibles interacciones con otros fármacos y suplementos herbales  
 
El paciente ____________________________ está inscrito en un ensayo clínico que usa el 
fármaco experimental en estudio, uproleselan.  Este ensayo clínico está patrocinado por el 
Instituto Nacional del Cáncer.  Este formulario está dirigido al paciente, pero incluye 
información importante para otras personas que atienden a este paciente.  
 
Esto es lo que usted como proveedor de atención médica debe saber: 
  
 
• Uproleselan no causa una inhibición directa o dependiente del tiempo de CYP1A, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6 o CYP3A4.  
• Uproleselan es un sustrato para los transportadores de eflujo P-gp y MRP2, puede ser un 
sustrato débil para BCRP y no es un sustrato del transportador de eflujo BSEP. Estas 
proteínas de transporte pueden afectar la cantidad o la rapidez con que se mueve 
uproleselan dentro y fuera de las células/órganos.   
• Uproleselan no es un inhibidor de los transportadores de eflujo P-gp, BCRP o BSEP. 
• Uproleselan no es un sustrato ni un inhibidor de los siguientes transportadores de captación: 
OATP1B1, OATP1B3, OAT1, OAT3, OCT1 y OCT2.  
    
 
Al paciente: Lleve este papel a sus citas médicas y guarde la tarjeta de información adjunta 
en su billetera.   
 
Uproleselan puede interactuar con otros fármacos que pueden causar efectos secundarios. Por 
esta razón, es muy importante que informe a los médicos del estudio sobre cualquier 
medicamento que esté tomando antes de inscribirse en este ensayo clínico.  También es muy 
importante que informe a sus médicos si deja de tomar algún medicamento habitual o si 
comienza a tomar un nuevo medicamento mientras participa en este estudio.  Cuando hable con 
sus médicos sobre sus medicamentos actuales, incluya los medicamentos que compra sin receta 
(remedio de venta libre) o cualquier suplemento herbal como la hierba de San Juan.  Es útil 
llevar con usted los envases de los medicamentos o una lista actualizada de los medicamentos. 
 
Muchos proveedores de atención médica pueden hacer recetas de medicamentos.  Debe informar 
a todos sus proveedores de atención médica (médicos, asistentes médicos, enfermeras 
profesionales, farmacéuticos) que está participando en un ensayo clínico.  
 
Esto es lo que usted y ellos deben saber:  
 
Uproleselan debe usarse con mucho cuidado con otros medicamentos que usan ciertas proteínas 
transportadoras para que sea eficaz o se elimine de su sistema.  Antes de inscribirse en el ensayo 

 
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clínico, el médico del estudio trabajará con sus proveedores de atención médica habituales para 
revisar los medicamentos y suplementos herbales que se consideren inductores/inhibidores 
potentes o sustratos de P-gp, MRP2 y BCRP. 
 
• ¡Tenga mucho cuidado!  Los medicamentos de venta libre (incluidos los suplementos 
herbales) pueden contener ingredientes que podrían interactuar con el fármaco del 
estudio.  Hable con sus médicos o farmacéuticos para determinar si podría haber algún 
efecto secundario.  
• Su proveedor de atención médica habitual debe consultar una fuente de consulta médica 
actualizada con frecuencia o llamar al médico del estudio antes de recetar cualquier 
medicamento nuevo o de suspender algún medicamento que esté tomando.  El nombre de 
su médico del estudio es  
_____________________________________ y se le puede contactar en  
 
_____________________________________. 
 

 
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TARJETA PARA LA BILLETERA CON 
INFORMACIÓN SOBRE EL FÁRMACO DEL 
ESTUDIO   
Está inscrito en un ensayo clínico que usa el fármaco experimental en 
estudio uproleselan.  Este ensayo clínico está patrocinado por el NCI.  
Uproleselan puede interactuar con medicamentos que usan ciertas 
proteínas de transporte en su cuerpo.  Por eso, es muy importante que: 
➢ Informe a sus médicos si deja de tomar algún medicamento o si 
comienza a tomar algún medicamento nuevo. 
➢ Informe a todos sus proveedores de atención médica (médicos, 
asistentes médicos, enfermeras profesionales o farmacéuticos) que está 
participando en un ensayo clínico. 
➢ Consulte con su médico o farmacéutico siempre que necesite usar 
un medicamento de venta libre o un suplemento herbal. 
 
 
 
Uproleselan interactúa con las proteínas de transporte P-gp, MRP2 y 
BCRP, y debe usarse con mucho cuidado con otros medicamentos que 
interactúan con estos transportadores.  
➢ Antes de inscribirse en el ensayo clínico, su médico del estudio 
trabajará con sus proveedores de atención médica habituales para 
revisar los medicamentos y suplementos herbales que se 
consideren inductores/inhibidores potentes o sustratos de P-gp, 
MRP2 o BCRP.  
➢ Antes de recetar nuevos medicamentos, sus proveedores de 
atención médica habituales deben consultar una referencia médica 
actualizada con frecuencia para obtener una lista de fármacos que 
deben evitarse o comunicarse con su médico del estudio.   
➢ El nombre de su médico del estudio es 
_____________________________ y se lo puede contactar en 
_________________________________.