Pediatric Acute Leukemia (PedAL) Screening Trial - Developing New Therapies for Relapsed Leukemias
Phase: PHASE1
Conditions: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia Post Cytotoxic Therapy, Juvenile Myelomonocytic Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Myelodysplastic Syndrome Post Cytotoxic Therapy, Myeloid Leukemia Associated With Down Syndrome
Sponsor: PedAL BCU, LLC

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY  
APAL2020SC 
 
 
 
1 
 
 
Activated: 10-28-2021 
Version Date: 
4-22-2024 
Closed: 
 
Amendment#: 
1A 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
APAL2020SC 
 
Pediatric Acute Leukemia (PedAL) Screening Trial – Developing New Therapies  
for Relapsed Leukemias 
 
 
A Leukemia & Lymphoma Society and COG Groupwide Screening Protocol 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON 
OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. 
THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY 
PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR 
TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
      
 
 
 
 
 
 
 
 

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CONTACT INFORMATION 
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_SYSTEM/ 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. Please 
see the Data Submission 
Schedule in the CRF packet 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)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 

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TABLE OF CONTENTS 
 
SECTION 
PAGE 
 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
2.0 
BACKGROUND 
10 
2.1 
Rationale for a PedAL Screening Protocol 
10 
2.2 
Goals and Objectives of the PedAL Screening Trial (Scientific Aims) 
11 
2.3 
PedAL Treatment Sub-trials 
12 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
14 
3.1 
Study Enrollment 
14 
3.2 
Patient Eligibility Criteria 
17 
4.0 
SUBMISSION OF MATERIALS AND DATA FOR SCREENING 
19 
4.1 
Required Biologic Materials for Initial Evaluation at Time of Suspected or Confirmed 
Relapse/Refractory Status 
19 
4.2 
Samples for Optional Banking 
20 
4.3 
Submission of Biologic Materials for Re-Screening 
20 
4.4 
Submission of Samples for Central Response Determination after Therapy for 
Relapse/Refractory Acute Leukemia (End of Cycle Disease Evaluations) 
21 
4.5 
Specimens for Correlative Studies on APAL2020SC Therapeutic Sub-trials 
21 
5.0 
SCREENING PROCEDURES FOR SUB-TRIAL ELIGIBILITY 
23 
5.1 
Specimen Testing 
24 
5.2 
Biomarker Results 
24 
5.3 
Sub-trial Recommendation 
25 
5.4 
PedAL Sub-Trial Eligibility 
25 
6.0 
FOLLOW-UP DATA 
26 
6.1 
Follow-up Time Points 
26 
6.2 
Data Collected During Follow-up 
26 
6.3 
Withdrawal of Consent Procedures 
26 
7.0 
OFF STUDY CRITERIA 
27 
7.1 
Off Study Criteria 
27 
8.0 
STATISTICAL CONSIDERATIONS 
28 
8.1 
Hypothesis 
28 
8.2 
Sample Size and Study Duration 
28 
8.3 
Statistical Analysis Methods 
28 
8.4 
Gender and Minority Accrual Estimates 
28 

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9.0 
EVALUATION CRITERIA 
30 
9.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
30 
9.2 
APAL2020SC Pediatric Specific Response Criteria for Patients with AML 
30 
9.3 
Relapse/Refractory Definitions for Patients with AML, ALL, and MPAL 
33 
10.0 
PATHOLOGY GUIDELINES 
36 
10.1 
Patients with AML and ALL 
36 
10.2 
Patients with Myeloid Sarcoma (Chloroma): 
37 
10.3 
Consultation Available 
37 
11.0 
RECORDS AND REPORTING 
38 
11.1 
Reporting 
38 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
39 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
39 
APPENDIX II: YOUTH INFORMATION SHEETS 
43 
APPENDIX III: SAMPLES FOR USE IN PEDAL THERAPEUTIC SUB-TRIAL CORRELATIVE 
BIOLOGY STUDIES 
45 
APPENDIX IV: RESPONSE CRITERIA FOR MDS 
47 
APPENDIX V: RESPONSE CRITERIA FOR JJML 
49 
REFERENCES 
52 
 
 

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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. The Certificate protects 
against the involuntary release of information about your subjects collected during the course of our 
covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings. However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances. 
For example, if the subject or his/her guardian requests the release of information in writing, the 
Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review 
our records under limited circumstances, such as a DHHS request for information for an audit or program 
evaluation or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm 
to self or others. 
 
 
ABSTRACT 
Therapeutic options for relapsed acute myeloid leukemia (AML) and some subsets of relapsed acute 
lymphoblastic leukemia (ALL) remain limited. Various re-induction regimens studied over the last decade 
have failed to improve our approach to relapsed AML.1, 2 Conventional approaches to improving survival 
following relapse in AML, and in many patients with ALL, are failing.   
 
Recent large-scale discovery efforts using next generation sequencing methods have identified recurrent 
mutational, signaling pathway and cell surface antigen targets for new therapies.  Of those recently 
approved, some have strong rationale for testing in pediatric patients. However, given the clinical and 
biologic differences between adult and pediatric AML, significant improvement in survival of children with 
AML cannot be accomplished if we rely exclusively on approved adult AML drugs for pediatric 
development.3, 4 The logistical barriers to studying new therapies for uncommon events in rare diseases in 
children are significant. Many of the high value targets in children (mesothelin, KMT2A, CD56, FLT3) are 
present in small subsets of patients, and this screening trial represents a mechanism by which we can 
efficiently interrogate agents in subsets of children with relapsed and refractory acute leukemias. While 
CAR-T therapy has shifted the paradigm for patients with ALL, relapse post CAR-T is challenging to treat. 
Identification of new targets in ALL will enable the development of specific therapies for relapse.  
 
The Leukemia & Lymphoma Society (LLS) Pediatric Acute Leukemia (PedAL) Screening Protocol will 
be conducted under a single IND sponsored by LLS and implemented through the Children’s Oncology 
Group (COG). APAL2020SC will provide a single portal of entry with longitudinal collection of clinical, 
immunophenotype and molecular data for all children with relapsed/refractory leukemia. This trial will 
provide a mechanism for target detection and increased efficiency for sub-trial activation. This screening 
trial will improve new agent availability for children, as well provide efficient pathway for our pharma 
partners to fulfill regulatory requirements and drug approval. 
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 

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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To utilize clinical and biological characteristics of acute leukemias to screen for 
patient eligibility for available Phase I/II PedAL sub-trials. 
 
1.1.2 
To maintain a longitudinal and comprehensive registry, as well as a specimen 
bank, from relapse in children and young adults with acute leukemias. 
 
 

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2.0 
BACKGROUND 
Therapeutic options for relapsed acute myeloid leukemia (AML) and some subsets of relapsed 
acute lymphoblastic leukemia (ALL) remain limited. Various re-induction regimens studied over 
the last decade have failed to improve our approach to relapsed AML.1, 2 The median remission re-
induction rate in first relapse is close to 60% with a range of 35% to 81% in studies that include as 
few as 11 patients and as many as 394 patients.5 Children who relapse within a year from first 
remission have lower response rates to re-induction chemotherapy and overall survival rates are 
dismal.2 Though anthracycline containing regimens generally induce better response rates, not all 
patients can tolerate additional anthracyclines at relapse. In ALL, overall survival of patients that 
experience first relapse is approximately 50% despite advances in salvage therapy including 
chimeric antigen receptor T-cell therapy (CAR-T) and allogeneic hematopoietic stem cell 
transplant (HSCT).6 However, regardless of the regimens used, it is clear that conventional 
approaches to improving survival following relapsed leukemia in children are failing.   
 
Recent large-scale discovery efforts using next generation sequencing (NGS) methods have 
identified recurrent mutational, signaling pathway and cell surface antigen targets for new 
therapies.  Though several drugs have been approved for adults with AML (glasdigib, venetoclax, 
gilteritinib, CPX-351, enasidenib and ivosidenib), drug development for childhood AML lags far 
behind.  Of those recently approved, some have strong rationale for testing in pediatric patients, 
but given the clinical and biologic differences between adult and pediatric AML, significant 
improvement in survival of children with AML cannot be accomplished if we rely exclusively on 
approved adult AML drugs for pediatric development.3, 4 Immunotherapies, including cellular 
therapies, for ALL have advanced retrieval strategies and are currently being evaluated in COG de 
novo ALL studies (AALL1721, AALL1731 and AALL1732).7-9 However, there are children with 
ALL that remain refractory to these therapies and additional targets and new agents need to be 
aggressively pursued. To this end, we must continue to identify therapeutic strategies for which 
there is both scientific rationale as well as regulatory incentives for development.   
 
With the exception of FLT3, there is a paucity of ‘druggable’ targets in AML that are shared 
between children and adults. Many of the high value targets in children (mesothelin, KMT2A, 
CD56, FLT3) are present in small subsets of patients, and this screening trial represents a 
mechanism by which we can efficiently interrogate agents in subsets of children with relapsed acute 
leukemias. The most rapid and efficient way to evaluate the current leukemia pipeline of novel 
agents is through a PedAL screening trial (APAL2020SC) that provides a single portal of entry for 
all patients for target screening to inform sub-trial enrollments.   
 
APAL2020SC will provide a single portal of entry with longitudinal collection of clinical, 
immunophenotype and molecular data for all children with relapsed/refractory leukemia. There are 
multiple development paths for relapse therapies in children with acute leukemia, yet few impactful 
trials and heterogeneous designs. Through the Pediatric Acute Leukemia (PedAL) initiative we 
intend to expand our trial portfolio and consolidate screening for eligible patients, while providing 
our Pharma partners an efficient path to fulfilling regulatory requirements. 
 
2.1 
Rationale for a PedAL Screening Protocol 
To evaluate novel targeted therapies in children with relapsed leukemia, we must address 
that fact that many recurrent somatic mutations and antigen targets of interest in AML and 
ALL are expressed in a minority of patients. The logistical barriers to studying new 
therapies for uncommon events in rare disease in children are significant. There needs to 
be an available assay for target detection and screening as well as a mechanism that makes 

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APAL2020SC 
 
 
11 
it efficient for sites to activate a sub-trial for the eligible patient. The recent success of 
ProjectEveryChild (APEC14B1) and Beat AML confirm the role of screening trials as 
efficient approaches for the assignment of patients to targeted therapies. There is, however, 
currently no central screening mechanism that includes relapsed leukemias in children and 
young adults. In response to an increasing number of targeted leukemia therapies requiring 
molecular and immuno-flow cytometry screening for trial eligibility, the Leukemia & 
Lymphoma Society (LLS) is committed to supporting the PedAL initiative to facilitate the 
study of new therapies for children with relapsed leukemia.   
 
Similar to ProjectEveryChild (APEC14B1), APAL2020SC will permit enrollment of 
patients with “known or suspected” relapsed AML or ALL that occurs in the pediatric, 
adolescent or young adult populations. This will permit early identification of patients for 
relapse trial eligibility determination, sub-trial activation and the collection of relapse 
specimens. All of these items have proven challenging and have limited the impact of past 
clinical trials at relapse through COG and other international cooperative groups. It is the 
intent of APAL2020SC to remove historical barriers to accrual on to relapse trials, to 
collection of vital clinical information, and to procurement of precious biologic samples 
that are vital to improving our understanding of relapsed acute leukemia in children. The 
PedAL screening trial will provide a mechanism for biospecimen collection, rapid central 
eligibility screening and longitudinal tracking of patients following relapse to address 
major barriers to the development of effective therapies in relapsed leukemias.   
 
The LLS/COG Pediatric Acute Leukemia (PedAL) Screening Protocol will be available to 
COG sites group-wide. Major European AML Cooperative Groups (DCOG, NOPHO, 
AIEOP, BFM, MRC as well as ANZCHOG) have agreed to participate in select PedAL 
sub-trials. Enrollment on APAL2020SC will be required for sub-trial enrollment for COG 
institutions and there will be a parallel screening process in the EU. The majority of patients 
in North America will have also enrolled on APEC14B1:ProjectEveryChild at diagnosis 
and will have had analytically validated comprehensive genomic profiling (CGP) through 
Foundation Medicine, Inc, as well as central immuno-flow cytometry for detection and 
quantification of cell surface targets performed at Hematologics, Inc. Although 
encouraged, participation in APEC14B1 is not required. Once enrolled on APAL2020SC, 
flow cytometry and CGP results from relapse will be provided to investigators to inform 
enrollment of patients onto PedAL sub-trials.  
 
 
2.2 
Goals and Objectives of the PedAL Screening Trial (Scientific Aims) 
Building on the success of the Beat AML initiative launched in 2012, LLS has 
committed to a substantial investment in relapsed childhood acute leukemias.  The 
intent is to create: 
 
1. A trial that provides a mechanism for collecting tissue and screening for specific 
cell surface, molecular and genetic targets for all patients with relapsed AML and 
select subsets of ALL patients. 
 
2. A screening mechanism that will incorporate standard diagnostic information 
(cytogenetics/FISH analysis), complete genomic profiling, molecular diagnostics, 
immunophenotyping and clinical data needed for sub-trial eligibility. 
 

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3. A data registry to capture treatment, response, toxicities, events and outcomes 
independent of trial assignment so that we may better understand and describe 
post-relapse survival in acute leukemia. 
 
4. A mechanism for collecting, processing and banking biological specimens from 
patients at multiple time points, to enable concurrent and future research to better 
understand and treat relapsed leukemias. 
 
2.3 
PedAL Treatment Sub-trials 
PedAL therapeutic sub-trials will be stand-alone clinical trials and enrollment on 
APAL2020SC screening will be required for enrollment onto all PedAL therapeutic sub-
trials. The primary endpoints for PedAL sub-trials will be safety and/or efficacy. The 
PedAL sub-trials fall into 2 general categories: Registration trials with a primary efficacy 
objective and safety/feasibility trials with a signal finding efficacy objective. The 
registration trials will either be randomized or employ a well-designed historical 
comparator.  
 
Most study drugs included in these sub-trials will include agents that have at least an adult 
recommended phase 2 dose (RP2D) and there will be an expectation of benefit for pediatric 
patients. If there are agents interrogated for pediatric-specific targets without adult data or 
without data in patients with leukemia, then safety assessments will be performed with 
industry and FDA guidance.  
 
2.3.1 
Agent Selection and Prioritization 
Through PedAL, the LLS also funds a preclinical prioritization team led by Dr. 
Kim Stegmaier and a biomarker discovery team led by Dr. Soheil Meshinchi. The 
PedAL Clinical Trial Committee works with Pharma partners to secure those 
agents most likely to provide benefit. All sub-trials will include background data 
to justify use of the agent in children, target expression, prognostic data associated 
with target expression, and agent-specific toxicity data.  Many of the highest value 
targets in pediatric AML are not mutation specific (e.g. CD123). Each sub-trial 
will include a rationale for use and an enrollment plan that accounts for other active 
studies.   
 
Agents selected for use in PedAL sub-trials will be reviewed according to the 
following steps:   
 
1. An Agent Prioritization Proposal will be presented to the PedAL Advisory 
Committee by the Concept Lead (Sub-trial study chair if approved). At 
minimum the proposal will review all available adult safety and efficacy data, 
target relevance and expression in children with leukemia, preclinical data, and 
a feasibility plan for testing in children.  
 
2. Agent Prioritization will be reviewed by the PedAL Advisory Committee. 
Only agents receiving a majority vote will advance to clinical development. 
 
2.3.2 
Regulatory Elements of APAL2020SC and Sub-Trials 
It will be the intent of PedAL to support development of therapies that are initiated 
with a goal to eventually obtain regulatory approval in children. The PedAL project 
team will seek FDA guidance and EMA Scientific Advice for therapeutic sub-trials 
funded by industry partners with an intent-to-file. Though APAL2020SC is a 

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Screening Trial, it is helpful to refer to recent published guidance. The FDA 
defined Master Protocols as “a protocol with multiple sub-studies, which may have 
different objectives and involves coordinated efforts to evaluate one or more 
investigational drugs in one or more disease subtypes within the overall trial 
structure.” The guidance strongly recommends for pediatric trials that there be 
sufficient adult data to define a reasonable pediatric starting dose and that the drug 
provide the “prospect of benefit” for the patients.  While this will be the goal, there 
are examples of targeted therapies appropriate for testing in children that have not 
been previously tested in adults with acute leukemia. In such instances, there will 
be detailed rationale presented and will incorporate a safety assessment.10, 11 
 
 

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3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every 
patient with a known or suspected neoplasm needs to be offered participation in 
APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. Enrollment on APEC14B1 is not required for enrollment on 
APAL2020SC. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
 
3.1.2 
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 

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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) and 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; 
• 
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.  
 
Additional Requirements 
Additional 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). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 

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documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. 
  
3.1.3 
Study Enrollment 
Patients may be enrolled on APAL2020SC if they meet the eligibility criteria 
outlined in Section 3.2.  
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (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;  
• 
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 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. 
 
To assign a Non-Investigational New Drug (IND)/Non-Treatment (NINT) as the 
treating, crediting, consenting, or receiving investigator for a patient transfer in 
OPEN, NINTs must list all clinical practice sites, Institutional Review Boards, and 
labs covering their practice sites on the NINT Investigator Acceptance Form in 
RCR. NINTs may only participate on studies flagged for NINT participation. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; 
and  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
 

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APAL2020SC 
 
 
17 
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. 
 
3.1.4 
Submission of Specimens 
Submission of specimens for screening via APAL2020SC must only be done after 
obtaining written informed consent. See Section 4.0 for submission requirements.  
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
Inclusion Criteria 
 
3.2.1 
Age 
Patients must be less than 22 years of age at the time of study enrollment. 
 
3.2.2 
Diagnosis 
Patient must have one of the following at the time of study enrollment: (See 
Section 9.3 for definitions of relapse and refractory disease) 
 
a. Patient has known or suspected relapsed/refractory (including primary 
refractory) AML as defined in Section 9.3. 
• 
This includes isolated myeloid sarcoma.  
 
b. Patient has known or suspected relapsed/refractory (including primary 
refractory) myeloid leukemia of Down syndrome (ML-DS). 
 
c. Patient has known or suspected relapsed ALL as defined in Section 9.3 
that meets one of the following criteria: 
1. Second or greater B-ALL medullary relapse, excluding KMT2Ar.  
2. Any first or greater B-ALL medullary relapse involving KMT2Ar. 
3. Any first or greater T-ALL medullary relapse with or without 
KMT2Ar. 
 
d. Patient has known or suspected relapsed/refractory (including primary 
refractory) mixed phenotype acute leukemia (MPAL) as defined in 
Section 9.3. 
 
e. Patient has known or suspected de novo or relapsed/refractory (including 
primary refractory) treatment-related AML (t-AML). 
 
f. Patient has known or suspected de novo or relapsed/refractory (including 
primary refractory) Myelodysplastic Syndrome (MDS or treatment-related 
Myelodysplastic Syndrome (t-MDS). See Appendix IV for additional 
information. 
 

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18 
Note: Relapsed/refractory disease includes Stable Disease, Progressive 
Disease, and Disease Relapse.  
 
Patient has known or suspected de novo or relapsed/refractory (including 
primary refractory) Juvenile Myelomonocytic Leukemia (JMML). See 
Appendix V for additional information. 
 
Note: Relapsed/refractory disease includes Stable Disease, Progressive 
Disease, and Disease Relapse.  
 
3.2.3 
Regulatory Requirements 
 
3.2.3.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.3.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
There are no Exclusion Criteria for APAL2020SC. 
 
 
 

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19 
4.0 
SUBMISSION OF MATERIALS AND DATA FOR SCREENING 
 
4.1 
Required Biologic Materials for Initial Evaluation at Time of Suspected or Confirmed 
Relapse/Refractory Status 
 
The initial evaluation is the first evaluation after consent is signed and the patient is 
enrolled onto APAL2020SC. It is preferable, but not required, that the initial evaluation 
samples are obtained within 7 days of enrollment. 
 
Please refer to the Manual of Procedures (MOP) for APAL2020SC for detailed instructions 
for collecting and shipping samples for initial evaluation of patients with 
relapsed/refractory disease. The manual can be found on the APAL2020SC web page on 
the COG members only site.   
 
Summary of Specimens at Time of Initial Evaluation on APAL2020SC 
 
Specimen 
Volume 
Tube Type 
Laboratory 
Consent 
All Patients Enrolled 
Bone Marrow 
2-4 mL  
Sodium Heparin  
(Green Top) 
Hematologics, 
Inc. 
 
Covered under 
APAL2020SC 
consent 
Peripheral Blood* 
10 mL 
Sodium Heparin 
(Green Top) 
 
Patients with AML, Treatment-Related AML, Myeloid Leukemia of Downs Syndrome,  
MDS, Treatment-Related MDS, and JMML  
 
For Foundation Medicine, only submit 1 type of specimen.  
DO NOT SEND BOTH BM AND PB. 
If both are available send the sample with the highest tumor content.  
 
Bone Marrow 
 
  
1.5-2.5 mL 
EDTA (purple top) 
Foundation 
Medicine Inc. 
Covered under 
APAL2020SC 
consent 
 
Peripheral Blood* 
 
2.5-10 mL 
EDTA (purple top) 
Samples should be shipped the same day they are collected.  
It is of the utmost importance that samples be shipped fresh and the day they are collected. If possible, 
make arrangements to time diagnostic procedures so that they can be shipped the same day as collected. 
This is true even if the diagnosis of relapse is not confirmed. It is vital for proper molecular and genetic 
analysis that specimens be shipped immediately. This is especially important for specimens going to 
Foundation Medicine Inc. (FMI).  
 
Obtaining bone marrow on Saturday or Sunday is strongly discouraged unless clinically indicated.  

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APAL2020SC 
 
 
20 
Patients with Myeloid Sarcoma 
 
Submit FFPE slides or block as outlined in Appendix II of the APAL2020SC 
MOP. 
 
*If marrow cannot be obtained, see the specific sections of the APAL2020SC MOP for requirements for 
submitting peripheral blood. Do not send both marrow and blood. 
 
4.2 
Samples for Optional Banking 
All patients enrolled may participate in the optional banking.  
 
Specimen 
Volume 
Tube Type 
Laboratory 
Consent 
Bone Marrow 
4-8 mL 
EDTA (purple top) OR 
COG Shipping Media 
BPC 
Patient must agree to 
optional banking in the 
APAL2020SC consent. 
Peripheral Blood* 
8-16 mL 
EDTA (purple top) OR 
COG Shipping Media 
BPC 
*If marrow cannot be obtained, see the specific sections of the APAL2020SC MOP for requirements for 
submitting peripheral blood. 
 
4.3 
Submission of Biologic Materials for Re-Screening  
After patients are enrolled and initially evaluated for APAL2020SC, investigators with 
patients who did not have confirmed relapse/refractory disease, who relapse after remission 
was achieved subsequent to treatment for relapsed leukemia or whose patients have 
detectable leukemia after a re-induction attempt may submit new samples for re-screening 
and banking in the amounts outlined below. Samples will have flow cytometry for blast 
enumeration. Sites will get access to these results. If the patient agrees to optional 
biobanking, any leftover samples will be banked. Submission of a dedicated sample for 
biobanking at re-screening is encouraged for patients who consented.  
 
A sample for next-generation sequencing should be submitted to FMI for re-screening only 
if sequencing of the initial APAL2020SC screening sample failed or if repeat FMI 
sequencing is specifically required as part of eligibility for a therapeutic sub-trial. See 
Section 4.1 for sample requirements. 
 
 
Summary of Specimens for Re-Screening Table 
 
Specimen 
Volume 
Tube Type 
Laboratory 
Bone Marrow 
2-4 mL  
Sodium Heparin (Green 
Top) 
Hematologics, Inc. 
Peripheral 
Blood* 
10 mL 
Sodium Heparin 
(Green Top) 
Hematologics, Inc. 
Bone Marrow 
4-8 mL 
EDTA (purple top) OR 
COG Shipping Media 
BPC 
Peripheral 
Blood* 
8-16 mL 
EDTA (purple top) OR 
COG Shipping Media 
BPC 

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21 
*Bone marrow is preferred. If marrow cannot be obtained, see the specific sections of the 
APAL2020SC MOP for requirements for submitting peripheral blood. Do not send both 
marrow and blood. 
 
 
4.4 
Submission of Samples for Central Response Determination after Therapy for 
Relapse/Refractory Acute Leukemia (End of Cycle Disease Evaluations)  
 
4.4.1 
Patients enrolled on a PedAL or COG therapeutic sub-trial 
Patients enrolled on PedAL or COG therapeutic sub-trial should follow the 
submission schedule for end of cycle samples as outlined in those protocols.  
 
4.4.2 
Patients not enrolled on a PedAL or COG therapeutic sub-trial 
 
If patients are not enrolled on a PedAL or COG therapeutic sub-trial, sites are 
strongly encouraged to submit bone marrow samples at the end of treatment cycles 
(or whenever a follow-up bone marrow evaluation is done for clinical purposes) to 
Hematologics for flow cytometry and MRD. Hematologics offers comprehensive 
panels and is a leader in residual disease testing by flow cytometry. This testing is 
a free resource for all patients on this study. Capturing central response to 
treatment is a critical component and a high priority for the APAL2020SC 
longitudinal data registry.  
 
Typically, peripheral blood cannot be evaluated due to low levels of disease. 
But, if the patient has peripheral blasts and site does not plan to do a bone marrow, 
then peripheral blood may be submitted. If the patient does not have any peripheral 
blasts and the site does not plan to do a bone marrow, no specimens should be 
submitted. If the patient agrees to optional biobanking, any leftover samples will 
be banked.  Submission of a dedicated sample for biobanking at re-screening is 
encouraged for patients who consented. 
 
Specimen 
Volume 
Tube Type 
Laboratory 
Bone Marrow only 
2-4 mL  
Sodium Heparin 
(Green Top) 
Hematologics, Inc. 
Peripheral Blood* 
10 mL 
Sodium Heparin 
(Green Top) 
Hematologics, Inc. 
Bone Marrow 
4-8 mL 
EDTA (purple top) OR 
COG Shipping Media 
BPC 
Peripheral Blood* 
8-16 mL 
EDTA (purple top) OR 
COG Shipping Media 
BPC 
*Typically, peripheral blood cannot be evaluated due to low levels of disease. But, if 
the patient has peripheral blasts and site does not plan to do a bone marrow, then peripheral 
blood may be submitted.  Do not send both marrow and blood. 
 
 
4.5 
Specimens for Correlative Studies on APAL2020SC Therapeutic Sub-trials 
Some PedAL therapeutic sub-trials may require the use of a specimen submitted through 
APAL2020SC at the time of relapse for a correlative biology objective within the 
therapeutic sub-trial. The priority for specimens in these cases will always be the screening 
studies outlined in APAL2020SC. However if there is adequate sample available, samples 

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APAL2020SC 
 
 
22 
collected via APAL2020SC may be sent from the BPC to the laboratory coordinating the 
correlative biology study.  
 
The correlative study objectives, sample requirements, collection, processing, and testing 
methods will be outlined in the APAL2020SC therapeutic sub-trial. The therapeutic sub-
trial should specify that the diagnostic specimen submitted for APAL2020SC may also be 
used for objectives related to the sub-trial. Consent to direct these specimens for sub-trial 
studies will be obtained through the sub-trial consent. The sub-trial study chair will 
communicate directly with the BPC to confirm consent. 
 
Appendix III includes a list of therapeutic sub-trials, for which specimens will be sent for 
correlative biology objectives. Within Appendix III the following are listed: 
• 
Number/ Title of APAL2020SC therapeutic sub-trial. 
• 
Correlative biology objectives for the sub-trial.  
• 
Sample requested collected via APAL2020SC. 
• 
Where the sample will be shipped.  

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23 
 
5.0 
SCREENING PROCEDURES FOR SUB-TRIAL ELIGIBILITY 
 
 
The schema below provides and overview of sample distribution and testing at baseline evaluation. 
 
 
 
 
 
 

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24 
 
5.1 
Specimen Testing 
 
5.1.1 
Hematologics 
Once specimens are received by Hematologics, the following will take place. 
 
 
 
 
• 
Samples will be analyzed to determine the leukemic burden expressed as the 
percentage of leukemic blasts.   
 
• 
Immunoflow cytometry will be performed to evaluate target markers to 
determine eligibility for PedAL sub-trials.  
 
If the patient agrees during the consenting process, any specimen that is left-over 
after testing will be banked.  
 
5.1.2 
Foundation Medicine Inc. 
Once specimens are received by FMI, the following will take place. 
 
• 
Samples will be analyzed for tumor content.  
o Samples with ≥ 10% blasts will have a complete genomic profile 
performed.  
o AML samples with < 10% blasts may not be sequenced and a failure 
report may be issued.  
o MDS and JMML samples will be sequenced regardless of blast 
percentage. 
 
5.1.3 
BPC 
Once specimens are received by the BPC, the following will take place.  
 
• 
Bone marrow and/or blood will be banked for future research. 
 
• 
For patients enrolled on a sub-trial, leftover samples may be sent from the BPC 
to the laboratory coordinating correlative biology on that trial. Consent to 
direct these specimens will be obtained through the sub-trial consent. 
 
 
 
 
5.2 
Biomarker Results 
 
5.2.1 
Results from Hematologics 
Results from testing performed at Hematologics will be accessed through their 
results portal called Hematolinx. Site will need to request access to this portal after 
APAL2020SC activation. Please refer to the APAL2020SC MOP for instructions 
on accessing reports. Results will include the following: 
 
• 
Confirmation of disease type and blast enumeration. 
o Results should be available within 3 days after sample received.  
 
• 
Target markers for PedAL sub-trial eligibility. 
o Results should be available within 4 days after sample received.  
 

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25 
• 
Central response assessment by flow cytometry for patients not enrolled on a 
PedAL or COG therapeutic sub-trial. 
o Sites are strongly encouraged to submit bone marrow samples at the 
end of treatment cycles (or whenever a follow-up bone marrow 
evaluation is done for clinical purposes). 
 
5.2.2 
Results from Foundation Medicine 
Sites will be required to access the Foundation Medicine Results Portal. Each site 
will need to request an account for access to the portal. This is required even if you 
have an account for other COG protocols (AAML1831) or an account for clinical 
care. Please refer to the APAL2020SC MOP for procedures regarding 
submitting the account access request.  
 
Sites will receive the full CLIA report via the portal. Results will be available a 
minimum of 14 days after being received by FMI. Sites will receive an email from 
the results portal when the results are available.  
 
5.3 
Sub-trial Recommendation 
After results are obtained from the central labs, site investigators should review eligibility 
criteria to determine if a particular sub-trial is an option for their patient.    
 
5.3.1 
Patients Not Enrolling on a PedAL Sub-Trial 
Patients who are either without a detectable target, are not eligible for a sub-trial, 
or who choose not to enroll in a sub-trial will continue to have post-relapse 
treatment, response, and outcome data collected for a maximum of 5 years. Sites 
are strongly encouraged to submit bone marrow samples at the end of treatment 
cycles (or whenever a follow-up bone marrow evaluation is done for clinical 
purposes) to Hematologics for flow cytometry and MRD (see section 4.4.2).  Site 
investigators may continue to review eligibility for sub-trials at any time to see if 
there are sub-trials for which their patient may be eligible.  
 
5.4 
PedAL Sub-Trial Eligibility 
PedAL sub-trials will be stand-alone clinical trials and APAL2020SC screening will be 
required for enrollment. Biomarker expression, prior therapy, organ function, and clinical 
features will be used to determine sub-trial eligibility. 
 
Eligibility criteria for each sub-trial will be included in each individual PedAL sub-trial. 
Patients must meet all sub-trial inclusion and exclusion criteria in order to be enrolled onto 
the sub-trial. Samples collected via APAL2020SC may be sent to outside laboratories for 
additional biomarker screening using proprietary companion diagnostic testing if required 
for specific sub-trial eligibility. Example: A pharmaceutical company may use a specific 
commercial or private lab not outlined in APAL2020SC to evaluate eligibility for a specific 
sub-trial. These labs/tests will be included in the specific sub-trial. 
 
 
 

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26 
 
6.0 
FOLLOW-UP DATA 
All patients enrolled onto APAL2020SC with disease confirmation will have follow-up submitted: 
 
6.1 
Follow-up Time Points 
Follow-up will be required for all patients enrolled on APAL2020SC regardless of 
whether the patient enrolled onto a PedAL or COG therapeutic sub-trial.  
 
• 
For patients enrolled onto a PedAL or COG therapeutic sub-trial.  
Sites should submit follow-up every 3 months for 2 years and then every 6 months 
for 3 years (total 5 years) from the date of enrollment onto the most recent 
PedAL/COG therapeutic protocol.  
 
• 
For patients not enrolled onto a PedAL or COG therapeutic sub-trial.  
Sites should submit follow-up every 3 months for 2 years and then every 6 months 
for 3 years (total 5 years) from the date of enrollment on APAL2020SC.  
 
6.2 
Data Collected During Follow-up 
Data to be collected during follow-up will include some or all of the following: 
• 
PedAL/COG therapeutic sub-trial status. 
• 
Vital status. 
• 
Disease response evaluation/status. 
• 
Anti-cancer therapy (including HSCT) received.  
• 
Cardiac function data. 
• 
Target toxicities (e.g. SOS, cardiac, infections).  
• 
Other important medical data.  
• 
Second malignant neoplasm. 
• 
Off study status 
 
* It is strongly recommended to utilize Hematologics for central evaluation for patients 
not enrolled on therapeutic clinical trials. 
 
6.3 
Withdrawal of Consent Procedures 
If a patient should withdraw consent, sites should follow the SOP titled “Capturing & 
Tracking Withdrawal of Consents for COG Trials” found on the COG members only 
website. This SOP can be found under the “Administration” tab, under “Policies and 
Procedures”, under “Study Conduct”.  
 
 
 

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27 
7.0 
OFF STUDY CRITERIA 
 
7.1 
Off Study Criteria 
a) 
Five years from the date of patient enrollment onto APAL2020SC if not enrolled 
onto a sub-trial. 
b) 
Three years from the date of patient enrollment onto APAL2020SC if enrolling 
site failed to obtain an evaluable sample associated with APAL2020SC enrollment 
with no plans to submit subsequent samples.  
c) 
Three years from the date of patient enrollment onto APAL2020SC if the 
diagnosis of protocol eligible disease (AML, ALL, t-AML, myeloid leukemia of 
Down Syndrome, MDS, t-MDS, JMML or MPAL) cannot be confirmed. 
d) 
The fifth anniversary of the most recent date of patient enrollment onto a PedAL 
or COG therapeutic protocol. 
e) 
Withdrawal of consent for any further data submission.  
f) 
The results from eligibility studies are outside the parameters required for 
eligibility. 
g) 
Death. 
h) 
Lost to follow-up. 
 
 
 

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28 
8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
Hypothesis 
Screening 
for 
genetic 
and immunophenotypic 
biomarkers 
in 
children 
with 
relapsed/refractory leukemia will improve and ensure enrollment on relevant targeted 
therapy sub-trials designed to produce clinically meaningful improvements in response 
rates. 
 
8.2 
Sample Size and Study Duration 
Based on the relapse rate of patients with AML and ALL, we anticipate 16 patients per 
month for 60 months for a total of up to 960 patients in 5 years.  
 
8.3 
Statistical Analysis Methods 
 
8.3.1 
Study Endpoints 
The primary goals of the APAL2020SC are:  
• 
To identify a priori specified genomic and immunophenotypic targets to 
inform sub-trial eligibility.  
• 
Maintain a longitudinal and comprehensive registry, as well as specimen 
bank, of children and young adults with acute leukemias.  
 
Detailed statistical plans will be included in the individual sub-trials. 
 
8.4 
Gender and Minority Accrual Estimates 
The gender and minority distribution of the study population is expected to be: 
 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian / Alaska 
Native 
1 
2 
2 
1 
6 
Asian 
13 
29 
1 
1 
44 
Native 
Hawaiian or 
Other Pacific 
Islander 
2 
2 
0 
0 
4 
Black or 
African 
American 
47 
56 
1 
3 
107 
White 
209 
269 
87 
109 
674 
More Than One 
Race 
1 
3 
0 
1 
5 
Total 
273 
361 
91 
115 
840 
 
 
 
 

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29 
 
 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian / Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
4 
3 
0 
0 
7 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or 
African 
American 
4 
8 
0 
0 
12 
White 
43 
34 
9 
12 
98 
More Than One 
Race 
0 
1 
0 
1 
2 
Total 
51 
47 
9 
13 
120 
 
This distribution was derived from AAML1031 and AALL1331. 
 
 
 

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30 
9.0 
EVALUATION CRITERIA 
 
9.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., v5.02 and all subsequent iterations prior to 
version 6.0). 
 
9.2 
APAL2020SC Pediatric Specific Response Criteria for Patients with AML 
 
It is highly recommended to submit specimens to Hematologics for central response 
determination on this study (see Section 4.4.2). Hematologics offers comprehensive panels 
and is a leader in residual disease testing by flow cytometry. This testing is a free resource 
for all patients on this study. Capturing response to treatment is a critical component and a 
high priority for the APAL2020SC longitudinal data registry. 
 
Individual PedAL therapeutic sub-trials will collect response data for that specific trial and 
should not be reported here.  
 
The following response criteria refer to patients with known or suspected 
relapsed/refractory (including primary refractory) AML, patients with isolated myeloid 
sarcoma, patients with known or suspected relapsed/refractory ML-DS, and patients with 
known or suspected de novo or relapsed/refractory (including primary refractory) 
treatment-related AML (t-AML). These criteria are for patients who are not enrolled on 
PedAL sub-trials and should be used when completing baseline and follow-up CRFs.  
 
AML patients who have 0.1 - 5% leukemic blasts at the time of enrollment must meet 
criteria for MRD negative response (< 0.1% leukemic blasts) to be considered to achieve 
a CR/CRp/CRi. For these cases, residual leukemic blasts > 0.1% will be considered 
Persistent Disease. The definition of Prolonged Aplasia is the same for this group of 
patients. 
 
This study will collect response based on bone marrow flow cytometry AND bone marrow 
morphology. If flow cytometry evaluation is done by both a non-central lab and 
Hematologics, the Hematologics result will be used for response assessment. 
 
9.2.1 
Flow Cytometry Response Definitions 
 
Flow Complete Response (Flow-CR):  
Attainment of an M1 bone marrow (< 5% leukemic blasts) as determined by flow 
cytometry with no evidence of circulating blasts or extramedullary disease and 
with recovery of peripheral blood counts (ANC ≥ 500/µL and platelet count ≥ 
50,000/µL).  The CBC used for response assessment must be drawn on the day of 
the marrow or up to 14 days after bone marrow. There is no requirement for bone 
marrow cellularity. 
 

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31 
MRD Negative Flow-CR:  
Meets the above definition AND has < 0.1% leukemic blasts in the bone marrow 
by flow cytometry.  
 
Flow Complete Response with Partial Recovery of Platelet Count (Flow-
CRp):  
Attainment of an M1 bone marrow (< 5% leukemic blasts) as determined by flow 
cytometry and no evidence of circulating blasts or extramedullary disease and with 
recovery of ANC ≥ 500/µL without platelet recovery to 50,000/µL. The CBC used 
for response assessment must be drawn on the day of the marrow or up to 14 days 
after bone marrow. 
 
MRD Negative Flow-CRp:  
Meets the above definition AND has < 0.1% leukemic blasts in the bone marrow 
by flow cytometry.  
 
Flow Complete Response with Incomplete Blood Count Recovery (Flow-CRi):  
Attainment of an M1 bone marrow (< 5% leukemic blasts) as determined by flow 
cytometry and no evidence of circulating blasts or extramedullary disease and with 
ANC > 200/µL and/or platelet count > 20,000/µL without dependence on platelet 
transfusions (defined as: a platelet count > 20,000/µL AND no platelet transfusions 
x 5 days). The CBC used for response assessment must be drawn on the day of the 
marrow or up to 14 days after bone marrow. 
 
MRD Negative Flow-CRi:  
Meets the above definition AND has < 0.1% leukemic blasts in the bone marrow 
by flow cytometry.  
 
Flow Partial Response (Flow-PR):  
M2 bone marrow (5% to 25% leukemic blasts) and at least a 50% decrease in bone 
marrow leukemic blast percent from pre-treatment baseline. A repeat bone marrow 
aspiration within 14 days may be required to distinguish between a PR and 
increased blasts caused by bone marrow regeneration and is left to the discretion 
of the investigator.  
 
Flow Prolonged Aplasia:  
Hypoplastic bone marrow for ≥ 60 days and failure to recover a peripheral ANC > 
200/μL and a non-transfusion dependent platelet count > 20,000/μL not due to 
malignant infiltration or severe infection (defined as ≥ Grade 3). 
 
Flow Persistent Disease (Flow-PD):  
M3 bone marrow (> 25% leukemic blasts) or M2 bone marrow (5% to 25% 
leukemic blasts) with < 50% decrease in leukemic blast percent from pre-treatment 
baseline. Patients who had 0.1% to 5% leukemic blasts pre-treatment and do not 
achieve MRD negativity (< 0.1% leukemic blasts in the bone marrow) after 
treatment also are considered to have PD. 
 
Flow Relapsed Disease: 
A bone marrow evaluation that meets the definition of relapse in Sections 9.3.2, 
9.3.3 or 9.3.4, in a patient who achieved CR, CRp or CRi after enrollment on 
APAL2020SC. 

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32 
 
9.2.2 
Morphological Response Definitions 
 
Morphological Complete Response (Morph-CR):  
Attainment of an M1 bone marrow (< 5% morphologic leukemic blasts) with no 
evidence of circulating leukemic blasts or extramedullary disease and with 
recovery of peripheral blood counts (ANC ≥ 500/µL and platelet count ≥ 
50,000/µL). The CBC used for response assessment must be drawn on the day of 
the bone marrow evaluation or up to 14 days after bone marrow evaluation. There 
is no requirement for bone marrow cellularity. 
 
Morphological Complete Response with Partial Recovery of Platelet Count 
(Morph-CRp):  
Attainment of an M1 bone marrow (< 5% morphologic leukemic blasts) and no 
evidence of circulating leukemic blasts or extramedullary disease and with 
recovery of ANC ≥ 500/µL without platelet recovery to 50,000/µL. The CBC used 
for response assessment must be drawn either on the day of the bone marrow 
evaluation or up to 14 days after bone marrow evaluation. 
 
Morphological Complete Response with Incomplete Blood Count recovery 
(ped-morph-CRi):  
Attainment of an M1 bone marrow (< 5% morphologic leukemic blasts) and no 
evidence of circulating leukemic blasts or extramedullary disease and with ANC 
> 200/µL and/or platelet count > 20,000/µL without dependence on platelet 
transfusions (defined as: a platelet count > 20,000/µL AND no platelet transfusions 
x 5 days). The CBC used for response assessment must be drawn either on the day 
of the bone marrow evaluation or up to 14 days after bone marrow evaluation. 
 
Morphological Partial Response (Morph-PR):  
Bone marrow with 5-25% morphologic leukemic blasts and decrease of at least 
50% from pre-treatment baseline. A repeat bone marrow evaluation within 14 days 
may be required to distinguish between a PR and increased blasts caused by bone 
marrow regeneration and is left to the discretion of the investigator. 
 
Morphological Prolonged Aplasia:  
Hypoplastic bone marrow for ≥ 60 days and failure to recover a peripheral ANC > 
200/μL and a non-transfusion dependent platelet count > 20,000/μL not due to 
malignant infiltration or severe infection (defined as ≥ Grade 3). 
 
Morphological Persistent Disease (Morph-PD):  
M3 bone marrow (> 25% leukemic blasts) or M2 bone marrow (5% to 25% 
leukemic blasts) with < 50% decrease in leukemic blast percent from pre-treatment 
baseline. 
 
Morphological Relapsed Disease: 
Following achievement of Morph-CR/CRp/CRi while enrolled on APAL2020SC, 
emergence of > 5% morphologic leukemic blasts in the bone marrow OR absolute 
leukemic blast count greater than 1,000 per microliter in the peripheral blood OR 
biopsy or imaging (MRI/PET) proven extramedullary disease. 
 
 

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33 
9.3 
Relapse/Refractory Definitions for Patients with AML, ALL, and MPAL 
Individual PedAL therapeutic sub-trials will include definitions of relapsed and refractory 
disease for that specific trial.  
 
The following definitions for relapsed/refractory disease are used to determine eligibility 
for patients with AML, ALL, and MPAL for APAL2020SC. In addition, these definitions 
are for patients not enrolled on PedAL sub-trials and should be used when completing 
baseline and follow-up CRFs for APAL2020SC.  
 
9.3.1 
Refractory Disease 
9.3.1.1 
AML 
• 
Patients with newly diagnosed AML refractory to ≥ 2 induction 
attempts as evidenced by ≥ 1% blasts confirmed by multidimensional 
flow cytometry (MDF).   OR 
 
• 
AML in first relapse or subsequent relapse refractory to ≥ 1 
reinduction attempt as evidenced by ≥ 1% blasts MDF. 
 
9.3.1.2 
MPAL 
• 
Patients with newly diagnosed MPAL refractory to ≥ 1 induction 
attempts as evidenced by ≥ 25% blasts identified by morphology 
and/or MDF  OR 
 
• 
MPAL in first relapse or subsequent relapse refractory to ≥ 1 
reinduction attempt as evidenced ≥ 1% blasts confirmed by 
morphology and/or MDF. 
 
9.3.2 
Bone Marrow Relapse (AML, ALL, and MPAL) 
Patient has one or more of the following after having achieved remission: 
 
1. 
A single bone marrow sample showing ≥ 5% leukemic blasts by flow 
cytometry, FISH testing or other molecular method.    
 
2. 
A single bone marrow sample with at least two tests showing ≥ 1% leukemic 
blasts. Examples of tests include: 
• 
Flow cytometry showing leukemia ≥ 1% by multidimensional flow 
cytometry (MDF).  
• 
Karyotypic abnormality.  
• 
FISH abnormality identical to one present at diagnosis (must be above 
level of sensitivity of specific FISH probe. 
• 
PCR or NGS-based demonstration of validated leukemogenic lesion 
(e.g., fusion, mutation) in a CLIA-approved laboratory that matches 
initial diagnosis and is quantifiable as ≥ 1%. 
 
3. 
Two consecutive marrows (spaced at least 7 days apart) with at least two tests 
showing a one log increase of leukemic involvement with the second tests 
quantified as ≥ 0.1%.  Examples of tests include:  
• 
MDF in CLIA-approved laboratory. 
• 
PCR or NGS-based demonstration of validated leukemogenic lesion 
(e.g., fusion, mutation) that matches diagnosis and is quantifiable where 

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34 
the positive result is at or above the assay sensitivity and meets the 
criteria above (one log increase and second test quantified as ≥ 0.1%). 
 
9.3.3 
Extramedullary Relapse 
Extramedullary relapse is defined as biopsy proven extramedullary disease after 
documented CR following initial therapy. 
 
9.3.4 
CNS Relapse 
CNS relapse is defined as a patient having one of more of the following: 
1. A single CSF sample with CNS3 status (see Section 9.3.4.2) after a 
previous status of CNS 1. 
 
2. Clinical signs of CNS leukemia such as facial nerve palsy, brain/eye 
involvement, or hypothalamic syndrome (Rel-CNS3c). 
 
9.3.4.1 
Equivocal CNS Relapse 
Patient has a single CSF sample with CNS2 status.  
1. In the case of equivocal relapse, CSF evaluation should be repeated 
at least 1 week and at most 4 weeks later; for repeat CSF, flow 
cytometric testing and FISH (if a diagnostic FISH marker is 
available) should be sent. 
 
2. To convert to definitive relapse, the repeat CSF or clinical status 
must: 
• 
Meet criteria for CNS relapse as defined in Section 9.3.4. OR 
• 
Re-demonstrate CNS2 status, but with blasts confirmed by 
flow cytometry and/or FISH (Rel-CNS2) on CSF samples from 
consecutive lumbar punctures.  
 
9.3.4.2 
CNS Status Definitions 
CNS1 Disease 
CNS1 (negative) at diagnosis is defined as no blasts in cytospin CSF 
regardless of CSF WBC or RBC counts AND does not meet CNS3c 
criteria. 
 
CNS2 Disease  
CNS2 disease at diagnosis is defined as any one of the following:  
a) CNS2a: Blasts present in cytospin CSF with CSF WBC < 5/µL 
and CSF RBC < 10/µL (atraumatic tap) 
 
b) CNS2b: Blasts present in cytospin CSF with CSF WBC < 5/µL 
and CSF RBC ≥ 10/µL (traumatic tap) 
 
c) CNS2c: Blasts present in cytospin CSF with CSF WBC ≥ 5/µL 
and CSF RBC ≥ 10/µL (traumatic tap) in which the WBC/RBC 
ratio in the CSF is less than twice that in the peripheral blood 
(see calculation method below in Section 10.3.4.3).  
 
CNS3 Disease 
CNS3 disease at diagnosis is defined as any one of the following:  

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35 
a) CNS3a: Blasts present in cytospin CSF with CSF WBC ≥ 5/uL 
and CSF RBC < 10/uL (atraumatic tap). 
 
b) CNS3b: Blasts present in cytospin CSF with CSF WBC ≥ 5/uL 
in a traumatic tap (CSF RBC ≥ 10/uL) in which the WBC/RBC 
ratio in the CSF is twice or greater that in the peripheral blood 
(see calculation method below in Section 10.3.4.3).  
 
c) CNS3c: Clinical signs of CNS leukemia (such as facial nerve 
palsy, brain/eye involvement or hypothalamic syndrome) OR 
radiographic evidence of an intracranial or intradural mass 
consistent with a chloroma. Retinal hemorrhage and extra-ocular 
orbital masses are not considered CNS leukemia.  
 
9.3.4.3 
Method of Evaluating Initial Traumatic Lumbar Puncture 
If the patient has leukemic cells in the peripheral blood and the lumbar 
puncture is traumatic (CSF RBC ≥ 10/µL) and CSF contains WBC ≥5/uL 
and blasts on cytospin, the following algorithm should be used to 
distinguish CNS2c and CNS3b.  
 
CNS2c: 
CSF WBC < 2 x Blood WBC 
CSF RBC 
     Blood RBC 
 
CNS3b 
CSF WBC ≥ 2 x Blood WBC 
CSF RBC 
     Blood RBC 
 
Example of CNS3b: CSF WBC = 60/μL; CSF RBC = 1,500/μL; blood 
WBC = 46,000/μL; blood RBC = 3 X 106 /μL:  
 
 60  = 0.04 which is ≥ 2x 46000  = 0.015 
1500  
              3.0 X 106 
 
 
 
 
 
 
 

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36 
 
10.0 
PATHOLOGY GUIDELINES 
 
10.1 
Patients with AML and ALL 
Immunophenotyping Studies 
 
Morphologic assessment and immunophenotyping studies are often done at the local 
institution as part of the initial diagnostic work-up of acute leukemia. Immunophenotyping 
studies are essential in confirming diagnosis and distinguishing AML from ALL.  
 
 
All pertinent diagnostic information should be included in the bone marrow pathology 
report (to include the institutional morphologic assessment, immunophenotyping and 
cytochemistry). In addition to the central immunophenotyping, these local results will be 
captured in this study as they are contributory to the diagnosis and study of ALL. 
 
The 2016 World Health Organization (WHO) classification requires assessment of a 
certain set of cytoplasmic and surface antigens, with or without use of cytochemistry to 
define myeloid, lymphoid or mixed/ambiguous lineage.  
 
We strongly encourage the use of the following markers as a minimum, especially in 
difficult cases to further exclude the possibility of mixed phenotype acute leukemia (see 
Table 10.1):  
 
1. MPO (by cytochemistry, flow cytometry or immunohistochemistry) 
2. Cytoplasmic CD3 by flow cytometry 
3. CD19 (by flow cytometry), and at least 2 additional B-cell markers such as 
CD10, CD79a or cytoplasmic CD22. 
 
-At least 3 markers of monocytic lineage: CD11c, CD14, CD64, lysozyme (by 
flow or immunohistochemistry) or NSE cytochemistry. 
 
- Additional markers as needed (example: CD56 will help exclude the rare Blastic 
Plasmacytoid Dendritic Cell Leukemia) 
 
- If Early T-cell Precursor Lymphoblastic leukemia (ETP) is suspected, CD1a, CD4, CD8, 
CD117, CD33, CD13, CD65 and CD11b should be included. These markers should also 
be used for the work up of Mixed Phenotype Acute Leukemia (MPAL). 
 
In this study, AML blasts will be classified based upon the 2016 WHO morphologic, 
immunophenotypic, and genetic criteria.12 
 
Table 10.1 
ASSIGNMENT OF LINEAGE IN ACUTE LEUKEMIA 
Lineage 
Criteria 
Myeloid lineage 
•Myeloperoxidase (by flow cytometry, immunohistochemistry or cytochemistry) 
OR 
•Monocytic differentiation (express at least 2 of the following: CD11c, CD14, 
CD64, lysozyme or NSE) 
T lymphoblastic 
•Cytoplasmic CD3 by flow cytometry with antibodies to CD3 epsilon chain 
OR 
•Surface CD3 (rare) 

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37 
B lymphoblastic 
•Strong CD19 and strong expression of at least one of the following: CD79a, 
cytoplasmic CD22 or CD10 
OR 
•Weak CD19 and strong expression of at least 2 of the following: CD79a, 
cytoplasmic CD22, CD10  
 
 
10.2 
Patients with Myeloid Sarcoma (Chloroma):  
If touch preps are prepared from the tumor, the institutional pathologist should 
distribute/triage order(s) for FISH to be performed accordingly (e.g., KMT2A, RUNX1T1-
RUNX1, CBFB). 
 
10.3 
Consultation Available  
If a consultation for a difficult case is desired, this can be arranged on a case-by-case basis 
only. Please contact the study pathologist (Dr. Samir Kahwash) to request a consult and 
verify what is needed for the consultation prior to submitting pathology materials. The 
institution may send pathology materials (stained and unstained slides from bone marrow 
and peripheral blood and pathology, bone marrow, flow cytometry reports including copies 
of blast gate and dot plots of markers) and pertinent cytogenetics data to the study 
pathologist. A fee for this service may be charged. Copies of consult reports will be sent to 
the submitting institution. 
 
Materials sent for consultation must be shipped using the institution’s courier account to: 
 
  
  
  
  
  
 
 
 

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38 
 
 
11.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
11.1 
Reporting 
 
Demography Monitoring 
Required submission of patient demographic data to NCI for this study will be submitted 
automatically via OPEN. 
 
 
 
 
 

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39 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations require sponsors to select qualified investigators. National 
Cancer Institute (NCI) policy requires all individuals contributing to NCI-sponsored trials to register with 
their qualifications and credentials and to renew their registration annually. To register, all individuals must 
obtain Cancer Therapy Evaluation Program (CTEP) credentials necessary to access secure NCI Clinical 
Oncology Research Enterprise (CORE) systems. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository (RCR). The RCR is a 
self-service online person registration application with electronic signature and document submission 
capability. 
RCR utilizes four person registration types that are applicable to this study. 
• 
Investigator (IVR) — MD, DO, or international equivalent; 
• 
Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
• 
Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; and 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, 
training, employment, 
licensure, and certification) 
 
 
 
 
GCP training  
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Selection as the treating, credit, or consenting person in OPEN; 
• 
Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
• 
Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).  
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting or treating investigator in OPEN, or as the CI on the DTL must be rostered at the 
enrolling site with a participating organization.  
 

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40 
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. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
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 COG, and 
protocol number (*insert study number*). 
• 
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.) 
 
Protocol-Specific Requirements For APAL2020SC Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU 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. 
 
Checking Your 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 site’s 5-character CTEP Institution Code and click on Go. 
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. 

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41 
 
Delegation of Task 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 describes DTL task assignments, CI signature, and CTEP registration 
requirements, as well as include a Master Task List.  
 
Data Submission / Data Reporting 
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: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as a Non-Investigational New Drug 
(IND)/Non-Treatment (NINT),  Non-Physician Investigator (NPIVR), or Investigator 
(IVR); and 
o Rave Read Only or RAVE SLA role must have at a minimum an Associates (A) 
registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. NINTs will only have write access in Rave for studies flagged for NINT 
participation. 
 
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 to the study 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 

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42 
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 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.   
 
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. 
This study does not use the Rave Calendaring functionality, and therefore the DQP Delinquent 
Forms module will not include details for this study, and the DQP Summary table on the Rave 
Home page will display N/A for the Total Delinquencies summary count.  
 
 
 

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43 
 
APPENDIX II: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY APAL2020SC 
(for children from 7 through 13 years of age) 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study to test bone marrow and blood in children with leukemia 
that has come back after treatment or is difficult to treat. 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group 
and is being done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because you 
have leukemia other treatments did not get rid of the leukemia. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are 
trying to learn more about how to treat the kind of leukemia that you have. 
 
 
4. What will happen to me in the study? Children who are part of this study will have their bone 
marrow and blood collected to see if the leukemia has certain features. Knowing that could help us 
decide what medicine might be best to treat the leukemia. If you are part of this study, we will test 
your bone marrow and blood to see if the leukemia has certain features that could help us decide 
what medicine might be best to treat the leukemia. The bone marrow and blood will be taken when 
you are having tests done for your regular medical care. You will not have extra bone marrow 
procedures or blood draws. The study will also collect data about your treatment for leukemia and 
how well it worked to get rid of the leukemia. 
 
Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you is that your doctors can use the results of the 
tests to find a medicine that may cause your leukemia to stop growing. The information we collect 
for this study may help children with leukemia and other cancers. But we don’t know for sure if 
there is any benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” A risk to you from being in this study is the very small chance that someone who 
does not have permission gets information about you, like your name, address or phone number. 
We will be working hard to make sure this does not happen. There may be risks that we don’t know 
about. 
 
5. Do I have to be in the study? Your family can choose to be part of this study or not. Your family 
can also decide to stop being in this study at any time once you start. Make sure to ask your doctors 
if you have any questions.  
 
6. Optional blood or bone marrow request. We are asking your permission to keep your blood or 
bone marrow for optional banking. We want to see if there are ways to tell how the cancer will 
respond to treatment. These samples would be taken as leftovers from other standard tests, so 
there would be no extra procedures. You can still take part in this study even if you don't allow us 
to keep your samples for research. 
 
 

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44 
INFORMATION SHEET REGARDING RESEARCH STUDY APAL2020SC 
(for children from 14 through 17 years of age) 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study to test bone marrow and blood in children with leukemia 
that has come back after treatment or is difficult to treat. 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group 
and is being done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because you 
have leukemia other treatments did not get rid of the leukemia. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are 
trying to learn more about how to treat the kind of leukemia that you have. 
 
 
4. What will happen to me in the study? Children and teens who are part of this study will have 
their bone marrow and blood collected to see if the leukemia has certain features. Knowing that 
could help us decide what medicine might be best to treat the leukemia. If you are part of this study, 
we will test your bone marrow and blood to see if the leukemia has certain features that could help 
us decide what medicine might be best to treat the leukemia. The bone marrow and blood will be 
taken when you are having tests done for your regular medical care. You will not have extra bone 
marrow procedures or blood draws. The study will also collect data about your treatment for 
leukemia and how well it worked to get rid of the leukemia. 
 
Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you is that your doctors can use the results of the 
tests to find a medicine that may cause your leukemia to stop growing. The information we collect 
for this study may help children with leukemia and other cancers. But we don’t know for sure if 
there is any benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” A risk to you from being in this study is the very small chance that someone who 
does not have permission gets information about you, like your name, address or phone number. 
We will be working hard to make sure this does not happen. There may be risks that we don’t know 
about. 
 
5. Do I have to be in the study? Your family can choose to be part of this study or not. Your family 
can also decide to stop being in this study at any time once you start. Make sure to ask your doctors 
if you have any questions.  
 
6. Optional blood or bone marrow request. We are asking your permission to keep your blood or 
bone marrow for optional banking. We want to see if there are ways to tell how the cancer will 
respond to treatment. These samples would be taken as leftovers from other standard tests, so 
there would be no extra procedures. You can still take part in this study even if you don't allow us 
to keep your samples for research. 
 
 

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45 
APPENDIX III: SAMPLES FOR USE IN PEDAL THERAPEUTIC SUB-TRIAL CORRELATIVE 
BIOLOGY STUDIES 
 
Specimens collected via APAL2020SC may be used for the correlative biology objectives contained within 
each sub-trial outlined below.  
 
ITCC101-APAL2020D: A Randomized Phase 3 Trial Of Fludarabine/Cytarabine/Gemtuzumab 
Ozogamicin With Or Without Venetoclax In Children With Relapsed AML 
 
Objective: 
The correlative biology objective for the sub-trial is to describe biomarkers of response to FLA+GO 
with and without venetoclax combination including BH3 profiling, genetic data obtained by NGS, 
and in vitro drug sensitivity to venetoclax. 
 
Sample requested to be collected via APAL2020SC: 
 
• 
Ampule of 10 x 106 viable frozen blasts- St. Jude for BH3 protein dependency profiling 
• 
107 frozen mononuclear cells or 1 microg RNA- Erasmus for molecular MRD testing  
• 
Ampule of 10 x 106 viable frozen blasts- Essen for BH3 gene expression profiling 
• 
Ampule of 40 x 106 viable frozen blasts- PMC for drug sensitivity testing 
 
Samples will be shipped from BPC to the following locations: 
 
Molecular MRD (ISO certified lab) 
Vincent van der Velden, immunologist,  
Erasmus Universitair Medisch Centrum  
Wytemaweg 80, 3015GN Rotterdam, Netherlands 
E-mail: v.h.j.vandervelden@erasmusmc.nl 
Phone: +31 10 704 0 704 
 
Central bone marrow morphology review, BH3 family gene expression profiling  
AML-BFM Reference Laboratories  
171 Virchowstraße 
45147 Essen Germany 
E-mail: nils.vonneuhoff@uk-essen.de 
Phone: +49 201 723 1055   
 
BH3 dependency profiling 
Paul Mead, PhD 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place, Memphis, Tennessee, 38105 USA 
E-mail: paul.mead@stjude.org 
 
In vitro drug sensitivity 
Pediatric Oncology Research lab  
Prof dr ML den Boer 
Princess Máxima Center, Utrecht, Netherlands 
E-mail: m.l.denboer@prinsesmaximacentrum.nl 
 

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46 
ITCC109-APAL2020K: A Phase 1 Trial of Menin-Inhibitor Ziftomenib in Combination with 
Chemotherapy for Children with Relapsed/Refractory KMT2A-r/NUP98-r/NPM1-m Acute 
Leukemia  
  
Objective: 
The correlative biology objective for the sub-trial is to perform pharmodynamic assays related to 
the activity of ziftomenib. Molecular MRD and in vitro drug sensitivity testing from baseline 
samples collected on APAL2020SC will be performed at the laboratories listed below. 
 
Specimens collected via APAL2020SC may be used for the correlative biology objectives 
detailed below: 
 
• 
One vial of 1 x 106 frozen nucleated white blood cells or 5 microg RNA- for molecular MRD 
testing to be performed at the University of Padova 
• 
One vial of 2 x 107 frozen nucleated white blood cells or 2 vials of 1 x 107  – for in vitro drug 
sensitivity testing at the Princess Maxima Center 
 
Samples will be shipped to the following locations: 
 
FOR EUROPE/MÁXIMA TERRITORY  
 
Molecular MRD (ISO certified lab)  
Martina Pigazzi 
University of Padova, Department for Woman and Child health  
Onco-Hematology Clinic and Lab 
Via Guistiniani, 3 
35128 Padova PD, Italy 
E-mail: martina.pigazzi@unipd.it 
 
 
In vitro drug sensitivity profiling and RNA sequencing 
Pediatric Oncology Research lab  
Olaf Heidenreich 
Princess Máxima Center, Utrecht,  Netherlands 
E-mail: o.t.heidenreich@prinsesmaximacentrum.nl 
 
 
 

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47 
 
APPENDIX IV: RESPONSE CRITERIA FOR MDS 
 
The MDS response criteria are derived from the revised MDS International Working Group (IWG) 
Criteria.13 
Response 
IWG 2023 Definitions 
Complete 
Remission (CR) 
BM: < 5% myeloblasts;* dysplasia may persist 
PB: Hb 10 g/dL, platelets 100 × 109/L; neutrophils 1.0 × 109/L; blasts 0%† 
CR equivalent* 
Patients with < 5% BM blasts at baseline 
BM: < 5% myeloblasts*; dysplasia may persist 
PB: Hb 10 g/dL, platelets 100 × 109/L; neutrophils 1.0 × 109/L; blasts 0%† 
Full cytogenetic clearance of baseline abnormalities (complete cytogenetic response) 
Partial Response 
(PR) 
All CR criteria except: 
BM blasts decreased by 50% over pretreatment but still 5% 
Cellularity and morphology not relevant 
CR with 
limited count 
recovery (CRL 
- CRunilinage and 
CRbilineage) 
BM: < 5% myeloblasts;* dysplasia may persist 
PB: blasts 0%† 
CRunlineage: PB, not meeting CR but only 1 of the following: Hb 10 g/dL; platelets 100 × 
109/L; neutrophils 1.0 × 109/L 
CRbilineage: PB, not meeting CR but only 2 of the following: Hb 10 g/dL; platelets 100 × 
109/L; neutrophils 1.0 × 109/L 
CR with partial 
hematologic 
recovery (CRh) 
BM: < 5% myeloblasts;* dysplasia may persist 
PB: Not meeting criteria for CR or CRL, no Hb threshold required, platelets 50 × 109/L; 
neutrophils 0.5 × 109/L; blasts 0%† 
Hematologic 
Improvement (HI) 
HI defined according to IWG 2018 response criteria: 
Not meeting criteria for CR (or CR equivalent) or CRuni or CRL 
HIerythroid (HI-E) 
HIplatelets (HI-P) 
HIneutrophils (HI-N) 
Overall Response 
Rate (ORR) 
ORR = CR (or CR equivalent)* + PR + CRL + CRh + HI 
No response 
Not meeting criteria for CR (or CR equivalent)*, PR, CRL, CRh, or HI‡ 
Not evaluable 
All registered patients should be reported in the denominator of response 
assessment analyses in line with the intention-to-treat principle. This category may 
include patients yet to have a response assessment, suffering early death, exiting 
the study early, or those with a technically suboptimal BM sample precluding 
assessment
Cytogenetic 
response¶ 
Complete: disappearance of the chromosomal abnormality without appearance of new 
ones. 
Partial: 50% reduction of the chromosomal abnormality. 
Progressive 
Disease (PD)  
Fulfilling any of the criteria below:#,**,†† 
Disease progression by blasts 50% relative increase in blasts and absolute increase of 
blast percentage by at least 5% from pretreatment sample taken before current line of 
therapy. 
Disease progression by worsening cytopenia: new, repeated (more than once and 

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48 
 
intercurrent illness (eg, sepsis, gastrointestinal tract bleed) or treatment effect, in the 
absence of HI of at least one other blood lineage as defined above. 
Progression to AML: 50% increase in blasts from baseline assessment to 20% blasts. 
Disease  
relapse 
Fulfilling any of the criteria below:# 
Disease relapse by blasts: absolute and relative increase in BM blasts by at least 5% and 
50%, respectively, from prior assessment, or reappearance of blasts in the blood, or 
development of extramedullary disease (myeloid sarcoma). 
Disease relapse by worsening cytopenias: decrement in one or more blood cell lineage 
counts by 50% from maximum remission/response levels for platelets or absolute 
neutrophil count or a reduction of Hb by 1.5 g/dL combined with an absolute reduction 
in the same lineage(s) as follows: Hb < 10 g/dL, platelets < 100 × 109/L, or absolute 
neutrophils < 1.0 × 109/L or repeated (more than once and separated by 7 days) need 
for RBC or platelet transfusions which are not related to acute intercurrent illness (eg, 
sepsis, gastrointestinal tract bleed) or treatment effect; in the absence of HI of at least 
one other blood lineage as defined above. 
*Patients require 5% blasts before treatment initiation to be considered evaluable for CR, PR, CRh, 
or CRL. For patients with < 5% blasts who have HR-MDS owing to adverse cytogenetics and/or 
severe cytopenias, full cytogenetic clearance (complete cytogenetic response) and blood counts that 
meet CR criteria are considered CR equivalent but should be reported separately. Full trilineage 
count recovery is defined as Hb 10 g/dL, platelets 100 × 109/L, and ANC 1.0 × 109/L independent 
of baseline PB. Given that molecular clearance has not been validated prospectively, it was not used 
for CR definition by the 2023 IWG. 
¶If cytogenetic analyses fail, repeating cytogenetics during a subsequent response assessment is 
recommended. MRD assessment in MDS is insufficiently validated at this time as a surrogate for OS. 
MRD-negative response can be reported as a provisional response category, and clinical trial protocols 
should predefine what techniques are used to detect MRD and what cutoffs are considered to define an 
MRD response. 
 
 
 

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49 
APPENDIX V: RESPONSE CRITERIA FOR JJML 
 
The JMML response criteria were developed by an international consensus panel.14 
 
Table 1: Variables for evaluation of response to therapy in JMML 
Variables for 
Response      
Definition of response 
Definition of disease 
progression or relapse  
(applicable to all patients) 
Assessment of 
CR and PR is 
feasible if the 
following are 
present before 
therapy 
Requirement 
for CR for each 
variable (vCR) 
Requirement for PR for 
each variable (vPR) 
Requirement for PD for each 
variable (vPD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1) BM blasts 
≥ 5% 
< 5% 
Decreased by ≥50% over 
pre-treatment but still 
≥5% 
≥ 20% 
 
 
 
 
 
 
 
2) Spleen size# 
 
a) Clinical  
evaluation 
or 
 
 
≥2 cm under the 
costal margin  
 
 
No 
splenomegaly 
 
 
50% decrease by cm under 
the costal margin  
 
 
Increase by ≥ 50% if baseline < 
10cm from under the costa 
margin  
or > 30% if baseline >10 cm 
 
 
 b) Sonography 
Length of 
spleen ≥ 150% 
of upper limit of 
normal range  
 
No 
splenomegaly 
> 25% decrease by length, 
but still splenomegaly  
 
Increase by ≥ 25% of length 
 
3) 
Extramedullary 
disease# 
Extramedullary 
leukemic 
infiltration   
No evidence of 
extramedullary 
leukemic 
infiltration  
 
Worsening or new lesions of 
extramedullary leukemic 
infiltration 
 
 
 
 
 
 
4) Cytogenetic 
response 
Somatic 
cytogenetic 
abnormality 
detected 
Normal 
karyotype 
- 
Reappearance or additional 
acquirement of cytogenetic 
abnormalities 
5) Molecular 
response 
Somatic genetic 
anomalies 
detected ** 
Absence of 
somatic genetic 
anomalies 
- 
Reappearance or additional 
acquirement of JMML-specific 
somatic gene abnormalities  
 
CR: complete response, PR: partial response, PD: progressive disease, WBC: white blood cell, PB: 
peripheral blood, BM: bone marrow 
*Myeloid precursors include promyelocytes, myelocytes, and metamyelocytes. The myeloid and erythroid 
precursors and blasts in PB are given as % of the total nucleated cells in PB (WBC including erythroblasts).  
Clinical variables   

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50 
**in NF-1, PTPN11, NRAS, KRAS, RRAS2, or CBL, thus the mutation are thought to be initiating. In patients 
with germ-line NF-1, PTPN11 or CBL mutation, only acquired mutations can be evaluated for response and 
relapse after therapy. The germ-line mutation remains even if patients achieved complete molecular 
response. The molecular response will be determined using the “JMML Mutant Allele Burden” assay. 
Criteria for progression including WBC, platelet count and spleen size cannot be used in the setting of an 
active infection. 
#Extramedullary disease includes infiltration of skin, lung, and very rarely cranial nerves or central nervous 
system. 
 
 
Table 2: Definition of response following therapy other than HSCT in JMML 
 
Clinical remission status: 
parameter 1-6 of table 1 
Genetic remission status: 
parameter 7-9 of table 1 
Clinical 
complete 
remission (cCR) 
 
Patient fulfills the criteria of CR of 
all applicable clinical variables 1-6 
of table 1  
The response parameters must be 
maintained for at least 4 weeks. 
Genetic 
complete 
remission 
(gCR) 
 
Defined if the patient shows a 
normal karyotype and absence 
of acquired mutations in 
PTPN11, NF-1, NRAS, KRAS, or 
CBL.  
Clinical partial 
remission (cPR) 
 
Defined if the patient does not 
fulfill the criteria of cCR, but vPR 
was achieved in at least one of 
clinical variables (1 – 6) and none 
of clinical variables showed vPD. 
- 
- 
Clinical stable 
disease (cSD) 
 
Defined if the patient does not 
fulfill the criteria of cCR and cPR, 
but none of the parameter 
showed vPD. 
Genetic 
stable 
disease (gSD) 
Defined if the patient does not 
fulfill the criteria of gCR, but 
none of the genetic 
parameters (7-9) showed vPD. 
Clinical 
progressive 
disease (cPD) 
Defined if any of the parameters 
1-6 showed vPD. 
Genetic 
progressive 
disease 
(gPD) 
Defined if any of the 
parameters 7-9 showed vPD. 
Clinical relapse 
(cRel) 
 
Defined if any of the parameters 1 
- 6 showed vPD after the 
achievement of cCR or cPR. 
Genetic 
relapse 
(gRel) 
 
Reappearance of an abnormal 
karyotype  
and/or  
mutation of genes related 
with JMML if previously 
undetected, and/or  
(only for patients after HSCT) 
increase in recipient 
chimerism with at least 10% of 
autologous cells and > 50% 
increase above the base line.  
**In patients with germ-line NF-1, PTPN11 or CBL mutation, the germ-line mutation remains even if 
patients achieved a genetic complete remission. 
 
Table 3: Evaluation of the overall response to therapy based on the clinical (c) and genetic (g) 
remission status as defined in Table 2 
 
Genetic remission status 
  
No 
genetic 
marker 
gCR 
gSD 
gPD/cRel 
Clinical 
cCR 
CR 
CR 
PR 
PD/Rel 

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51 
remission 
status 
cPR 
PR 
CR* 
PR 
PD/Rel 
cSD 
SD 
CR* 
SD 
PD/Rel 
cPD/cRel 
PD/Rel 
(CR**) 
PD/Rel 
PD/Rel 
CR: complete remission, PR: partial remission, SD: stable disease, PD: progressive disease, Rel: relapse. 
*It is conceivable that a patient with complete remission as indicated by genetic studies has persistent 
splenomegaly or leukocytosis from other causes such as infections despite of remission of JMML  
**It is unlikely that a patient has sign of progressive disease of JMML despite a genetic complete 
remission. In such a patient, any possible errors of genetic examinations, or other disorders which 
cause JMML like clinical features, should be excluded. 
 
 

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52 
 
 
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