A Phase 1/ 2 Study of BAY 1895344 (Elimusertib, NSC#810486) in Pediatric Patients With Relapsed or Refractory Solid Tumors
Phase: PHASE1
Conditions: Recurrent Alveolar Rhabdomyosarcoma, Recurrent Ewing Sarcoma, Recurrent Lymphoma, Recurrent Malignant Solid Neoplasm, Refractory Alveolar Rhabdomyosarcoma, Refractory Ewing Sarcoma, Refractory Lymphoma, Refractory Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
elizabeth.fox@stjude.org 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Research 
Institute  
Mailstop: JMB 9 
1900 9th Avenue 
Seattle, WA 98101 
P 206 884 1107 
doug.hawkins@seattlechildrens       
.org  
 
 
 
PEP-CTN Operations Data & 
Statistics Center 
800 Royal Oaks Drive 
Suite 210  
Monrovia, CA 91016 
 
P 626 241 1500 
F 626 445 4334 
 
 
A National Cancer Institute-  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
     
 
i 
 
 
April 15, 2022 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Please find attached Amendment #1 to PEPN2112, A Phase 1/ 2 Study of BAY 1895344 
(elimusertib, IND#
, NSC#810486) in Pediatric Patients with Relapsed or Refractory 
Solid Tumors. 
 
The primary purpose of this amendment is to provide clarifications to the eligibility criteria. 
This amendment also provides updates to sample processing and shipping instructions. 
 
Administrative changes have been made; specific changes are detailed in the Summary of 
Changes table below. Minor administrative updates (such as the correction of typographical 
errors, spelling, or updates to the numbers of referenced sections) are tracked in the protocol 
but not specified. 
 
Please contact us if you have any further questions. 
 
Sincerely, 
 
Samuel Baird, MPH, Protocol Coordinator (for) 
 
Michael Ortiz, M.D., PEPN2112 Study Chair, and 
Brenda Weigel, M.D., PEP-CTN Chair 
Elizabeth Fox, M.D., PEP-CTN Vice Chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 PEPN2112 
ii 
SUMMARY OF CHANGES: PROTOCOL 
In accordance with the above discussion, the following specific revisions have been made to the protocol. Additions are in 
boldfaced font and deletions in strikethrough font. 
# 
Section 
Comments 
1.  
Throughout 
Updated version date. 
2.  
Title Page 
Updated amendment number 
3.  
Table of 
Contents 
Updated on repagination.  
4.  
Cover Page 
Updated CTSU protocol template language. 
5.  
Study 
Committee 
• 
Included study pathologist, study pharmacist, updated Study RN and included COG PEP-
CTN research coordinator.  
• 
Included “PEP-CTN” next to the COG PEP-CTN pharmacist for consistency with all 
other COG PEP-CTN staff. 
6.  
Abstract 
Deleted the word “double” and replaced with the word “single” in the sentence… 
“Ataxia telangiectasia and Rad3 related (ATR) protein kinase is a key regulator involved in 
repairing single stranded DNA breaks, particularly secondary to oncogenic replication fork stress,” 
as double had been included in error. 
7.  
3.0 
• 
Ensured Section 3 is updated per the most recently approved PEP-CTN template. 
• 
Updated CTSU protocol template language for patient enrollment. 
• 
Removed screening procedures language that was originally included in error. 
8.  
4.1.5.1; 
4.1.5.2 
• 
Revised sentence for Part A and B3 eligibility, to be more precise and less ambiguous 
“Any (non-CNS primary) solid tumor including lymphoma with inactivating alterations 
(monoallelic or biallelic) mutation of any of the DNA Damage Repair (DDR) genes:” 
• 
Included note: “Please note that a FISH showing FOXO1 breakapart is NOT sufficient 
for eligibility onto this cohort since it cannot distinguish between FOXO1 partners” 
for both parts A and B eligibility. 
9.  
4.1.6.1 
• 
Replaced the word “considered” with “categorized”, as this is more precise language. 
10. 
5.2.1 
• 
Ensured that the eligibility criteria referenced for ANC and platelets are consistent with 
section 4.1.11.1. Removed ANC > 1000/μL and Platelets > 100,000/μL and replaced with 
ANC ≥ 1000/μL and Platelets ≥ 100,000/μL. 
11. 
5.6; 5.7 
• 
Removed the word “received” for those patients on Part B who are greater than or equal to 
18, as it was erroneously placed there in the previous protocol version. 
• 
In the Cycle 1 TDM, ensured that observations g, f and h are also included in Day 1, 
Cycle 1, as this is consistent with the observation table in section 8.1. 
12. 
5.7 
• 
Removed weekly vital signs and medication diary as a requirement for subsequent cycles, 
as they are only needed weekly in Cycle 1. 
• 
Clarified footnote for CBCs in subsequent cycles to be obtained within 72 hours before the 
start of each cycle and ensured that CBC footnote is consistent with footnote for CBCs in 
section 8.1. This includes that patient who experience a dose reduction as a result of a 
DLT attributable to BAY 1895344 (elimusertib) will be required to have CBCs 
performed weekly. Additionally, CBC will only be required before the start of cycles 
2+ and on day 15 of cycles 2+. 
• 
Ensured observations are consistent with the observation table in section 8.1 and included 
additional observations for the end of therapy in Cycles 2 +, where history, physical 
exam, height, weight and BSA and vital signs and optional correlative studies were 
included and included end of therapy knee x-ray that is required if not already taken 
within the last month of therapy. 
13. 
8.1 
• 
Removed weekly observations for medications diary, CBCs and vitals in Cycles 2+, to be 
consistent with changes made in the TDMs. 
• 
Revised schedules for tumor samples to be consistent with sections 8.3.1-8.3.3. 

 
 
 PEPN2112 
iii 
# 
Section 
Comments 
• 
Moved footnote 7 to be in the pre-study column for CBC and serum chemistry 
observations, as this is more appropriate.  
• 
Added clarifying information to the knee x-ray observation that it is also required at 
the end of study treatment, if not already obtained within the last month of therapy. 
14. 
8.3.1.4 
Removed the word “archival” from the Tumor Tissue for WGS transmittal form, as the form found 
in RAVE will be revised to also remove the word “archival”. 
15. 
8.3.2 
In the description of the R-loop and PGDB5 study, removed reference to obtaining samples that 
are post treatment, as this is inconsistent with the sample schedule that only require one, pre-
therapy sample to be submitted.  
16. 
8.3.1; 8.3.2; 
8.3.3 
Including clarifications to the handling and processing information for optional tumor samples.  
17. 
8.3.6 
Updated archival tumor tissue for biobanking labelling and shipping instructions.  
18. 
8.3.3.4 
Updated shipping information for Tumor Tissue for Immunohistochemistry pH2AX, pKAP1 and 
pATR. 
19. 
8.3.4.1 
Clarified that ctDNA samples are to be collected “after enrollment, but before treatment” as 
opposed to “at time of enrollment”. 
20. 
8.3.4.2 
• 
Edited language to specify tube type preferences for collection of ctDNA samples. 
• 
Included sample labelling instructions, as they were not previously added. 
21. 
8.3.4.3 
Clarified centrifuging temperature, excursion temperature and processing of ctDNA samples. 
22. 
8.3.4.4 
Clarified shipping information for ctDNA samples, that were not previously included. 
23. 
8.5.4 
• 
Clarified that PK samples should be centrifuged for 15 minutes and not 10 minutes. 
• 
Clarified that plasma samples should be transferred “…into two separate cryovials or 
small (2-4) mL polypropylene screw-capped tubes,” as this was not previously 
included. 
24. 
8.5.6 
Included clarifying language that a copy of the PK worksheets for A or B will be submitted with 
PK samples to the receiving lab and that they will also be uploaded into RAVE. 
25. 
8.7 
Included that a knee x-ray is also required at the end of study treatment if it has not already been 
conducted within the last month of therapy. This is consistent with the observation table in section 
8.1 and was erroneously left out of the previous version of the protocol.  
26. 
Appendix I 
• 
Updated CTSU protocol template language for IRB approval. 
• 
Updated CTSU protocol template language for Submitting Regulatory Documents 
• 
Updated CTSU protocol template language for Data Submission/ Data Reporting 
• 
Updated CTSU protocol template language for Data Quality Portal 
27. 
Appendix 
VII 
Included optional tumor tissue to the youth information sheets, because it was not previously 
included due to oversight. 
28. 
Appendix X 
For PK sample 13, corrected day the sample is taken from day 1 to day 10 and the window for 
obtaining the sample from 15 to 30 minutes. 
29. 
Appendix XI  Included Dose given line for Cycle 1, Day 1, as it was erroneously left out of the previous version 
of the protocol. 
30. 
Appendix 
VIII;  
• 
Revised quantity of blood for ctDNA samples being obtained from ~5 10mL to just 
~10mL, upon request by receiving lab PI. 
• 
Included archival tumor tissue samples for biobanking, as it was not previously included. 
31. 
Appendix IX 
• 
Included pH2AX, pKAP1 and pATR Tumor Tissue, archival tumor tissue for biobanking, 
and pharmacokinetic studies into the appendix, as it was not previously included.  
• 
Revised quantity of blood being obtained. 
 

 
 PEPN2112 
Version Date: 04/15/2022 
 
 Page 1 
 
 
 
Activated: 
12/03/2021 
Version Date: 
04/15/2022 
Closed: 
 
Amendment: 
1 
 
 
 
 
PEPN2112 
 
A Phase 1/ 2 Study of BAY 1895344 (elimusertib, IND#
 NSC#810486) in Pediatric Patients with Relapsed 
or Refractory Solid Tumors  
 
Lead Organization: COG Pediatric Early Phase Clinical Trials Network (PEP-CTN) 
 
NCI Supplied Agent: BAY 1895344 (elimusertib) (NSC# 810486, IND# 
  
 
 
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. 
 
 
STUDY CHAIR 
 
Michael V. Ortiz, MD 
Memorial Sloan Kettering Cancer Center 
Phone: (212) 639-6057 
E-mail: ortizm2@mskcc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 PEPN2112 
Version Date: 04/15/2022 
 
 Page 2 
CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at http://www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU to receive 
further instruction and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-CTSU for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN) which can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol must be downloaded from the protocol-specific Web page of the CTSU 
Member Web site located at https://www.ctsu.org. Access to the CTSU members’ website is managed through the 
Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires user log on with CTEP-IAM username and password. 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 CTSU RSS. 
For clinical questions (ie, patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (ie, 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. 
 
 

 
 
 PEPN2112 
Version Date: 04/15/2022 
 
 Page 3 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
8 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development in Pediatric Population 
9 
2.2 
Preclinical Studies 
9 
2.3 
Adult Studies 
19 
2.4 
Pediatric Studies 
21 
2.5 
Overview of Proposed Pediatric Study 
21 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
23 
3.1 
Current Study Status 
23 
3.2  
IRB Approval 
23 
3.3  
Patient Registration 
25 
3.4 
Reservation and Contact Requirements 
25 
3.5 
Informed Consent/Assent 
25 
3.6 
Screening Procedures 
Error! Bookmark not defined. 
3.7 
Eligibility Checklist 
25 
3.8 
Institutional Pathology and Genomics Report 
25 
3.9 
Study Enrollment 
25 
3.10 
Dose Assignment 
26 
4.0 
PATIENT ELIGIBILITY 
26 
4.1 
Inclusion Criteria 
27 
4.2 
Exclusion Criteria 
31 
5.0 
TREATMENT PLAN 
33 
5.1 
Overview of Treatment Plan 
33 
5.2 
Criteria for Starting Subsequent Cycles 
33 
5.3 
Dose Escalation Schema 
34 
5.4 
Grading of Adverse Events 
34 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
34 
5.6: THERAPY DELIVERY MAPS (TDMS) FOR CYCLE 1 
36 
5.7: THERAPY DELIVERY MAPS (TDMS) FOR CYCLES 2 + 
38 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
40 
6.1 
Dose Modifications for Hematological Toxicity 
40 
6.2 
Dose Modifications for Non-Hematological Toxicity 
40 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
41 
7.1 
Concurrent Anticancer Therapy 
41 

 
 
 PEPN2112 
Version Date: 04/15/2022 
 
 Page 4 
7.2 
Investigational Agents 
41 
7.3 
Supportive Care 
41 
7.4 
Growth Factors 
41 
7.5 
Concomitant Medications 
41 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
42 
8.1 
Required Clinical, Laboratory and Disease Evaluation (See Section 4.0) 
42 
8.2 
Required Observations Following Completion of Protocol Therapy 
43 
8.3 
Research Studies for which Patient Participation is Optional 
44 
8.4 
Radiology Studies 
50 
8.5 
Pharmacology (Required) 
50 
8.6 
Tumor Tissue for Immunohistochemistry: ATM (Required) 
52 
8.7 
Monitoring for Specific Toxicities 
53 
9.0 
AGENT INFORMATION 
54 
9.1 
BAY 1895344 
54 
9.2 
Clinical Drug Request 
57 
9.3 
Agent Inventory Records 
58 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
59 
10.1 
Criteria for Removal from Protocol Therapy 
59 
10.2 
Off Study Criteria 
59 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
60 
11.1 
Sample Size and Study Duration 
60 
11.2 
Definitions 
60 
11.3 
Dose Escalation and Determination of MTD 
61 
11.4 
Pharmacokinetic and Correlative Studies and Response Analysis 
62 
11.5 
Study Design - Phase 2 
62 
11.6 
Method of Analysis - Phase 2 
63 
11.7 
Evaluability for Toxicity 
64 
11.8 
Evaluability for Pharmacokinetic Analysis 
64 
11.9 
Gender and Minority Accrual Estimates 
64 
11.10 
Analysis of the Pharmacokinetic Parameters 
65 
11.11 
Analysis of Biological and Correlative Endpoints 
65 
12.0 
EVALUATION CRITERIA 
65 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
65 
12.2 
Response Criteria for Patients with Solid Tumors 
65 
12.3 
Best Response 
66 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
67 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
67 
13.2 
When to Report an Event in an Expedited Manner 
69 
13.3 
Expedited Reporting Methods 
70 
13.4 
Specific Examples for Expedited Reporting 
70 
13.5 
Definition of Onset and Resolution of Adverse Events 
72 
13.6 
Other Recipients of Adverse Event Reports 
73 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
73 
14.1 
Categories of Research Records 
73 

 
 
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 Page 5 
14.2 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
73 
14.3 
CRADA/CTA/CSA 
73 
14.4 
Monitoring 
75 
14.5 
Data and Safety Monitoring Plan 
75 
REFERENCES 
76 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
78 
IRB Approval 
79 
Additional Requirements 
79 
Downloading Site Registration Documents 
Error! Bookmark not defined. 
Submitting Regulatory Documents 
80 
Rave CTEP-AERS Integration 
81 
Data Quality Portal 
82 
Central Monitoring 
82 
APPENDIX II: PROTOCOL CENTRAL MONITORING PLAN 
84 
APPENDIX III: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
86 
APPENDIX IV: TOXICITY-SPECIFIC GRADING 
89 
APPENDIX V: BAY 1895344 (ELIMUSERTIB) DOSING NOMOGRAM 
90 
APPENDIX VI: MEDICATION DIARY FOR BAY 1895344 (ELIMUSERTIB) 
91 
APPENDIX VII: YOUTH INFORMATION SHEETS 
93 
APPENDIX VIII: BIOMARKER STUDIES 
95 
APPENDIX IX: CORRELATIVE STUDIES GUIDE 
97 
APPENDIX X: PART A PHARMACOKINETIC WORKSHEET (SAMPLE) 
100 
APPENDIX XI: PART B PHARMACOKINETIC WORKSHEET (SAMPLE) 
102 
APPENDIX XII: RESPONSE CRITERIA FOR LYMPHOMA 
103 
APPENDIX XIII: RESPONSE CRITERIA FOR SOLID TUMORS 
111 
APPENDIX XIV:  PATIENT INSTRUCTIONS FOR SUN PROTECTION 
115 
APPENDIX XV: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
116 
PATIENT DRUG INTERACTION WALLET CARD 
118 
 
 
 

 PEPN2112 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
Version Date: 04/15/2022 
 
 Page 6 
STUDY COMMITTEE 
STUDY CHAIR 
Michael V. Ortiz, MD 
Pediatric Hematology/Oncology 
Memorial Sloan Kettering Cancer Center 
Phone: (212) 639-6057 
E-mail: ortizm2@mskcc.org 
 
STUDY VICE CHAIR 
Julia Glade Bender, MD 
Pediatric Hematology/Oncology 
Memorial Sloan Kettering Cancer Center 
Phone: (212) 639-6729 
E-mail: gladebej@mskcc.org 
 
STUDY STATISTICIAN 
Charles Minard, PhD 
Biostatistics 
Baylor College of Medicine/Dan L Duncan 
Comprehensive Cancer Center 
Phone: (713) 798-2353 
E-mail: minard@bcm.edu 
 
STUDY NURSE 
Sue Ehling, MN ARNP 
Pediatric Oncology 
Seattle Children’s Hospital 
Phone: (206) 987-2043 
E-mail: susan.ehling@seattlechildrens.org 
 
STUDY PATHOLOGIST 
Alanna Church, MD 
Pathology 
Boston Children’s Hospital / Dana Farber 
Phone:  (617) 355-7431 
E-mail:  alanna.church@childrens.harvard.edu 
 
STUDY PHARMACIST 
Amy Helvie, PharmD 
Pharmacy 
Riley Hospital for Children 
Phone:  (317) 944-2025 
E-mail: ahelvie@iuhealth.org 
 
STUDY PHARMACOLOGIST  
Joel M. Reid, Ph.D. 
Mayo Clinic 
Phone: (507) 284-0822 
E-mail: reid@mayo.edu 
 
STUDY COMMITTEE MEMBERS 
Brenda J. Weigel, MD 
Chair, PEP-CTN 
University of Minnesota Medical Center - Fairview 
Phone:  (612) 616-5501 
E-mail: weige007@umn.edu 
 
Elizabeth Fox, MD 
Vice Chair, PEP-CTN 
St. Jude Children’s Research Hospital 
Phone: (910) 595-3300 
E-mail: elizabeth.fox@stjude.org 
 
COG PEP-CTN RESEARCH COORDINATOR 
Jeffrey Carpio, BS 
Children's Oncology Group 
Phone: (626) 241-1610 
E-mail: jcarpio@childrensoncologygroup.org 
 
COG PEP-CTN PROTOCOL COORDINATOR 
Samuel Baird, MPH 
Children's Oncology Group 
Phone: (626) 241-1619 
E-mail: sbaird@childrensoncologygroup.org 
 
COG PEP-CTN STATISTICIAN 
Xiaowei Liu, MS 
Children's Oncology Group 
Phone: (626) 241-1535 
E-mail: xwliu@childrensoncologygroup.org 
 
COG PEP-CTN PHARMACIST 
Olga Militano, PharmD 
Pharmacy 
Children’s Oncology Group - Operations 
Phone: (626) 241 - 1517 
E-mail: omilitano@childrensoncologygroup.org 
 
 
 
 
 
 
AGENT 
NSC# 
Supplier 
BAY 
1895344 
(elimusertib) 
810486 
Bayer 
IND Number (or IND Exempt): 
 
IND Sponsor: CTEP 
 

 PEPN2112 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
Version Date: 04/15/2022 
 
 Page 7 
This trial is covered by 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 
Dysregulation of the DNA damage response (DDR) is both a hallmark of cancer and a potential targetable vulnerability.  
Ataxia telangiectasia and Rad3 related (ATR) protein kinase is a key regulator involved in repairing single stranded DNA 
breaks, particularly secondary to oncogenic replication fork stress.  BAY 1895344 (elimusertib) is a highly potent and 
selective ATR inhibitor which has been shown to be well tolerated in adult cancer patients, most commonly causing 
myelosuppression, particularly anemia, as well as nausea and fatigue.  Tumors with complementary DNA repair pathway 
defects, particularly the loss of ataxia-telangiectasia mutated (ATM), exhibited durable objective responses during the phase 
I monotherapy study in adult cancer patients.  Future clinical trials, including combination studies, are now underway in 
several medical oncology settings. 
 
Many childhood solid tumors are driven by genomic alterations which may render them vulnerable to ATR inhibitors.  BAY 
1895344 (elimusertib) has specifically demonstrated promising preclinical activity in both Ewing Sarcoma (EWS) and 
PAX3-FOXO1 fusion positive Alveolar Rhabdomyosarcoma (ARMS) tumors for which there are few effective treatments 
in the relapsed setting.  PEPN2112 is a phase 1/2 trial of BAY 1895344 (elimusertib) in children and young adults with 
relapsed or refractory non-CNS solid tumors and lymphomas which exhibit an EWS-fusion, PAX3-FOXO1 fusion, as well 
as loss of function mutations in ATM, ATRX, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, 
PALB2, PARP1, POLD1, RAD51, or XRCC2.  The study will require confirmation of qualifying genomic alterations but 
will allow for such genomic testing to have been performed in any CLIA certified setting.  The phase 1 dose-determining 
portion will evaluate children less than 18 years of age with qualifying genomic findings with either evaluable or measurable 
tumors using a Rolling 6 design with up to 2 dose levels, starting at the adult maximum tolerated dose (MTD) and 
recommended phase 2 dose (RP2D) and then de-escalating if not well tolerated in children.  The phase 2 portion will 
evaluate children and young adults with measurable tumors at the pediatric RP2D determined in the phase 1 portion of the 
study and patients at least 18 years of age will receive the recommended phase 2 dose determined in previous studies in 
adults.  A Simon 2 stage design in separate cohorts of EWS-fusion positive tumors, PAX3-FOXO1 fusion positive ARMS, 
and non-CNS solid tumors and lymphomas with a qualifying DDR panel defects will be utilized.  Eligible patients at least 
18 years old may enroll on the Phase 2 portion of the trial while the Phase 1 component of the study is being conducted in 
patients younger than 18 years old. The aims of the trial will be to establish the RP2D and MTD of BAY 1895344 
(elimusertib) in children less than 18 years old, to investigate the toxicities, pharmacokinetics, and pharmacodynamics of 
BAY 1895344 (elimusertib) in children with these tumors, to explore the anti-tumor efficacy in children and young adults 
with EWS-fusion positive tumors, PAX3-FOXO1 fusion positive ARMS and tumors with qualifying DDR panel defects, 
and to evaluate whether response is influenced by ATM, PGBD5, R-loops, alternative lengthening of telomeres (ALT), as 
well as other tumor mutations as evaluated using whole genome sequencing.  
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
Phase 1 Dose Escalation Primary Aim  
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of 
BAY 1895344 (elimusertib) administered as an oral tablet, twice per day for 3 days on and 4 days 
off to patients < 18 years of age with recurrent or refractory Ewing Sarcoma, PAX3-FOXO1 
Alveolar Rhabdomyosarcoma, and non-CNS solid tumors or lymphoma with specific DDR 
pathway alterations. 
 
Phase 2 Primary Aim 
1.1.2 
To define the antitumor activity of BAY 1895344 (elimusertib) in pediatric patients and young 
adults with recurrent or refractory Ewing Sarcoma. 
 
1.1.3 
To define the antitumor activity of BAY 1895344 (elimusertib) in pediatric patients and young 
adults with recurrent or refractory PAX3-FOXO1 fusion positive Alveolar Rhabdomyosarcoma. 
 
Additional Primary Aims (Phase 1)  
1.1.4 
To define and describe the toxicities of BAY 1895344 (elimusertib) administered on this schedule. 
 
1.2 
Secondary Aims 
1.2.1 
To characterize the pharmacokinetics of BAY 1895344 (elimusertib) in children and adolescents 
with recurrent or refractory cancer. 
 
1.2.2 
To assess the biologic activity of BAY 1895344 (elimusertib) by immunohistochemical 
assessments of pATR, pH2AX, and pKAP1 in paired tissue samples before and after treatment 
with BAY 1895344 (elimusertib). 
 
1.2.3 
To assess whether the activity of BAY 1895344 (elimusertib) is influenced by ALT, as well as 
tumor tissue expression of ATM, PGBD5, and/or R-loops. 
 
1.2.4 
To assess whether the activity of BAY 1895344 (elimusertib) is associated with tumor mutational 
processes, as measured by whole genome tumor tissue sequencing. 
 
1.2.5 
To preliminary determine the anti-tumor activity of BAY 1895344 (elimusertib) in children < 18 
years of age within the confines of a phase 1 study (Part A). 
 
Phase 2 Secondary Aims  
1.2.6 
To assess the antitumor activity of BAY 1895344 (elimusertib) in pediatric patients with non-CNS 
solid tumors or lymphomas with specific deleterious alterations in DDR pathway genes. 
 
 
Days 1-3 
BAY 1895344 
(elimusertib) PO 
BID 
Days 8-10 
BAY 1895344 
(elimusertib) PO 
BID 
Days 15-17 
BAY 1895344 
(elimusertib) PO 
BID 
Days 22-24 
BAY 1895344 
(elimusertib) PO 
BID 
Day 28 
End of Cycle  

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2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development in Pediatric Population 
DNA damage occurs frequently in all cells because of exposure to endogenous or environmental toxins.  
The DNA damage response (DDR) is a coordinated network of proteins which recognizes DNA damage, 
signals to cell cycle checkpoints to stall cell cycle progression, initiates DNA repair, and if unable to repair 
DNA damage, directs the cell to undergo apoptosis.  Dysregulation of genes involved in DDR leading to 
genomic instability is a hallmark of cancer, allowing for more rapid acquisition of mutations critical to 
cancer evolution.1 When cancers develop a defect in one DDR pathway, they may compensate by 
overexpressing alternative pathways or developing dependency on another.2 This overexpression or 
addiction can be leveraged as a synthetic lethality, as described in BRCA mutant cancers which are sensitive 
to PARP inhibition due to inability of cells to undergo homologous recombination (HR). 
 
When double stranded DNA undergoes breaks or replication forks are stalled, single stranded DNA is 
exposed and to prevent further degradation, they are coated by the replication protein A (RPA). 2-5 RPA 
coated single stranded DNA is recognized by the ataxia telangiectasia and Rad3 related (ATR) protein 
kinase and a related complex of proteins leading to CHEK1 phosphorylation, replication fork stabilization, 
deceleration of cell cycle progression, and ultimately DNA repair.2-5 Since ATR is a ubiquitous regulator 
of DNA damage repair, we hypothesize that DDR pathway aberrations recurrent in pediatric cancers, 
particularly those leading to increased replication fork stress, will create a dependency on the ATR-CHEK1 
pathway which can be rationally inhibited. 
 
BAY 1895344 (elimusertib) is a highly potent and selective ATR inhibitor which is available as an oral 
tablet and demonstrates potent preclinical activity in a variety of malignancies with DDR pathway 
aberrations. A Phase 1 study of BAY 1895344 (elimusertib) has been completed in adults with solid tumors 
demonstrating promising activity in selected patients with pathogenic DDR mutations, particularly in those 
with ATM loss. We propose a pediatric Phase 1/2 study with 1 planned and 1 potential lower dose level in 
the Phase 1 portion followed by signal finding cohorts to determine the objective response rate to BAY 
1895344 (elimusertib) in pediatric patients with tumors for which there is pre-clinical rationale. Given the 
significant evidence to support ATR inhibition in Ewing Sarcoma and PAX3-FOXO1 fusion positive 
Alveolar Rhabdomyosarcoma, separate cohorts for patients with relapsed or refractory disease in either of 
these diagnoses are planned as well as a histology-agnostic cohort for patients with tumors with pre-defined 
deleterious genomic alterations in related DDR pathways. We will evaluate the pharmacokinetics of BAY 
1895344 (elimusertib) in children and young adults and confirm pharmacodynamic targeting by evaluating 
pKAP1, pATR, and pH2AX.  Finally, in addition to whole genomic sequencing, this study will explore 
alternative lengthening of telomeres (ALT) as measured by C-circle analysis as well as 
immunohistochemical expression of ATM, PGBD5, and R-loops as potential predictive biomarkers of 
response. 
 
2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
 
2.2.1.1  DDR pathway defects predicted to sensitize to BAY 1895344 (elimusertib): 
The DDR pathway alterations included in this study which are anticipated to sensitize 
pediatric tumors to inhibition with BAY 1895344 (elimusertib) include loss of function 
of ATM, ATRX, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, 
MRE11, PALB2, PARP1, POLD1, RAD51, and XRCC2.  This panel was chosen 
because it had been previously clinically validated through its use on the adult phase 1 
study of BAY 1895344 (elimusertib). Figure 1A demonstrates the prevalence of these 
genomic alterations in a series of pediatric pan-cancer studies using cBioPortal (Figure 
1A) as well as the NCI-COG Pediatric MATCH (Figure 1B).6-10 Using cBioPortal, 
putative driver mutations were detected in 3.7% of all pediatric tumors in this pan-

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pediatric cohort and another 12.6% of tumors also exhibited mutations of unknown 
significance in one or more genes on this panel.  On the NCI-COG Pediatric MATCH, 
3.8% of screened relapsed/refractory pediatric solid tumor patients tested exhibited 
inactivating mutations in one of the panel of genes tested.  Excluding Ewing Sarcoma, 
ARMS, and CNS tumors this would account for 2.2% of screened patients, although 
notably the MATCH did not include all the genes on the proposed panel.  Of note, in 
addition to the genomic alterations included in this DDR panel, several additional 
genomic alterations have potential to influence response to BAY 1895344 (elimusertib) 
therapy, such as loss of function in TP53, ARID1A, XRCC1, and ERCC4 as well as 
increased activity of MYC, CHEK1, APOBEC, MLL, CCNE1, and CDC24A.11  In order 
to evaluate the contribution of these known vulnerabilities and discover novel 
dependencies, whole genome sequencing will be performed on all available tumors with 
frozen samples available for testing. 
 
Patients who have biallelic inactivating mutations in sensitizing DDR genes are most 
likely to respond to ATR inhibition.  However, an important and currently unknown 
question is whether clonal monoallelic inactivating mutations would sensitize to BAY 
1895344 (elimusertib).  The conditional haploinsufficiency model proposes that 
germline carriers of DDR pathway defects are more prone to malignancy, because 
oncogenic activity in pre-malignant lesions leads to increased replication fork stress 
which would normally be resolved in normal tissues but exceed a stress threshold in 
haploinsufficient cells.12  Analogously, in tumors which have resulted from such 
haploinsufficiency and thereby exhibit monoallelic inactivation of a DDR pathway gene, 
they too will have significantly increased replication fork stress such as is caused by 
oncogenic activation, ALT, PGBD5, R-loops, or other factors.  As replication fork stress 
is chiefly repaired by ATR, we hypothesize that such tumors may similarly be sensitive 
to BAY 1895344 (elimusertib).4 
 
This hypothesis that monoallelic inactivating mutations may respond to BAY 1895344 
(elimusertib) is predicated upon clinical data with related therapies. A pan-cancer study 
evaluating the effectiveness of DNA damaging radiation therapy amongst 357 patients 
harboring ATM alterations in their tumors revealed that, as compared with ATM variants 
of uncertain significance, biallelic loss of function mutations were most susceptible to 
radiation with a hazard ratio of 0.19, however the hazard ratio was still 0.57 for 
monoallelic inactivating mutations suggesting a clinical benefit.13  This is further 
corroborated by clinical data in adult oncology with DDR pathway inhibitors. For 
example, in the landmark TOPARP study which administered the PARP inhibitor 
Olaparib to adults with metastatic colorectal cancer, 16/49 (33%) evaluable patients 
exhibited an objective response, and 3/16 (19%) of these responders had monoallelic 
inactivation of DDR genes.14  Berzosertib (M6620) is the first-in-class ATR inhibitor, 
and during the adult phase 1 study a durable complete response was evident in a patient 
with metastatic colorectal cancer with monoallelic deleterious mutations in CHK1, 
FANCM, RAD50, POLD1, and FANCP as well as compound heterozygous truncating 
mutations in ARID1A, although notably this tumor did exhibit complete loss of ATM by 
IHC.15 As shown in Figure 11, of the 4 adult patients with a partial response to BAY 
1895344 (elimusertib) during the dose escalation, a durable partial response was seen in 
an appendiceal tumor that exhibited a frameshift mutation in ATM (mutant allele 
frequency 45%) and 60% ATM protein expression by immunohistochemistry.16,17 
 
 

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single stranded DNA structures that activate ATR, whereas nucleases cleave single 
stranded DNA to yield double stranded breaks that activate ATM.   Cancers with 
a deficiency in ATM are thus expected to be dependent upon ATR, which can be 
leveraged to create synthetic lethality using an ATR inhibitor.  This paradigm has 
been validated preclinically for BAY 1895344 (elimusertib) in several adult 
malignancies including ATM-deficient chronic lymphocytic leukemia, mantle cell 
lymphoma, non-small cell lung cancer, gastric cancer, and pancreatic cancer.  In 
vitro studies of BAY 1895344 (elimusertib) treated for 72-96 hours (Figure 2) 
demonstrate particular sensitivity of ATM deficient, as compared with ATM wild 
type, cancer cell lines to BAY 1895344 (elimusertib).19  ATM loss of expression 
via IHC may be evident even in tumors without biallelic ATM mutations so we 
plan to evaluate ATM via IHC as a predictive biomarker of response in this trial.  
 
Figure 2. In vitro sensitivity of cancer cell lines to BAY 1895344 (elimusertib) 
stratified by ATM status 
 
 
b. 
PGBD5: 
Recent studies from the laboratory of Dr. Alex Kentsis (Memorial Sloan Kettering 
Cancer Center, New York, NY) suggest that a previously uncharacterized human 
gene, PGBD5, with homology to the PiggyBac DNA transposase from the looper 
moth capable of catalyzing bona fide ‘cut-and-paste’ DNA transposition in human 
cells may also confer susceptibility to ATR inhibition.  PGBD5 is highly expressed 
in most childhood solid tumors and ectopic expression of PGBD5 in primary 
human cells is sufficient to promote penetrant cell transformation in vitro and in 
immunodeficient mice in vivo.  This activity requires specific catalytic residues in 
the PGBD5 transposase domain, as well as efficient non-homologous end-joining 
(NHEJ) DNA repair, and induces distinct structural rearrangements characterized 
by deletions and inversions involving PGBD5-specific signal sequence (PSS) 
motifs.20  Clinical grade DDR inhibitors were screened against PGBD5-expressing 
tumor cells and isogenic controls lacking PGBD5 and demonstrated that the ATR 
inhibitor AZD6738 had exceptional selective activity against the majority of 
PGBD5-expressing childhood solid tumor cells in vitro.21  For example, Figure 3A 
reveals the exquisite sensitivity of rhabdoid tumor (RT), medulloblastoma (MB), 
neuroblastoma (NB), and Ewing sarcoma (ES) cells to ATR inhibition and in 
Figure 3B, it is evident that the relative PGBD5 expression levels correlate with 
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PGBD5 is both necessary and sufficient to confer the dependency on ATR kinase 
signaling and susceptibility to ATR kinase inhibition which we will further 
investigate on this trial. 
 
Figure 3. PGBD5 expression is a candidate biomarker of susceptibility to ATR 
inhibition 
 
 
c. 
R-Loops: 
During transcription, the nascent RNA generated by RNA polymerases can 
hybridize with the DNA template, giving rise to a three-stranded structure called 
an R-loop.22  Although physiologic in some contexts, R-loops can accumulate and 
cause genomic instability, chiefly via collisions with DNA replication forks 
causing double stranded breaks.  Recently it was shown that in response to aberrant 
R-loop accumulation, ATR is recruited to facilitate DNA repair or cell death.22 
Moreover, R-loop associated chromosomal instability is an emerging hallmark of 
certain pediatric tumors, notably including Ewing sarcoma as well as Embryonal 
Tumor with Multilayered Rosettes (ETMR).23, 24  Current studies are ongoing to 
investigate the degree to which R-loops are prognostically relevant. In the context 
of this study, the presence of R-loops and any relationship to response to BAY 
1895344 (elimusertib) will be investigated. 
 
d. 
Alternative Lengthening of Telomeres (ALT): 
Telomeres are repetitive sequences at the ends of chromosomes that are 
progressively lost during successive rounds of cell division and eventually lead to 
p53 and RB dependent permanent growth arrest which is termed senescence.25, 26  
Inactivation of p53 and Rb allows for continued cell division and further 
shortening until telomeres eventually erode to a length at which they are unable to 
protect chromosome ends resulting in crisis of end to end chromosome fusions and 
apoptotic cell death.25, 26  However, in cancers, rare cells may emerge that are able 
to maintain their telomere length, thereby allowing the cancer cell to continue to 
divide.25, 26  These cells can do so by either increasing the activity of telomerase, 
which happens in most situations, or rarely alternative repair DNA mechanisms, 
termed ALT, are invoked to lengthen telomeres, and this is well described in 
pediatric tumors with ATRX mutations.27  During ALT, ATR is recruited to RPA 
coated single stranded DNA to enact repair processes.  In fact, ATRIP the ATR 
associated DNA repair protein, has been found associated with telomeres in cancer 
cells that utilize ALT, but not in those with increased telomerase activity.25  Hence, 
we anticipate that tumors which utilize ALT to maintain telomere length will be 
more sensitive to BAY 1895344 (elimusertib).  This study will utilize DNA C-
circles, a specific and quantifiable marker of ALT, to evaluate the degree of ALT 

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in both tumors and peripheral blood.28  Concurrent with this, telomerase activity 
will be measured by TERT RT-PCR. 
 
2.2.1.3 
Currently Planned Dose Expansion Cohorts, Based on Preclinical Studies 
 
a. 
Ewing Sarcoma:  
Ewing Sarcomas demonstrate elevated levels of endogenous replication stress and 
have a unique dependency on the ATR-CHK1 pathway.24,29  As a result, there are 
several studies which have shown that this tumor histology is sensitive to ATR 
inhibition. 20,21,24,29,30  Although likely multifactorial, posited mechanisms of this 
dependency include elevated expression of PGBD5 20,21,31, increased presence of the 
DNA/RNA hybrid R-loops 24,32, and decreased expression of compensatory DNA 
pathway genes such as BRCA1 and ATM 29,32,33  A query of the “Genomics of Drug 
Sensitivity in Cancer” (https://www.cancerrxgene.org/) revealed that there was a 
statistically significant decreased IC50 (suggesting increased sensitivity) for both 
EWS-FLI1 mutant and STAG2 mutant cells compared with cancer cell lines wild 
type for these molecular aberrations, tested with two different ATR inhibitors.34 
Notably, both the EWS-FLI1 and EWS-ERG translocations have been shown to 
sensitize cells to ATR inhibitors so dependency is not unique to the fusion partner 
nor junction.11,30  Although much of the initial data was developed with other ATR 
inhibitors, exquisite sensitivity to several Ewing Sarcoma cell lines has been shown 
with the BAY 1895344 (elimusertib), as shown in Figure 4. 
 
Figure 4. Ewing Sarcomas are sensitive to BAY 1895344 (elimusertib)  
 
Panel A: All cell lines are EWS except 1 OS (Saos-2) and 2 control cell lines (BJ 
fibroblasts and RPE epithelial cells) the latter two only shown on right panel; AUC 
is denoted in arbitrary units (a.u.).  (Source: Anton Henssen, MD; Charite, Berlin, 
Germany) Panel B is derived from Figure 4 of Nieto-Soler, et al. Oncotarget, 2016 
and compares the single agent activity of two different ATR inhibitors, AZ20 and 
MSC253. 
 

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b. 
PAX3-FOXO1 Fusion Positive Alveolar Rhabdomyosarcoma (ARMS): 
The laboratory of Dr. Anton Henssen (Charité, Berlin, Germany) has been 
investigating the role of ATR inhibitors, both AZD6738 and BAY 1895344 
(elimusertib), in rhabdomyosarcomas (Figure 5A-D).  They determined that the 
presence of the PAX3-FOXO1 fusion is predictive of sensitivity to both ATR 
inhibitors (Figure 5) and often, but not always, are associated with increased 
MYCN, ALT, loss of ATM, loss of TP53, as well as PGBD5 expression (Figure 
5E). Ultimately, these replication stress-inducing molecular factors confer a 
synthetic lethal dependency on ATR-mediated DNA damage repair and signaling 
in alveolar, PAX3-FOXO1-expressing rhabdomyosarcomas. Consistent with 
previous reports of oncogenic fusion gene-induced replication stress in Ewing 
sarcoma, expression of PAX3-FOXO1 itself induced replication stress, as 
measured by Tunel positive cells in ATR treated rhabdomyosarcoma cells with or 
without the fusion (Figure 5F). These effects, observed specifically in PAX3-
FOXO1 expressing rhabdomyosarcoma cells, resulted from decreased 
phosphorylation of homologous recombination pathway members, and were 
accompanied by induction of genomic instability, increased G2/M arrest and 
apoptosis (not shown). In turn, single agent treatment with the ATR signaling 
inhibitor AZD6738 exhibited potent antitumor activity against high-risk patient-
derived rhabdomyosarcoma models expressing PAX3-FOXO1 (Figure 5G/H). 
Moreover, 
decreased 
homologous 
recombination 
activity 
through 
pharmacological ATR inhibition sensitized cells to PARP inhibition and platinum 
chemotherapy (Figure 5G/H).  Further studies are still needed to establish whether 
PAX7-FOXO1 or other variant fusion positive rhabdomyosarcomas will exhibit 
analogous sensitivity to ATR inhibition. 
 
Figure 5. Alveolar Rhabdomyosarcomas are sensitive to ATR pathway 
inhibition35 
 
(Source: Anton Henssen, MD; Charite, Berlin, Germany) 
 
c. 
DNA Damage Repair Pathway Aberrations: 
As described previously, loss of function mutations in complementary DNA 
pathways are predicted to increase the dependency on ATR repair within tumor 
cells only, leading to synthetic lethality for patients with deleterious alterations in 
ATM, ATRX, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, 
MRE11A, PALB2, PARP1, POLD1, RAD51, and XRCC2.  Hence, pediatric 
patients with either biallelic or monoallelic loss of function in these specific DDR 
pathway genes within their tumors will be eligible for this expansion cohort. 
 

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2.2.2 
Preclinical In Vitro Studies: 
In vitro, BAY 1895344 (elimusertib) potently inhibits proliferation of a broad spectrum of human 
tumor cell lines (median IC50 7.8 × 10−8 mol/L; mean IC50 1.5 × 10−7 mol/L).19  As shown previously 
in Figure 2, 72-96 hour treatment and viability assessment using crystal violet staining or Cell Titer 
Glo in a panel of 38 pan-cancer cell lines demonstrates increased sensitivity of ATM deficient 
cancer cell lines to BAY 1895344 (elimusertib).19 Furthermore, as shown in Table 1, the 
combination of BAY 1895344 (elimusertib) with a variety of DNA-damaging agents or DDR 
pathway inhibitors results in exquisite synergy in several cell lines, particularly with the platinum 
chemotherapy agent cisplatin and the irinotecan metabolite SN-38.19  Note that a combination index 
(CI) ≤ 0.8 is synergism; 0.8 < CI < 1.2 is additivity; CI ≥ 1.2 is antagonism.  
 
Table 1: Combination index of BAY 1895344 (elimusertib) at the EC50 plus the following 
drugs at their EC50 
  
HT-29 
LOVO 
PC-3 
HT-144 
Cisplatin 
DNA platination 
0.14 
0.17 
0.15 
0.27 
Bleomycin 
dsDNA breaks 
0.59 
0.80 – 1.0 
0.21 
0.32 
SN-38 
Topo 1 inhibitor 
0.43 
0.55 
0.27 
0.21 
AZD0156 
ATM inhibitor 
0.45 
0.52 
0.48 
1.0 – 1.2 
M9831 
DNA-PK inhibitor 
< 0.61 
0.85 – 1.16 
< 0.69 
< 0.72 
AZD7762 
CHEK1/2 inhibitor 
0.49 
0.19 
  
  
PF00477736 
CHEK1 inhibitor 
0.69 
< 0.43 
  
  
MK8776 
CHEK1 inhibitor 
0.72 
0.63 
  
  
AZD1775 
WEE1 inhibitor 
0.64 
< 0.29 
  
  
 
2.2.3 
Preclinical In Vivo Studies: 
BAY 1895344 (elimusertib) was compared with other DNA damage repair inhibitors, including 
Berzosertib (M6620; in red) and Ceralasertib (AZD6738; in blue) and found to be superior in both 
the GRANTA-519 (Figure 6A) and Rec-1 (Figure 6B) human mantle cell lymphoma models in 
vivo.36  BAY 1895344 (elimusertib) was shown to synergize with carboplatin in the IGROV-1 
human ovarian adenocarcinoma model (Figure 7A).36  BAY 1895344 (elimusertib) was shown to 
synergize with the PARP inhibitor Olaparib in the 22Rv1 human prostate carcinoma model (Figure 
7B).).36 In addition to synergizing with DNA damaging chemotherapy, BAY 1895344 (elimusertib) 
synergized with DNA damaging radiation both in an in vitro colony forming assay as well as in a 
LoVo human colorectal cancer model in vivo, shown below in Figure 8.36 
 
 

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Figure 6: BAY 1895344 (elimusertib) compared with other ATR inhibitors19 
 
 
Figure 7: Combination of BAY 1895344 (elimusertib) in vivo with DNA damaging agents 
and DDR pathway inhibitors19 
 
 
 

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Figure 8. In vivo synergy of BAY 1895344 (elimusertib) and radiation at non-curative 
doses19 
 
 
2.2.2 
Dosing Strategy: 
Evaluation of BAY 1895344 (elimusertib) efficacy and tolerability in preclinical xenograft models 
in mice indicated optimal dosing using 40 mg/kg twice daily (BID) using a 3 day on and 4 day off 
schedule, as shown below in Table 2.  As described below, to date the 3 day on and 4 day off 
schedule has been tested clinically, although an alternative 3 day on and 11 day off schedule is still 
in the early phases of clinical investigation. 
 
Table 2. Preclinical Efficacy of Optimized Dosing Schedule of BAY 1895344 (elimusertib) 
Tumor Name 
(Type)mutations 
Treatment 
Dose 
Schedule 
Tumor/Control 
Ratio 
Day of Assessment 
HCC1806 (TNBC)1 
Vehicle 
--- 
--- 
1.0 
16 
BAY 1895344 
(elimusertib)  
40 mg/kg BID  
3 on / 4 off PO 
0.32 
MKN-45  
(Gastric Cancer)2 
Vehicle 
--- 
--- 
1.0 
18 
BAY 1895344 
(elimusertib)  
40 mg/kg BID  
3 on / 4 off PO 
0.57 
Hs746T  
(Gastric Cancer)3 
Vehicle 
--- 
--- 
1.0  
21 
BAY 1895344 
(elimusertib)  
40 mg/kg BID 
3 on / 4 off PO 
0.03  
Rec1 
(MCL)4 
Vehicle 
--- 
--- 
1.0 
27 
BAY 1895344 
(elimusertib)  
40 mg/kg BID  
3 on / 4 off PO 
0.00 
22RV1 
(Prostate Cancer)5 
Vehicle 
--- 
--- 
1.0 
29 
BAY 1895344 
(elimusertib)  
40 mg/kg BID  
3 on / 4 off PO 
0.04 
1 - CCNE1amp [CN 8], TP53 T256fs 
2 - FANCAA636V;T508A, POLD1R1086W, TP53R110C , BRCA1S1598P, EGFRA1048V, LIG4I840V, PPP6R3T845A, RPA4R254W 
3 - APCD1688H;S2625I, ARID1AG444S, PPP4R4Q241H, TP53K319* , BRCA1S186F, FANCGK317N, HFM1A1003E 
4 - ATMS707P, p53Q317*, G245D 
5 - BRAF L597R, PIK3CA Q546R , BRCA2 V1810I, TP53 Q331R, TP53BP1 P1059X, ARID1A1847-1848X;Y1324X;P1325X, ATM K1101E 
 
2.2.3 
Pharmacodynamic Biomarkers of Response to BAY 1895344 (elimusertib): 
ATM kinase phosphorylates histone H2AX (pH2AX) at the site of DNA damage where it acts as a 
scaffolding for the assembly of repair machinery.37  KAP1, another phosphorylated substrate of 
ATM, is a co-repressor for Kruppel-associated box zinc finger proteins that bind to and repress 
DNA through their zinc fingers.37  Replication stress and more broadly DNA damage, are 
commonly measured by the presence of pH2AX and pKAP1.11,37  In this study, pH2AX and pKAP1 
as well as the activated pATR will be evaluated in matched pre- and post- treated tumor samples, 
where available, in order to evaluate the impact of BAY 1895344 (elimusertib) on DNA damage 
repair. 

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2.3 
Adult Studies 
 
2.3.1 
Clinical Trials of ATR inhibitors: 
In addition to BAY 1895344 (elimusertib), as of September 2020, there are 5 additional ATR 
inhibitors undergoing clinical development. The first-in-class ATR inhibitor was Berzosertib 
(M6620, VX-970) and the first oral ATR inhibitor was Ceralasertib (AZD6738), both of which 
have been studied in numerous clinical trials in the adult oncology setting.2  M4344 (VX-803) 
(NCT04149145; NCT02278250), M1774 (NCT04170153) and RP-3500 (NCT04497116) are the 
other ATR inhibitors with clinical trials although have been less well studied than BAY 1895344 
(elimusertib).   
 
BAY 1895344 (elimusertib) has a strong rationale for its use in pediatric tumors, as previously 
described, and promising preclinical evidence to suggest it may be more effective than other ATR 
inhibitors (Figure 6).  The “First-in-human Study of ATR Inhibitor BAY 1895344 (elimusertib) in 
Patients with Advanced Solid Tumors and Lymphomas” (NCT03188965) was recently published 
and has provided much of the essential clinical data to support the proposed design of this pediatric 
trial.16  As of January 2021, there are now 7 additional ongoing human clinical studies involving 
this drug, including combination studies with the anti-PD1 checkpoint inhibitor Pembrolizumab 
(NCT04095273),  Pembrolizumab and radiation (NCT04576091), the PARP inhibitor Niraparib 
(NCT04267939), the topoisomerase 1 inhibitors topotecan and liposomal irinotecan 
(NCT04514497), as well as DNA damaging chemotherapeutics cisplatin and gemcitabine 
(NCT04491942), gemcitabine alone (NCT04616534) and the FOLFIRI (irinotecan, fluorouracil, 
and leucovorin) chemotherapy regimen (NCT04535401).   
 
2.3.2 
Dose Escalation and MTD Determination: 
The first-in-human study of BAY 1895344 (elimusertib) began with a dose escalation which 
included 22 patients. Six cohorts of patients were treated using a 3 day on and 4 day off schedule 
weekly whereas 1 cohort of patients was treated with a 3 day on and 4 day off schedule for 2 weeks 
followed by 1 week off drug.  The adult maximum tolerated dose (MTD) and recommended phase 
2 dose (RP2D) was determined to be 40 mg BID 3 days on and 4 days off weekly on the basis of 
dose limiting toxicities observed at the higher dose levels which were predominately 
myelosuppression, as shown in Table 3 below. 
 
MTD Determination of BAY 1895344 (elimusertib)16 
Cohort 
Dose level 
(mg) 
All 
patients  
Evaluable 
patients 
DLTs  
DLT description  
1 
5 
1 
1 
0 
--- 
2 
10 
2 
1 
0 
--- 
3 
20 
2 
1 
0 
--- 
4 (MTD) 
40 
2 
2 
0 
--- 
5 
80 
3 
2 
2 
G4 neutropenia; G4 leukopenia & G4 thrombocytopenia 
6 
60 
8 
7 
2 
G4 neutropenia & G3 leukopenia; G2 fatigue 
7 
60* 
4 
3 
2 
G3 thrombocytopenia; G3 neutropenia 
* Patients in this cohort were given a 3 day on and 4 day off schedule for 2 weeks followed by 1 week off drug 
 
2.3.3 
Pharmacokinetics: 
In humans, BAY 1895344 (elimusertib) is 96-97.5% protein bound, primarily binding to albumin.  
Relative bioavailability comparison of the oral suspension and 40 mg tablets in adults has been 
completed.  At the 40 mg dose level in adults the 40 mg tablet geomean (%CV) Tmax was 1 (1-1) h, 
Cmax 1468 µg/L (37%), and AUC0-24h 10437 µg•h/L (61%).  
 
Preliminary PK from the first-in-human study (Figure 9) show that after oral administration BAY 
1895344 (elimusertib) is rapidly absorbed with a median Tmax of 1 hour and a geometric mean 

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terminal half-life of 11.5 hours.16 In the dose expansion portion of the trial, 64 patients had first 
dose pharmacokinetics and 52 patients had repeat sampling on day 10 at the 40 mg BID dose level 
on the 3 day on 4 day off schedule.  On day 1, the Cmax was 1226 µg/L (3 µM), AUC0-12h was 7118 
µg•h/L (17 µM•h); on day 10, the Cmax was 1661 µg/L (4 µM) and AUC0-12h was 11539 µg•h/L (28 
µM•h).  Unit conversion was based on BAY 1895344 (elimusertib) MWT 412 g/mol). Exposure 
was observed to be broadly dose-proportional across the dose range investigated (5-80 mg), and 
accumulation was consistent with observed half-life.16 
 
2.3.4 
Pharmacodynamics: 
Pre-therapy and on-therapy biopsies were obtained during the dose escalation and studied for 
increased expression of pH2AX and pKAP1.  For example, a patient with BRCA1 mutant ovarian 
cancer who had stable disease demonstrated increased pH2AX and pKAP1; this increase in DNA 
damage markers was evident in many of the matched tumor pairs, as shown in Figure 10.16 
 
2.3.5 
Efficacy: 
In the dose escalation of the first-in-human study of BAY 1895344 (elimusertib), 4 of 20 patients 
treated in the dose escalation exhibited a partial response (PR) (Figure 11).  Notably, all 4 of these 
responders had ATM loss of expression on immunohistochemistry and/or ATM loss of function 
mutations.16 
 
Figure 9. BAY 189544 PK Profile for Single Dose (Cycle 1, Day 1) and Multiple Dose 
Administration (Cycle 1, Day 10)38 
 
 
 

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average adult BSA of 1.7 m2, the corresponding pediatric dose of BAY 1895344 (elimusertib) is 
24 mg/m2/dose BID 3 days on and 4 days off, repeated 4 times per cycle (28-day cycle).  Patients 
who do not have progression of disease or meet other criteria for discontinuation of protocol therapy 
may continue BAY 1895344 (elimusertib) for up to 26 cycles (since each cycle is 28 days, 26 cycles 
is equal to 2 years of treatment). 
 
2.5.2 
Rationale for Phase 2 Cohorts and Biomarker Selected Cohorts: 
The initial Phase 1 portion will utilize the Rolling 6 design and will initially treat pediatric patients 
at dose level 1 (24 mg/m2/dose), approximately the adult RP2D.  If this dose level is not well 
tolerated, we will next evaluate dose level -1 (18 mg/m2/dose), a 25% dose reduction.  The RP2D 
will be the highest dose level for which < 33% of evaluable patients experience a dose limiting 
toxicity during Cycle 1. Once the RP2D is defined, a PK expansion cohort will be opened and will 
enroll up to 6 additional patients for PK analysis. Three phase 2 expansion cohorts will also open 
for enrollment: 
(1) EWS cohort 
(2) PAX3-FOXO1 ARMS cohort 
(3) DDR cohort 
 
The Phase 2 cohorts will initially open concurrently with the Phase 1 portion but will only enroll 
patients at least 18 years of age. Patients <18 years of age will be included in the Phase 2 cohorts 
only after the RP2D/MTD has been estimated in the Phase 1 portion.  
 
Eligibility criteria for the phase 1 and 2 portions of the study will be identical except for the 
following:  
(1) The phase 1 portion will allow tumors which are either evaluable or measurable whereas the 
phase 2 will only allow measurable tumors.  
(2) In phase 2 expansion cohorts for EWS and PAX3-FOXO1 ARMS, the upper age of eligibility 
will be increased to 30 years to enhance access of this drug to young adults with biologically 
analogous tumors.  
 
Both the EWS and PAX3-FOXO1 ARMS cohorts will utilize the 10+10 Simon optimal two-stage 
design.  Given that qualifying deleterious mutations are expected to occur quite rarely, as 
summarized in Figure 1, the DDR cohort will utilize a smaller 7+6 Simon two-stage design. 
 
 

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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
Patient Enrollment: 
Patient enrollment for this study will be facilitated using the Slot Reservation System in conjunction with the 
registration system in Oncology Patient Enrollment Network (OPEN). Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on the protocol is 
available to the patient. Once a slot reservation confirmation is obtained, site staff may then proceed to enroll the 
patient to this study. 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available on a 24/7 basis. 
OPEN is integrated with CTSU regulatory and roster data and with the LPOs registration/randomization systems or 
the Theradex Interactive Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment. OPEN will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
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, drug 
shipment (IVR only), or receiving investigator for a patient transfer in OPEN, the IVR or NPIVR must list the IRB 
number used on the site’s IRB approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the 
IVR or NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment 
information.  You may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. Further instructional 
information is in the OPEN section of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For 
any additional questions, contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Please see Appendix I for detailed CTEP and CTSU Registration Procedures including: Registration and Credential 
Repository (RCR), requirements for site registration, submission of regulatory documents and how to check your 
site’s registration status. 
 
3.1 
Current Study Status 
Investigators should refer to the COG website to determine if the study is currently open for accrual.  
 
3.2  
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be 
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U.S. sites participating in the PEP-CTN network are required to use the NCI CIRB as of 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 with the NCI CIRB must submit the Study Specific Worksheet for Local Context (SSW) 
to the CIRB using IRBManager to indicate their intent to open the study locally. The NCI CIRB’s approval 
of the SSW is automatically communicated to the CTSU Regulatory Office, but sites are required to contact 
the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network or protocol 
level. Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or 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 in order for the processing of the IRB/REB approval record to be 
completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and on at least 
one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating Organization 
(PO); and 
• 
Compliance with all 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 documentation to the CTSU Regulatory Office for 
initial, continuing or amendment review. 
 

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3.3  
Patient Registration  
Prior to enrollment on study, patients must be assigned a COG patient ID number. This number is obtained 
via the COG Registry in the OPEN system once authorization for the release of protected health information 
(PHI) has been obtained.   
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. 
 
3.4 
Reservation and Contact Requirements 
Prior to enrolling a patient, a reservation must be made following the steps below and the Study Chair or 
Vice Chair notified. (The patient will need a COG patient ID number in order to obtain a reservation). 
Reservations may be obtained 24 hours a day through the OPEN system. Patients must be enrolled within 
7 calendar days of making a reservation. 
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and password.  
2) In order to make a reservation, the patient must have an OPEN patient number. Click on the ‘Slot 
Reservation’ tab to create an OPEN patient number, under ‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient. 
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the COG Patient ID, and 
choose the required stratum (if applicable) in order to obtain a reservation. 
 
Refer to the ‘Slot Reservation Site User Guide’ posted under the ‘Help’ tab in OPEN for detailed 
instructions: 
https://www.ctsu.org/open/Site_Resources/Training/Users_Manual/CTSU-OPEN-
SlotReservationSiteUserGuide.pdf  
 
3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the patient 
or the patient’s parents or guardian if the patient is a child. All patients and/or their parents or legally 
authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained 
according to institutional guidelines 
 
3.6 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and date the 
completed eligibility checklist. A signed copy of the checklist will be uploaded into RAVE immediately 
following enrollment. 
 
3.7 
Institutional Pathology and Genomics Report 
Immediately following enrollment, the institutional pathology report for the diagnosis under which the 
patient is being enrolled must be uploaded into RAVE. All pathology testing will be completed at a CLIA 
certified lab. For Part A patients with confirmation of an eligible mutation, and all Part B expansion cohorts, 
documentation of eligible mutation and/or pathology report are required (See section 4.1.4.3). The reports 
must include the associated study number and COG patient registration and accession numbers. Personal 
identifiers, including the patient’s name and initials must be removed from all institutional reports prior to 
submission. 
 
3.8 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Patients 
who give informed consent for the protocol in order to undergo screening for eligibility are not considered 

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enrolled and should not be enrolled until the screening is completed and they are determined to meet all 
eligibility criteria. 
 
Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must be 
no later than five (5) calendar days after the date of study enrollment. Patients must not receive any 
protocol therapy prior to enrollment. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment 
information. Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. Further 
instructional information is in the OPEN section of the CTSU website at https://www.ctsu.org or 
https://open.ctsu.org. For any additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
3.9 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
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 or research record which will serve as the source document for verification at the 
time of audit. 
 
Laboratory Studies: 
All laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise 
indicated.  
 
Laboratory values used to assess eligibility must be no older than seven (7) days at the start of therapy. Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility.  
 
If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are older than 7 days, then the 
following laboratory evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT), albumin and serum creatinine. If the recheck is outside the limits of eligibility, 
the patient may not receive protocol therapy and will be considered off protocol therapy. 
 
Clinical Studies: 
All clinical studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise 
indicated.  Imaging studies must be obtained within 14 days prior to enrollment (repeat the tumor imaging if 
necessary).  
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day of prior therapy 
is September 1st, and the protocol requires waiting at least 7 days for that type of prior therapy, then that patient 
cannot be enrolled until September 8th. 
 

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4.1 
Inclusion Criteria 
 
4.1.1 
Part A: 
 
4.1.1.1 
Age: 
Patients between ≥ 12 months and < 18 years of age. 
 
4.1.2 
Part B: 
 
4.1.2.1 
Age: 
Patients between ≥ 12 months and ≤ 30 years of age for the phase 2 expansion cohorts 
for both EWS and PAX3-FOXO1 ARMS.  
 
Patients between ≥ 12 months and ≤ 21 years of age for the phase 2 DDR expansion 
cohort. 
 
The Phase 2 cohorts will initially open concurrently with the Phase 1 portion but will 
only enroll patients at least 18 years of age. Patients <18 years of age will be included in 
the Phase 2 cohorts only after the RP2D/MTD has been estimated in the Phase 1 portion.  
 
4.1.3 
BSA: 
All patients for both Parts A and B must have a minimum BSA > 0.74 m2 
 
4.1.4 
All patients for both Parts A and B must have the ability to swallow BAY 1895344 (elimusertib) 
tablets intact. 
 
4.1.5 
Diagnosis: 
Patients with recurrent or refractory solid tumors. Patients must have had histologic verification of 
malignancy at original diagnosis or relapse. 
 
4.1.5.1 
Part A Diagnosis Criteria: 
Any (non-CNS primary) solid tumor diagnosis including lymphoma which meets one of 
the following criteria: 
 
a. Any Ewing Sarcoma (histological confirmation alone is adequate) or any EWS-
fusion positive solid tumor (i.e. including related Ewing’s family of tumors with 
EWS fusions such as EWS-WT1, EWS-ATF1, etc.). 
 
Alveolar rhabdomyosarcoma (ARMS) with the PAX3-FOXO1 fusion.  This does not 
include PAX7-FOXO1 or other variant fusion ARMS. Please note that a FISH 
showing FOXO1 breakapart is NOT sufficient for eligibility onto this cohort since it 
cannot distinguish between FOXO1 partners. 
 
b. Any (non-CNS primary) solid tumor including lymphoma with inactivating 
alterations of any of the DNA Damage Repair (DDR) genes: ATM, ATRX, BRCA1, 
BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, PALB2, PARP1, 
POLD1, RAD51, or XRCC2. 
 
4.1.5.2 
Part B Diagnosis Criteria: 
Any (non-CNS primary) solid tumor diagnosis including lymphoma which meets one of 
the following criteria:  
 

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a. B1, EWS Cohort: 
Any Ewing Sarcoma (histological confirmation alone is adequate) or any EWS-
fusion positive solid tumor (i.e. including related Ewing’s family of tumors with 
EWS fusions such as EWS-WT1, EWS-ATF1, etc.). 
 
b. B2, PAX3-FOXO1 ARMS Cohort: 
Alveolar rhabdomyosarcoma (ARMS) with the PAX3-FOXO1 fusion.  This does not 
include PAX7-FOXO1 or other variant fusion ARMS.  Please note that a FISH 
showing FOXO1 breakapart is NOT sufficient for eligibility onto this cohort since it 
cannot distinguish between FOXO1 partners. 
 
c. B3, DDR Non-statistical Cohort:  
 Any (non-CNS primary) solid tumor including lymphoma with inactivating 
alterations of any of the DNA Damage Repair (DDR) genes: ATM, ATRX, BRCA1, 
BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, PALB2, PARP1, 
POLD1, RAD51, or XRCC2. 
 
4.1.6 
Genomic Testing: (all parts) with the exception of histologically verified Ewing Sarcoma 
 
4.1.6.1 
Determination of whether a mutation is oncogenic:  
All the genes on the DDR panel are annotated with OncoKB, a precision oncology 
knowledge base which is publicly available here: https://www.oncokb.org/.  Alterations 
which are categorized either ‘Oncogenic’ or ‘Likely Oncogenic’ would be considered 
sufficient for eligibility on either the phase 1 or phase 2 portions of this study.  Alterations 
which are not annotated in OncoKB will need to be reviewed with locally qualified experts 
in molecular pathology, such as via an established molecular tumor board, in order to 
determine the likely oncogenicity AND will require approval by the study chair, Dr. 
Michael Ortiz.  If such experts are not available at any institution, the study chair will 
review. 
 
4.1.6.2 
How to address multiple tumor samples or mutations:  
In cases where multiple mutations are present or multiple samples are available, either at 
different locations or different points in time, the presence of a single qualifying genomic 
alteration in any of those samples will is considered sufficient for eligibility on the phase 
2 portions of this study. 
 
4.1.6.3 
Determination of adequacy of genomic testing: 
Qualifying aberrations must be detected in either DNA or RNA in any tumor tissue 
sample (i.e. detection of a variant on circulating tumor DNA/RNA is not sufficient to 
qualify) using a somatic (and/or germline) mutational testing approach with either a 
targeted panel or whole exome/genome sequencing in the context of a Clinical 
Laboratory Improvement Amendments (CLIA)-certified laboratory setting.  Any CLIA 
certified laboratory is acceptable to use.  A list of qualifying CLIA-certified laboratories 
is here: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCLIA/search.cfm 
 
4.1.7 
Disease Status: 
 
4.1.7.1 
Part A: Patients must have either measurable or evaluable disease. 
 
4.1.7.2 
Part B (1, 2, 3): Patients must have measurable disease.   
 

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4.1.7.3 
CNS Metastases: Patients with a prior history of CNS metastases may enroll on study, 
provided there is no current evidence of active disease at the time of enrollment.   
 
4.1.8 
Therapeutic Options: 
Patient’s current disease state must be one for which there is no known curative therapy or therapy 
proven to prolong survival with an acceptable quality of life.  
 
4.1.9 
Performance Level: 
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky 
> 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age.  Note that 
neurologic deficits in patients with tumors previously metastatic to the CNS (or other non-
oncologic reasons) must have been stable for at least 7 days prior to study enrollment.  Patients 
who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
See https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials under 
Standard Sections for Protocols.  
 
4.1.10 Prior Therapy: 
 
4.1.10.1 
Patients must have fully recovered from the acute toxic effects of all prior anti-cancer 
therapy and must meet the following minimum duration from prior anti-cancer 
directed therapy prior to enrollment. If after the required timeframe, the numerical 
eligibility criteria are met, e.g., blood count criteria, the patient is considered to have 
recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: 
≥ 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior 
nitrosourea). See DVL homepage on the COG Members site for commercial and 
investigational agent classifications. For agents not listed, the duration of this 
interval must be discussed with the study chair and the study-assigned Research 
Coordinator 
prior 
to 
enrollment. 
Refer 
here 
for 
details: 
https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfM
yelosuppressiveAnti-CancerAgents.pdf 
 
b. Anti-cancer agents not known to be myelosuppressive (eg, not associated with 
reduced platelet or ANC counts): ≥ 7 days after the last dose of agent. See the DVL 
homepage on the COG Members site for commercial and investigational agent 
classifications. For agents not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research Coordinator prior to 
enrollment. 
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and 
toxicity related to prior antibody therapy must be recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth 
factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. For agents that 
have known adverse events occurring beyond 7 days after administration, this period 
must be extended beyond the time during which adverse events are known to occur. 
 

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f. 
Interleukins, Interferons and Cytokines (other than Hematopoietic Growth Factors): 
≥ 21 days after the completion of interleukins, interferon or cytokines (other than 
Hematopoietic Growth Factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem 
cell infusion including donor lymphocyte infusions (DLI) or boost infusion: ≥ 
84 days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion: ≥ 30 days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of cellular therapy (e.g., 
modified T cells, NK cells, dendritic cells, etc.). 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after local XRT; ≥ 150 
days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis; ≥ 42 days if 
other substantial BM radiation. 
 
j. 
Radiopharmaceutical therapy (eg, radiolabeled antibody, 131I-MIBG): ≥ 42 days after 
systemically administered radiopharmaceutical therapy. 
 
k. Study specific prior therapy: Patients must not have received prior exposure to BAY 
1895344 (elimusertib) or any other specific ATR inhibitors including Berzosertib 
(M6620, VX-970), Ceralasertib (AZD6738), M4344 (VX-803), M1774, and RP-
3500.  Treatment with other DNA damage repair inhibitors which do not specifically 
inhibit ATR (e.g., PARP inhibitors, WEE1 inhibitors, CHEK1 inhibitors, etc.) does 
not exclude them from eligibility on this study.  
 
4.1.11 Organ Function Requirements 
 
4.1.11.1 Adequate Bone Marrow Function Defined As: 
a. For patients with solid tumors without known bone marrow involvement  
• 
Peripheral absolute neutrophil count (ANC) ≥ 1000/uL 
• 
Platelet count ≥ 100,000/uL (transfusion independent, defined as not receiving 
platelet transfusions for at least 7 days prior to enrollment) 
• 
Hemoglobin ≥ 8.0 g/dL at baseline (may receive RBC transfusions) 
b. 
Patients with known or possible bone marrow metastatic disease will be eligible for 
study provided they meet the blood counts in 4.1.11.1.a (may receive transfusions 
provided they are not known to be refractory to red cell or platelet transfusions). 
These patients will not be evaluable for hematologic toxicity. At least 5 of every 
cohort of 6 patients must be evaluable for hematologic toxicity for the dose-
escalation part of the study. If dose-limiting hematologic toxicity is observed, all 
subsequent patients enrolled must be evaluable for hematologic toxicity. 
 
4.1.11.2 Adequate Renal Function Defined As: 
• 
Serum creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
• 
A creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 

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2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR39 utilizing child length and stature data published by the CDC. 
 
4.1.11.3 Adequate Liver Function Defined As: 
• 
Bilirubin (sum of conjugated + unconjugated or total) ≤ 1.5 x upper limit of 
normal (ULN) for age.  
• 
SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 
45 U/L.  
 
4.1.11.4 Adequate Neurologic Function Defined As: 
• 
Patients with seizure disorder may be enrolled if on anticonvulsants and well 
controlled as evidenced by no increase in seizure frequency in the prior 7 days. For 
patients a history of seizure but not on anticonvulsants, no seizure in the past 3 
months. If needed, evaluate use of enzyme-inducing anticonvulsants as stated in 
Section 4.2.2. 
 
• 
Nervous system disorders (CTCAE v5) resulting from prior therapy must be ≤ Grade 
2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and 
teratogenic adverse events as seen in animal/human studies, OR because there is yet no available 
information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in 
girls who are post-menarchal. Males or females of reproductive potential may not participate unless 
they have agreed to use two effective methods of birth control, including a medically accepted 
barrier or contraceptive method (e.g., male or female condom) for the duration of the study and for 
3 months + 2 days for males and 6 months + 2 days for females after receiving the last dose of BAY 
1895344 (elimusertib) on the study. Abstinence is an acceptable method of birth control. Female 
patients must not breastfeed during treatment and until 4 months after last study drug 
administration.  
 
4.2.2 Concomitant Medications: 
 
4.2.2.1 
Corticosteroids: Patients receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. 
If used to modify immune adverse events related to prior therapy, ≥ 14 days must have 
elapsed since last dose of corticosteroid (see Section 4.1.7.1.d). 
 
4.2.2.2 
Investigational Drugs: Patients who are currently receiving another investigational drug 
are not eligible. 
 
4.2.2.3 
Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not 
eligible. 
 

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4.2.2.4 
Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus 
or other agents to prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.2.5 
CYP3A4 Agents: Patients who are currently receiving drugs that are strong inducers or 
inhibitors of CYP3A4 are not eligible. Strong inducers or inhibitors of CYP3A4 should 
be avoided from 14 days prior to enrollment to the end of the study. Drugs that are 
considered sensitive or narrow therapeutic range CYP3A4 substrates should be avoided 
for the duration of protocol therapy. See Appendix III for a list of agents.  
 
 
4.2.3 
Study Specific: 
Dedicated CNS imaging is not required but patients with current active CNS metastasis whether 
symptomatic or discovered incidentally without clinical symptoms, will be excluded from study 
participation.   
 
4.2.4 
Infection: 
Patients who have an uncontrolled infection are not eligible. 
 
4.2.5 
Solid Organ Transplant: 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.6 
Compliance: 
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring 
requirements of the study are not eligible. 
 
 

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5.0 
TREATMENT PLAN 
 
5.1 
Overview of Treatment Plan 
Week  
Day  
Agent 
1 
1-3 
BAY 1895344 (elimusertib) PO BID 
4-7 
 
2 
8-10 
BAY 1895344 (elimusertib) PO BID 
11-14 
 
3 
15-17 
BAY 1895344 (elimusertib) PO BID 
18-21 
 
4 
22-24 
BAY 1895344 (elimusertib) PO BID 
25-28 
End of Cycle on day 28 
 
A cycle of therapy is considered to be 28 days. A cycle may be repeated for a total of 26 cycles, up to a 
total duration of therapy of approximately 24 months. 
 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of each cycle.  The starting dose for patients ≥ 18 years of age is 40 mg BID 3 
days on and 4 days off per week. 
 
If a patient vomits within 30 minutes after the dose of BAY 1895344 (elimusertib) is administered, that 
dose should NOT be repeated.  
 
On days that BAY 1895344 (elimusertib) is due to be given, it should be administered twice daily, 
preferably at the same time of day each day. Take BAY 1895344 (elimusertib) on an empty stomach one (1) 
hour before or two (2) hours after a meal with plenty of water.  If a dose of BAY 1895344 (elimusertib) is 
missed and it is less than 4 hours since the scheduled dosing time, the dose should be taken immediately, 
otherwise the dose should be skipped. 
 
Patient or caretaker must complete the medication diary with the date, time and number of agent tablets 
taken each day (see Appendix VI).  The medication diary should be reviewed after completion of each 
treatment cycle and loaded into Rave. 
 
See Section 5.6 for Therapy Delivery Maps for each cycle. 
 
5.2 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient 1) has at least stable disease 2) all pre-cycle studies 
required per Section 8.1 meet eligibility criteria as defined in Section 4.0 and 3) is otherwise eligible to 
continue agent administration per the requirements in Section 6.0. 
 
5.2.1 
Recommendations for Starting Each Weekly 3-day Course: 
BAY 1895344 (elimusertib) is administered on a 3-day on and 4-day off schedule, repeated 4 times 
each cycle.  Hematologic toxicities are the most common toxicities with BAY 1895344 
(elimusertib).  Eligibility criteria require an ANC ≥ 1000/μL and Platelets ≥ 100,000/μL, hence 
these parameters also need to be met to start any cycle (See section 4.1.11.1). Once a cycle has 
started, patients are required to have an ANC > 500/μL and Platelets > 50,000/μL within 48 hours 
prior to initiation of each 3 day interval of BAY 1895344 (elimusertib) administration (i.e. ANC 
and platelet parameters must be met (without transfusion) within 48 hours of initiation of days 8, 
15, and 21). If parameters are not met, this 3-day interval of BAY 1895344 (elimusertib) will be 
omitted and attempted to restart the following week (e.g. day 15 or 21).  If more than one 3-day 
block of BAY 1895344 (elimusertib) is missed within a cycle (i.e. < 75% of planned therapy is 
given for a particular cycle), that would be considered a hematologic DLT.   

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5.3 
Dose Schema 
 
5.3.1 
Part A Interpatient dosing: 
Part A is restricted to patients < 18 years of age.  The starting dose will be 24 mg/m2/dose BID 
(Dose Level 1) with dose levels for subsequent groups of patients as follows. 
Dose Level 
Dose (mg/m2) 
-1 
18 mg/m2/dose BID (maximum 30 mg/dose BID)
  
1* 
24 mg/m2/dose BID (maximum 40 mg/dose BID) 
* Starting Dose Level 
 
There will be no planned escalations beyond Dose Level 1 (24 mg/m2), the adult RP2D.  Please see 
dosing nomogram in Appendix V. 
 
If the MTD has been exceeded at the first dose level, then the subsequent cohort of patients will be 
treated at a dose of 18 mg/m2/dose BID (Dose Level -1). If Dose Level -1 is not well tolerated, 
further de-escalation will not occur and Part A will close to accrual and Part B will continue and 
be limited to those age 18 years and older.  
 
Note: Part A, PK expansion cohort will be opened when the RP2D/MTD has been defined and 
treated at that RP2D/MTD.  If required number of responses per the Simon two-stage design for 
expansion is not met for either the ARMS or EWS phase 2 cohorts whilst the PK expansion is still 
enrolling, the PK expansion will be closed to those patients.  Patients who have qualifying DDR 
alterations will always be allowed on the PK expansion cohort. 
    
5.3.2 
Part B Dose Level: 
Patients <18 years of age in the B1, B2 and B3 phase 2 expansion cohorts defined in section 4.1.2 
will be treated at the RP2D/MTD defined in Part A. Patients ≥ 18 years of age will be treated at the 
adult RP2D (40 mg BID 3 days on and 4 days off of each week of a 28 day cycle). 
 
If the patient experiences a toxicity, please refer to Section 6.0 for dose modifications.  
 
5.3.3 
Intra-Patient Escalation: 
Intra-patient dose escalation is not allowed.  
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Any 
suspected 
or 
confirmed dose-limiting toxicity should be reported immediately (within 24 hours) to the Study Chair. For 
laboratory values in CTCAE with grading definitions including both baseline and ULN definitions, utilize 
the ULN for CTCAE grading.  
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely attributable to 
protocol therapy. The DLT observation period for the purposes of study dose-escalation (Part A) will be 
the first cycle of therapy. Please refer to Section 13.5.4 for AE resolution definitions 
 
Dose limiting hematological and non-hematological toxicities are defined differently. 
 

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5.5.1 
Non-Hematological Dose-Limiting Toxicity: 
 
5.5.1.1  Any Grade 3 or greater non-hematological toxicity attributable to protocol therapy with 
the specific exclusion of: 
- 
Grade 3 nausea and vomiting of < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to Grade ≤ 
1 within 7 days. See Appendix IV for Adverse Event grading for liver function 
grading parameters in children and adolescents.  
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L. 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to supplementation 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered 
sufficiently medically significant or sufficiently intolerable by patients that it requires 
treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not be 
considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity: 
• 
Grade 4 neutropenia (ANC < 500/μL) that persists for > 7 days despite holding BAY 
1895344 (elimusertib) for 3 days 
• 
Grade 4 thrombocytopenia (Platelet count < 25,000/μL)  
• 
Grade 3 thrombocytopenia (Platelet count < 50,000/μL) that persists for > 7 days 
despite holding BAY 1895344 (elimusertib) for 3 days OR is associated with 
clinically significant bleeding 
• 
Failure to meet hematological criteria to initiate weekly dosing (Section 5.2.1) or 
subsequent cycles of therapy (Section 5.2) by cycle day 42 (within 14 days of planned 
start of the subsequent cycle) will be considered dose limiting toxicity. 
• 
Failure to receive at least 75% of the planned number of BAY 1895344 (elimusertib) 
doses during any cycle (i.e., 9 of 12 planned doses) due to delays attributable to 
myelosuppression would be considered a hematologic DLT. 
5.5.2.1 
Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-limiting toxicity. 
 

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Cycle 1 
Observations in Cycle 1 
 
a. History 
b. Physical Exam 
c. Performance Status 
d. Height, Weight, BSA 
e. Vital Signs 
f. CBC, differential, platelets: *Once weekly. If patients develop Grade 4 neutropenia or Grade 3 or 4 thrombocytopenia, 
CBC/differential/platelets should be checked at least twice per week (every 3-4 days) until recovery to Grade 3 
neutropenia or Grade 2 thrombocytopenia, or until the criteria for dose limiting toxicity are met. For patients who 
experience hematological dose limiting toxicity, CBCs should be checked at least weekly until recovery of ANC and 
platelet count to eligibility criteria  
g. SGPT (ALT), Albumin, Bilirubin 
h. Electrolytes including serum creatinine, calcium (Ca++), phosphorus (PO4), magnesium (Mg++) 
i. Creatinine Clearance or GFR 
j. Tumor disease evaluation: ^can occur any time during the last week of cycle 1. Should be obtained on the next consecutive 
cycle after initial documentation of either a PR or CR. Subsequent scans may restart 2 cycles after the confirmatory 
scan. Please note that for solid tumor patients, if the institutional investigator determines that the patient has progressed 
based on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
k. Pregnancy test: Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control. Abstinence is an acceptable methods of birth control. All 
women of childbearing potential must have a pregnancy test done every cycle prior to initiation of a new cycle. 
l. Medication Diary 
m. Pathology & Genomics Report: #Indicate a qualifying molecular aberration to enroll on study. Must be submitted via 
upload to MediData/RAVE.  Details of genomic studies noted in Section 4.1.4.3. 
n. Knee X-Ray: % Knee X-Ray should only be obtained in patients without epiphyseal closure at the time of enrollment, 
prior to start of therapy.  If the baseline tibial radiographs demonstrate open growth plates (epiphysis) then knee X-rays 
for tibial growth plate assessment will be obtained after cycle 1, every 3 cycles thereafter and at the end of study 
treatment. The end of study treatment observation is not required, if already obtained within the final month of therapy. 
.Reference Section 8.7 for further instruction on monitoring for growth plate toxicity. 
o. Pharmacokinetics (required): &See Section 8.5.2 for timing of PK studies 
p. Pharmacokinetics (optional): !See Section 8.3.5 for timing of optional PK studies 
q. Correlative Studies (required): $See Section 8.6 for details  
r. Correlative Studies (optional): @See Section 8.3 for details 
 
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Cycle 2 + 
Required Observations in Cycle 2 + 
 
a. History 
b. Physical Exam 
c. Height, Weight, BSA 
d. Vital Signs 
e. CBC, differential, platelets: * Must be obtained within 72 hours of the start of each cycle and on day 15 of all subsequent 
cycles. If patients develops Grade 4 neutropenia or Grade 3 or 4 thrombocytopenia, CBC/differential/platelets should be 
checked at least twice weekly (every 3-4 days) until recovery to Grade 3 neutropenia, Grade 2 thrombocytopenia or until 
the criteria for dose limiting toxicity are met. For patients who experience hematological dose limiting toxicity, CBCs 
should be checked at least weekly until recovery of ANC and platelet count to eligibility criteria. Patients who have dose 
adjustment due to hematologic toxicity attributable to BAY 1895344 (elimusertib), are required to have CBCs once 
weekly to confirm the safety of this adjusted dose during the cycle. Please see Section 6.1 for details. 
f. SGPT (ALT), Albumin, Bilirubin 
g. Electrolytes including serum creatinine, calcium (Ca++), phosphorus (PO4), magnesium (Mg++) 
h. Tumor disease evaluation: ^.Can occur any time during the last week of cycles 2, 4 and 6 and then every 3 cycles thereafter. 
Should be obtained on the next consecutive cycle after initial documentation of either a PR or CR. Subsequent scans 
may restart 2 cycles after the confirmatory scan. Please note that for solid tumor patients, if the institutional investigator 
determines that the patient has progressed based on clinical or laboratory evidence, he/she may opt not to confirm this 
finding radiographically. 
i. Medication Diary 
j. Knee X-Ray: & Knee X-Ray should only be obtained in patients without epiphyseal closure at the time of enrollment, 
prior to start of therapy.  If the baseline tibial radiographs demonstrate open growth plates (epiphysis) then knee X-rays 
for tibial growth plate assessment will be obtained after cycle 1, every 3 cycles thereafter and at the end of study 
treatment. The end of study treatment observation is not required, if already obtained within the final month of therapy. 
k. Tumor Tissue for Immunohistochemistry pH2AX, pKAP1 and pATR (Optional): !See Section 8.3.3 for details. 
l. Tumor Tissue for Whole Genome Sequencing (Optional): #See Section 8.3.1 for details. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth factor. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
Patients who have dose-limiting thrombocytopenia or neutropenia (defined in section 5.2, section 
5.2.1 and section 5.5.2) should receive subsequent cycles with at least a 25% dose reduction (75% 
of the original dose). Please see dosing nomograms in Appendix V.  For patients ≥18 years of age 
with starting dose of 40 mg BID, dose should be reduced to 30 mg BID 3 days on, 4 days off per 
week (25% dose reduction). 
 
6.1.2 
Patients who experience dose-limiting thrombocytopenia and/or neutropenia (as defined in Section 
5.5.2) after one dose reductions must be removed from protocol therapy. 
 
6.1.3 
Patients who have a dose-limiting hematological toxicity that does not resolve to eligibility 
parameters within 14 days after the planned start of the next treatment cycle (42 days from start of 
previous cycle) must be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
Patients who have any dose-limiting non-hematological toxicity (as defined in Section 5.5.1) may 
continue on protocol therapy upon meeting eligibility lab requirements or Grade ≤ 1 but should 
receive subsequent doses with at least a 25% dose reduction (75% of the original dose). . Please 
see dosing nomograms in Appendix V. For patients ≥18 years of age with starting dose of 40 mg 
BID, dose should be reduced to 30 mg BID 3 days on, 4 days off per week (25% dose reduction). 
 
6.2.2 
If a non-hematological dose-limiting toxicity recurs after one dose reduction, the patient must be 
removed from protocol therapy. 
 
6.2.3 
Patients who have a dose-limiting non-hematological toxicity that does not resolve to Grade ≤ 1 or 
eligibility within 14 days after the planned start of the next treatment cycle (42 days from start of 
previous cycle) must be removed from protocol therapy 
 
 

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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or biologic therapy 
may NOT be administered to patients receiving study drug. If these treatments are administered the patient 
will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to 
be 
used 
as 
necessary. 
Please 
see 
COG 
Supportive 
Care 
guidelines 
at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. Based on the UV absorption 
properties of BAY 1895344 (elimusertib), patients should be instructed to use topical sun block and UV-
blocking sunglasses during treatment with BAY 1895344 (elimusertib). Direct exposure of patients to sun light 
after administration should be avoided. Please see Patient Instructions for Sun Protection in Appendix XIV. 
 
BAY 1895344 (elimusertib) has low emetogenic potential. Please see COG Guidelines on Chemotherapy 
Induced 
Nausea 
and 
Vomiting 
for 
recommendations 
on 
prevention 
options 
https://childrensoncologygroup.org/downloads/COG_SC_CINV_Guidelines_Document.pdf. 
 
7.4 
Growth Factors 
Growth factors are not approved for use on this study. 
 
7.5 
Concomitant Medications  
In vitro, BAY 1895344 (elimusertib) is metabolized mainly by CYP3A4 and to a much lesser extent 
CYP1A1.  
Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of 
the study. BAY 1895344 (elimusertib) is predicted to be a moderate inducer toward sensitive CYP3A4 
substrates. Drugs that are considered sensitive or narrow therapeutic range CYP3A4 substrates should be 
avoided for the duration of protocol therapy. See Appendix III for a list of agents. Substrates of CYP2C8, 
2C9, and 2C19 should be used with caution. 
 
BAY 1895344 (elimusertib) was identified as an in vitro inhibitor of BCRP, P-gp, BSEP, OATP1B1, and 
OATP1B3.  The risk for clinically relevant drug-drug interactions due to inhibition of BSEP is considered 
to be negligible, but substrates of BCRP, P-gp, OATP1B1, and OATP1B3 should be used with caution. 
BAY 1895344 (elimusertib) is not a P-gp or BCRP substrate.   
 
Because of pH dependent solubility, antacid drugs, H2-blockers, and proton pump inhibitors may affect 
absorption and exposure of BAY 1895344 (elimusertib). 
 
Because there is a potential for interaction of BAY 1895344 (elimusertib) with other concomitantly 
administered drugs, the case report form will capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies only in Cycle 1.  Appendix XV– Patient Drug Interactions Handout 
and Wallet Card should be provided to patients and includes recommendations on medications to avoid due 
to potential interactions. 
 

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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the protocol) 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation (See Section 4.0 for eligibility criteria 
to start therapy) 
 
STUDIES TO BE OBTAINED 
 
Pre-
Study 
During Cycle 1 
Prior to and 
During Cycles 2 +^ 
End of Study 
Treatment  
History 
X 
X6 
X 
X 
Physical Exam  
X 
X6 
X 
X 
Performance Status 
X 
 
 
 
Height, weight, BSA 
X 
X6 
X 
X 
Vital Signs 
X 
Weekly 
X 
X 
CBC, differential, platelets1 
X7 
Weekly 
X6 
As clinically 
indicated 
SGPT (ALT), Albumin, Bilirubin 
X7 
X  
X 6 
As clinically 
indicated 
Electrolytes including serum creatinine, Ca++, 
PO4, Mg++ 
X7 
X 
X 6 
As clinically 
indicated 
Creatinine Clearance or GFR 
X 
 
 
 
Pregnancy Test2 
X 
 
 
 
Tumor Disease Evaluation3 
X 
Last week of 
Cycle 1 
Last week of cycles 
2, 4, and 6 then q 3 
cycles 3 
X 
Tibial Radiographs (Knee X-Ray)4 
X 
 
X 
X 
Medication Diary see Appendix VI 
 
Weekly 
X 
 
Pathology & Genomics Report5 
X 
 
 
 
Pharmacokinetics (Required), See Section 8.5 
 
X 
 
 
Pharmacokinetics (Optional) See Section 8.3.5 
 
X 
 
 
Archival 
Tumor 
Tissue 
for 
immunohistochemistry: ATM. (Required) See 
Section 8.6. 
X 
 
 
 
Tumor Tissue for Whole Genome Sequencing 
(Optional) Section 8.3.1 
X 
 
 
X 
Archival 
Tumor 
Tissue 
for 
Immunohistochemistry: PGBD5 and R-Loops 
(Optional) Section 8.3.2 
X 
 
 
 
Tumor 
Tissue 
for 
Immunohistochemistry 
pH2AX, pKAP1 and pATR (Optional) Section 
8.3.3 
X 
 
 
X 
Blood for ctDNA for ALT (Optional) Section 
8.3.4 
X 
 
 
 
Archival 
Tumor 
Tissue 
for 
Biobanking 
(Optional) Section 8.3.5 
X 
 
 
 
^ Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 If patients develop Grade 4 neutropenia or Grade 3 or 4 thrombocytopenia, CBC/differential/platelets should be 
checked twice per week (every 3 to 4 days) until recovery to Grade 3 neutropenia, Grade 2 thrombocytopenia, or until 
the criteria for dose limiting toxicity are met. For patients with hematological dose limiting toxicity, CBCs should be 
checked at least weekly until recovery to eligibility criteria. Please see Section 5.2.1 for details.  

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2 Women of childbearing potential require a negative pregnancy test prior to starting treatment; See Section 4.2.1 
3 Tumor Disease Evaluation ^should be obtained on the next consecutive cycle after initial documentation of either a 
PR or CR. Subsequent scans may restart 2 cycles after the confirmatory scan. Please note that for solid tumor 
patients, if the institutional investigator determines that the patient has progressed based on clinical or 
laboratory evidence, he/she may opt not to confirm this finding radiographically.  
4 Tibial Radiographs should only be obtained in patients without epiphyseal closure at the time of enrollment, prior to start of 
therapy and if baseline tibial radiographs are open then another will be obtained after cycle 1, every 3 cycles thereafter and 
at the end of study treatment. The end of study treatment observation is not required, if already obtained within the final 
month of therapy. Reference Section 8.7 for further instruction on monitoring for growth plate toxicity. 
5 Tumor pathology and genomics report indicating a qualifying molecular aberration to enroll on study must be 
submitted via upload to MediData/RAVE.  Details of genomic studies noted in Section 4.1.3. 
6 Must be obtained within 72 hours of the start of each cycle and on day 15 of all subsequent cycles. If patients develop 
Grade 4 neutropenia or Grade 3 or 4 thrombocytopenia, CBC/differential/platelets should be checked at least twice 
weekly (every 3-4 days) until recovery to Grade 3 neutropenia, Grade 2 thrombocytopenia or until the criteria for dose 
limiting toxicity are met.  For patients who experience hematological dose limiting toxicity, CBCs should be checked at 
least weekly until recovery of ANC and platelet count to eligibility criteria. Patients who have a dose adjustment due to 
hematologic toxicity attributable to BAY 1895344 (elimusertib), are required to have CBCs checked once weekly to 
confirm the safety of this adjusted dose during the cycle. Please see Section 6.1 for details. 
7 If greater than 7 days from pre study labs, please collect CBC, differential, platelets, bilirubin, albumin and serum 
creatinine within 48 hours prior to cycle 1, dose 1. These labs must still meet eligibility to receive dose 1 (as per 
Section 4.0). 
 
8.2 
Required Observations Following Completion of Protocol Therapy 
 
The following studies are required until the patient is off study as defined in Section 10.2. These 
observations are not applicable to patients enrolled on Part A who are not treated at the MTD/ RP2D.  
 
See COG Late Effects Guidelines for recommended post treatment follow-up: 
http://www.survivorshipguidelines.org/  
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) schedule. 
 
STUDIES TO BE 
OBTAINED 
Every 3 Months up 
to 12 Months1 
(Months 3, 6, 9, 12) 
Every 6 Months up 
to 24 Months1 
(Months 18, 24) 
Annually up to 60 
Months1 
(Months 36, 48, 60) 
History 
X 
X 
X 
Physical Exam  
X 
X 
X 
Vital Signs 
X 
X 
X 
CBC with differential3 
X 
X 
X 
SGPT (ALT), Albumin, 
Bilirubin3 
X 
X 
X 
Electrolytes, Ca++, PO4, 
Mg++, Creatinine3 
X 
X 
X 
Disease evaluation2 
X 
X 
X 
1 Only for phase 2 cohort patients that come off protocol therapy and have long-term responses.  
2 Imaging studies should be obtained only if required as per standard of care or if disease progression is suggested by 
symptoms, physical findings, or abnormal laboratory values. 
3 As clinically indicated. 
 

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8.3 
Research Studies for which Patient Participation is Optional 
Every effort should be made to include these optional studies.  Sites which cannot collect samples for any 
reason other than lack of availability should contact the study chair.  If insufficient amount for all tests, the 
priority from highest to lowest is as follows: 
1. PGBD5 
2. R-Loops 
3. pKAP1 
4. pH2AX 
5. pATR 
 
8.3.1 
Tumor Tissue for Whole Genome Sequencing (Optional): 
Whole genome sequencing (WGS) can be performed on up to 3 tumors samples per patient.  We 
will request additional blood for control in patients who submit for WGS.  The goal of this study is 
to evaluate whether other genomic findings sensitize patients to BAY 1895344 (elimusertib). 
 
DNA C-circles will also be utilized from surplus DNA collected for WGS to evaluate the degree 
of ALT in tumor tissue and to investigate the sensitivity of tumors exhibiting ALT to BAY 1895344 
(elimusertib). Concurrent with this, telomerase activity will be measured by TERT RT-PCR.  
 
8.3.1.1 
Sampling Schedule 
• 
At diagnosis 
• 
At relapse 
• 
Post-treatment 
 
Note: Peripheral blood can be collected at any time. 
 
8.3.1.2 
Sample Collection and Handling Instructions: 
 
a. Frozen Tumor Tissue 
No minimum size if frozen tumor is available; Up to 3 samples may be 
sent, preferably one at diagnosis one at relapse and one at post-study. 
Tissues should be processed per standard institutional pathology 
guidelines. Tumor tissue should be kept frozen at -80 ℃ and should not 
be thawed prior to or during shipping. The tumor tissue collection date and 
time as well as the ID label should be included. 
 
b. Peripheral Blood  
This is only required if a patient is submitting a frozen tumor sample.  
Blood samples (3mL +/- 1mL) will be collected in EDTA tubes from a 
peripheral vein and should be kept frozen at -80 ℃ and should not be 
thawed prior to or during shipping. Note that even if multiple tumor 
samples are available, this sample is for control blood so is only required 
once per patient. 
 
8.3.1.3 
Frozen tumor sample processing as per standard institutional pathology guidelines. 
 
8.3.1.4 
Sample Shipping Instructions 
Frozen tumors and peripheral blood should not be thawed prior to or during shipping.  
Tumor samples and peripheral blood will be held until all samples have been obtained 
and then sent as a single batch frozen on dry ice using overnight delivery to the address 
listed below: 
 

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Dr. Alex Kentsis 
Kentsis Research Group  
408 East 69 Street, ZRC-1845  
New York, NY 10065, USA 
 
Phone: 1-646-888-3557 
E-mail: kentsisresearchgroup@gmail.com 
 
Friday collections are not permitted. Deliveries will be accepted Tuesday through Friday. 
Saturday and holiday shipments are not accepted. Please contact lab, prior to shipping. 
 
Please include qualifying genomic testing report. Additionally, complete the PEPN2112 
Tumor Tissue for Whole Genome Sequencing transmittal form in RAVE. Include the 
transmittal form with the shipment. 
 
NOTE: DNA for WGS will be extracted at the Kentsis lab. If sufficient DNA is able to 
be extracted for WGS and there is at least 200 ng surplus, this will be then sent to the 
Reynolds lab from the Kentsis lab for ALT evaluation.  
 
8.3.2 
Archival Tumor Tissue for Immunohistochemistry: PGBD5 and R-Loops (Optional): 
The archival tumor tissue will be used to identify biomarkers of response. Tumor tissue will be 
analyzed by Dr. Alex Kentsis’ lab. Immunohistochemistry for R-loops and PGBD5 will be 
performed on pre-treatment tumor samples.  This study will primarily investigate whether R-Loop 
presence and/or PGBD5 expression predicts response to BAY 1895344 (elimusertib).  Secondarily, 
we will evaluate the prevalence of R-loops and PGBD5 loss in certain pediatric tumors. 
 
8.3.2.1 
Sample Schedule  
• 
Archival tumor tissue sample(s) must be submitted for all consenting patients at 
time of enrollment, prior to the start of therapy. 
 
8.3.2.2 
Sample Collection and Handling 
A minimum of 1 and a preference of 2, unstained slides of FFPE tumor tissue samples 
will be obtained at the above time point for PGBD5 and R-Loops, respectively. 
 
8.3.2.3 
Sample Processing 
Samples can be processed at any institution and either slides or blocks may be sent. Both 
slides and blocks can be stored prior to shipment, refrigerated at 4 ℃. 
 
If sending slides, cut tumor into 5 μm sections and place, unstained, on a positive charged 
glass slide for conventional IHC (Superfrost plus slides are recommended). Place 
unstained slides in a plastic slide holder with sample ID label affixed. Place the slide 
holder in a Zipper lock bad and eliminate as much air (and therefore moisture) as possible 
prior to sealing the bag.  
 
FFPE tumor blocks may alternatively be sent to the Kentsis lab if preferable. If sending 
a block, aim to submit a piece approximately 0.5-1 cm3. After cutting an appropriately 
sized FFPE tumor block, place appropriate sample ID label onto the back of the cassette 
then place labeled cassette in a Zipper lock bag.  
 
8.3.2.4 
Sample Shipping Instruction 
Samples will be held until all samples have been obtained and then sent as a single batch 
kept cold using ice packs with overnight delivery to the address below. 

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Dr. Alex Kentsis 
Kentsis Research Group  
408 East 69 Street, ZRC-1845  
New York, NY 10065, USA 
 
Phone: 1-646-888-3557 
E-mail: kentsisresearchgroup@gmail.com 
 
Friday collections are not permitted. Deliveries will be accepted Tuesday through Friday. 
Saturday and holiday shipments are not accepted. Please contact lab, prior to shipping. 
 
Please include qualifying genomic testing report. Additionally, complete the PEPN2112 
Archival Tumor Tissue for IHC transmittal form in RAVE. Include the transmittal form 
with the shipment. 
 
8.3.3 
Tumor Tissue for Immunohistochemistry pH2AX, pKAP1 and pATR (Optional): 
Immunohistochemistry for pH2AX, pKAP1 and pATR will be performed on pre- and, where 
available, post- treatment tumor samples.  These studies will primarily investigate whether 
treatment with BAY 1895344 (elimusertib) increases pH2AX and pKAP1 and decreases pATR and 
thus supports the proposed mechanism of DNA damage repair inhibition and ATR inhibition.  
Secondarily, we will evaluate whether pH2AX and pKAP1 and pATR are expressed at baseline in 
certain pediatric tumors. 
 
8.3.3.1 
Sampling Schedule 
• 
Prior to the start of therapy 
• 
With any biopsy occurring on-study or within 30 days of end-of treatment. 
 
8.3.3.2 
Sample Collection and Handling Instructions 
A minimum of 1 and a preference of 2, unstained slides of FFPE tumor tissue samples 
will be obtained at the above time points for pH2AX, pKAP1 and pATR, respectively. 
An FFPE tumor block instead would also be sufficient.  
 
8.3.3.3 
Sample Processing 
Samples can be processed at any institution and either slides or blocks may be sent. Both 
slides and blocks can be stored prior to shipment, refrigerated at 4 ℃. 
 
If sending slides, cut tumor into 5 μm sections and place, unstained, on a positive glass 
slide for conventional IHC (Superfrost plus slides are recommended).  Place the slide 
holder in a Zipper lock bag and eliminate as much air (and therefore moisture) as possible 
prior to sealing the bag.  
 
FFPE tumor blocks may alternatively be sent to the Kentsis lab if preferable. If sending 
a block, aim to submit a piece approximately 0.5-1 cm3. After cutting an appropriately 
sized FFPE tumor block, place appropriate sample ID label onto the back of the cassette 
then place labeled cassette in a Zipper lock bag.  
 
8.3.3.4 
Sample Shipping Instructions 
Samples will be kept cold using ice packs with overnight delivery to the address below. 
Include the corresponding copy of the completed PEPN2112 Tumor Tissue for 
Immunohistochemistry pH2AX, pKAP1 and pATR Transmittal form (from RAVE) with 
each shipment. 
Dr. Alex Kentsis 

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Kentsis Research Group  
408 East 69 Street, ZRC-1845  
New York, NY 10065, USA 
 
Phone: 1-646-888-3557 
E-mail: kentsisresearchgroup@gmail.com 
 
Please include qualifying genomic testing report. 
 
Friday collections are not permitted. Deliveries will be accepted Tuesday through Friday. 
Saturday and holiday shipments are not accepted. Please contact lab, prior to shipping. 
 
NOTE: Prioritize pKAP1, pH2AX, and pATR if there are matched samples pre-/post- 
BAY 1895344 (elimusertib) therapy. 
 
8.3.4 
Blood for ctDNA for ALT (Optional): 
ctDNA will be utilized to identify patients with alternate lengthening of telomeres (ALT) tumors, 
to investigate the sensitivity of tumors using ALT to BAY 1895344 (elimusertib).  
 
8.3.4.1 
Sampling Schedule  
• 
Collected prior to the start of therapy, after enrollment but before the start of 
treatment.  
 
8.3.4.2 
Sample Collection and Handling Instructions 
 
a. Peripheral Blood  
Blood samples (~10mL) will be collected in EDTA anticoagulant tubes 
from a central line of from a peripheral vein, and then stored on ice or at 4 
℃. When clinically necessary, collecting 5mL of blood is acceptable.   
 
label samples with the following information: 
• 
COG patient ID 
• 
Sample Collection Date 
• 
Study Name (PEPN2112) 
 
8.3.4.3 
Sample Processing 
1. The plasma samples are prepared within 2 hours of blood draw by centrifuging the 
blood tube at 1350g for 12 minutes at 4 ℃. 
2. the faint yellow plasma samples are carefully transferred (free of any of the cell 
pellet) into a 15mL DNase tube. Do not touch buffy coat with pipet when 
transferring plasma.  
3. The plasma is then centrifuged at 1350g for 12 minutes at 4 ℃. 
4. the supernatant is transferred to 1.5-3mL DNase free tubes. 
5. Ensure the plasma is cleared of cells. Freeze plasma and blood cell pellet samples 
separately at -80 ℃ immediately and store at -80 ℃ until both plasma and blood cell 
pellet samples are shipped in separate containers to the lab listed in section 8.3.4.4 
on dry ice. 
 
All the steps are processed at 4℃ (or on ice) until samples are stored.  
 

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8.3.4.4 
Sample Shipping Instructions 
Ensure samples are stored at -80 ℃, prior to shipment and ship on dry ice Monday 
through Wednesday. Batch shipment is accepted. Include the corresponding copy of the 
completed PEPN2112 Blood for ctDNA for ALT Transmittal form (from RAVE) with 
each shipment. 
 
Dr. Charles Patrick Reynolds 
Cancer Center, TTUHSC School of Medicine 
3601 4th Street, STOP 94451 
Lubbock, TX 79430-94451, USA 
 
Phone: (806) 743-1558 
E-mail: 
Dr. 
Reynolds: 
patrick.reynolds@ttuhsc.edu; 
Kristyn 
McCoy: 
Kristyn.Mccoy@ttuhsc.edu; Jonas Nance Jonas.Nance@ttuhsc.edu.  
 
Please notify those listed above via email when samples have been shipped and provide 
the shipment tracking number. 
 
8.3.5 
Part A Additional Pharmacokinetic Samples (Optional): 
 
8.3.5.1 
Description of Studies 
In addition to the required pharmacokinetic samples for Part A outlined in Section 8.5.2.1, 
we are requesting two optional samples. 
 
8.3.5.2 
Sample Schedule 
• 
Day 1 of Cycle 1: 12 hours post dose. 
 
• 
Day 10 of Cycle 1: 12 hours post dose. 
 
Each sample will consist of 1-2 mL per sample. 
 
NOTE: 12-hour sample collection is optional and should be a trough, obtained prior to 
the next dose. 
 
8.3.5.3 
Sample Collection and Handling 
Please reference Section 8.5.3. 
 
8.3.5.4 
Sample Processing 
Please reference Section 8.5.4. 
 
8.3.5.5 
Sample Labeling 
Please reference Section 8.5.5.  
 
8.3.5.6 
Sample Shipping Instruction 
Please reference Section 8.5.6.  
 
8.3.6 
Archival Tumor Tissue for Biobanking (Optional): 
 
8.3.6.1 
Description of Studies 
The archival tumor tissue will be used for future research. 
 

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8.3.6.2 
Sample Schedule  
• 
Archival tumor tissue sample(s) must be submitted for all consenting after they 
are determined to be eligible and after enrollment is completed. 
 
8.3.6.3 
Sample Collection and Handling 
A formalin-fixed paraffin-embedded (FFPE) tissue block that has not been acid 
decalcified, will be shipped to the Biopathology Center. If a block is not available then 
submit 1 H&E stained slide (3-5 µm) and 10 unstained, uncharged, air-dried slides (10 
µm).  
Labelling: 
 
Blocks: 
• 
COG patient ID 
• 
Surgical Pathology ID (SPID) number and block number from the corresponding 
pathology report 
 
Slides: 
• 
COG patient ID 
• 
Surgical Pathology ID (SPID) and block number from the corresponding 
pathology report 
• 
Number slides sequentially 
 
Labeling must be on the frosted end of slide. 
 
Pathology Report: 
• 
COG patient ID 
 
Redact personally identifiable information such as the name, date of birth, medical record 
number and insurance information. The procedure/collection date, surgical pathology ID, 
block number, and diagnosis must be left on the report. 
 
8.3.6.4 
Sample Shipping Instruction 
FFPE Blocks and slides must be shipped at room temperature.  Ship on Monday – 
Thursday for receipt on Tuesday – Friday. Include the corresponding pathology report 
and a copy of the completed PEPN2112 Archival Tumor Tissue for Biobanking 
Transmittal form (from RAVE) with each shipment.  
 
Ship specimens to the following address: 
 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, Room WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
*The room number is required. Packages not listing the room number will be denied and 
returned to the sender. 
 

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8.4 
Radiology Studies 
 
8.4.1 
Central Radiology Review for Response: 
Patients who respond (CR, PR) to therapy or have long term stable disease (SD) (≥ 6 cycles) on 
protocol therapy will be centrally reviewed. Patients with osteosarcoma who are on therapy for 4 
months or more, will have all imaging centrally reviewed.  PEP-CTN ODSC will notify the Imaging 
Center of any patient requiring central review. The Imaging Center will then request that the 
treating institution forward the baseline and all on-study imaging for central review. The imaging 
evaluation results will be entered into RAVE for review by the PEP-CTN ODSC and for data 
analysis. The results will not be returned to the sites. 
 
The images are to be forwarded electronically to the Imaging Research Center at Children’s 
Hospital Los Angeles via the LifeImage. 
 
Institutions that are not connected via the LifeImage can send the images on CD ROM or USB 
flash drive. Submitted imaging studies should be clearly marked with the COG patient ID, study 
number PEPN2112 and date and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP 
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone: (323) 361-3898 
Fax: (323) 361-3054 
E-mail: saamer@chla.usc.edu  
 
8.5 
Pharmacology (Required) 
 
8.5.1 
Description of Studies and Assay: 
BAY 1895344 (elimusertib) pharmacokinetic (PK) studies will be determined by a validated 
LC/MS/MS method.  Samples will be analyzed by the laboratory of Dr. Joel Reid (Mayo Clinic, 
Rochester, MN), PEP-CTN Pharmacology Vice Chair. 
 
8.5.2 
Sampling Schedule (See Appendix XI for Part A schedule and Appendix XII for Part B schedule): 
 
8.5.2.1 
Part A:  
Blood samples will be obtained prior to drug administration and at the following time 
points:  
• 
Day 1 of Cycle 1:  
o Pre-dose. 
o Within ± 15 minutes of 1 hour post-dose. 
o Within ±15 minutes of 2 hours post-dose. 
o Within ± 15 minutes of 4 hours post-dose. 
o Within ± 30 minutes of 8 hours post dose. 
 
• 
Day 3 of Cycle 1:  
o Pre-dose (within 1-hour before AM dose). 
o Within ± 15 minutes of 1 hour post-dose. 
 
• 
Day 10 of Cycle 1:  
o Pre-dose (within 1-hour before AM dose) 

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o Within ± 15 minutes of 1 hour post-dose. 
o Within ± 15 minutes of 2 hour post dose. 
o Within ± 15 minutes of 4 hours post-dose. 
o Within ± 30 minutes of 8 hours post dose. 
 
Each sample will consist of 1-2 mL per sample hence in the Part A (phase 1) we will 
request 12 samples for a total of 12-24 mL of peripheral blood. 
 
8.5.2.2 
Part B: 
Plasma samples will be obtained at the following time points: 
• 
Day 1 of Cycle 1:  
o Pre-dose 
o Within ± 15 minutes of 1 hour post-dose. 
 
• 
Day 3 of Cycle 1:  
o Pre-dose (within 1-hour before AM dose). 
o Within ± 15 minutes of 1 hour post-dose. 
 
• 
Day 10 of Cycle 1:  
o Pre-dose (within 1-hour before AM dose). 
o Within ± 15 minutes1 hour post-dose. 
 
Each sample will consist of 1-2 mL per sample hence in the Part B (phase 2) we will 
request 6 samples for 6-12 mL of peripheral blood. 
 
8.5.3 
Sample Collection and Handling Instructions: 
Blood samples (1-2 mL) will be collected in EDTA tubes from a peripheral vein. Collection from 
a central line is also acceptable. Record the exact time that the sample is drawn along with the exact 
time that the drug is administered. 
 
8.5.4 
Sample Processing: 
Blood collected into EDTA tubes should be gently mixed by immediately inverting the tubes.  
Blood samples will then be centrifuged immediately for 15 minutes in a refrigerated centrifuge set 
at 4 degrees C.  After centrifugation (805 g for 15 min), remove the plasma using a transfer pipette 
and transfer the plasma into two separate cryovials or small (2-4) mL polypropylene screw-capped 
tubes.  Next, immediately freeze the tubes at -80 degrees C and store until delivery to the Mayo 
Clinic (see section 8.5.6 for shipping instructions) 
 
8.5.5 
Sample Labeling: 
Each tube must be labeled with the patient’s study registration number, the study I.D., and the date 
and time the sample was drawn. Data should be recorded on the Pharmacokinetic Study Form 
(Appendix X for Part A and Appendix XI for Part B), which must accompany the sample(s). 
 
8.5.6 
Sample Shipping Instructions: 
Samples will be held until all samples have been obtained and then sent as a single batch.  Batched 
samples should be sent frozen on dry ice by FedEx priority overnight to: 
 
Dr. Joel Reid 
Pharmacology Shared Resource 
Guggenheim 17-37 
Mayo Clinic 
200 First street, SW 

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Rochester, MN 55905 
 
Phone: 507-284-4303 
 
A copy of the BAY 1895344 (elimusertib) Pharmacokinetics Study Form for Parts A and B 
(Appendix X for Part A and Appendix XI for Part B) should accompany the shipment and a second 
copy emailed to Dr. Reid (reid@mayo.edu). One copy of the Pharmacokinetics Study Forms used 
for either Parts A or B should be uploaded into RAVE. 
 
Samples should only be shipped on a Monday-Wednesday to allow for weekday delivery.  Avoid 
holiday shipments.  Email the tracking number to Dr. Reid (reid@mayo.edu) at the time of sample 
shipment. 
 
8.6 
Tumor Tissue for Immunohistochemistry: ATM (Required) 
 
8.6.1 
Description of Studies: 
Immunohistochemistry for ATM will be performed on pre-treatment tumor samples, using archival 
tumor tissue.  This study will primarily investigate whether ATM loss predicts response to BAY 
1895344 (elimusertib).  Secondarily, we will evaluate the prevalence of ATM loss in certain 
pediatric tumors. 
 
8.6.2 
Sampling Schedule (See Appendix IX): 
• 
Archival tumor tissue sample(s) must be submitted at time of enrollment, prior to the start 
of therapy. 
• 
After the end of therapy, with any biopsy occurring within 30 days of end-of treatment. 
 
NOTE: If no tissue is available prior to the start of therapy, the patient will still be eligible for 
therapy. 
 
8.6.3 
Sample Collection and Handling Instructions: 
A minimum of 1 and a preference of 2, unstained slide of FFPE tumor tissue samples will be 
obtained at the above time points. 
 
8.6.4 
Sample Processing: 
Samples can be processed at any institution. Cut tumor into 5µm sections and place, unstained, on 
a glass slide for conventional IHC.  FFPE tumor blocks may alternatively be sent to the Kentsis lab 
if preferable. Samples can be stored prior to shipment, for up to 5 years, refrigerated at 4 ℃. 
 
8.6.5 
Sample Shipping Instructions: 
Samples will be held until all samples have been obtained and then sent as a single batch kept cold 
using ice packs with overnight delivery to the address below. Include the corresponding copy of 
the completed PEPN2112 Tumor Tissue for Immunohistochemistry: ATM transmittal form (from 
RAVE) with each shipment.  
 
Dr. Alex Kentsis 
Kentsis Research Group  
408 East 69 Street, ZRC-1845  
New York, NY 10065, USA 
 
Phone: 1-646-888-3557 
E-mail: kentsisresearchgroup@gmail.com 
 

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Please include qualifying genomic testing report. 
 
Friday collections are not permitted. Deliveries will be accepted Tuesday through Friday. Saturday 
and holiday shipments are not accepted. Please contact lab, prior to shipping. 
 
8.7 
Monitoring for Specific Toxicities  
 
8.7.1 
Growth Plate Toxicity: 
Patients will have a plain AP radiograph of a single proximal tibial growth plate obtained prior to 
the first dose of protocol therapy. 
 
a. If patients are found to have a closed tibial growth plate, no further radiographs will be required.  
 
b. If patients are found to have an open tibial growth plate, then repeat plain AP radiographs of 
the same tibial growth plate will be obtained after cycle 1, every 3 cycles thereafter and at the 
end of study treatment.  
 
NOTE: The end of study treatment observation is not required, if already obtained within the 
final month of therapy. 
 
• Patients with evidence of growth plate thickening or other changes should have a knee MRI 
performed to further assess the degree of physeal pathology and may undergo more 
frequent x-ray follow up as clinically indicated. MRI should be performed without contrast. 
• Patients with knee MRI changes should be managed in an individualized manner. 
Decisions regarding continuation of BAY 1895344 (elimusertib) should be made after 
discussion with the Study Chair or Study Vice-Chair and DVL Leadership, taking into 
account the presence of any symptoms referable to the knee as well as the patient’s 
response to BAY 1895344 (elimusertib). Consultation with an orthopedic surgeon may 
also be indicated. Plans for follow-up imaging will also be made on an individualized basis, 
taking into account the presence of symptoms at the knee or other joints as well as the 
decision to continue BAY 1895344 (elimusertib) or not. 
 
 

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9.0 
AGENT INFORMATION 
 
9.1 
BAY 1895344 
(Elimusertib) NSC# (810486) IND# 
 
 
9.1.1 
Structure and molecular weight: 
BAY 1895344 (elimusertib) is a potent, selective inhibitor of ataxia telangiectasia and Rad3-related 
(ATR) pathway. Activation of the ATR pathway may be critical for survival in tumors harboring 
defects in DNA repair or DNA damage signaling pathways.  
 
Chemical Name: 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol5-
yl)-1, 7-naphthyridine 
 
Molecular Formula: C20H21N7O  M.W.: 375 g/mol 
 
Structure: 
 
 
9.1.2 
Supplied by: 
BAY 1895344 (elimusertib) is supplied by Bayer and distributed by the Division of Cancer Treatment 
and Diagnosis (DCTD), NCI.  
 
9.1.3 
Formulation: 
The agent is supplied as oral film-coated tablets.  
 
Tablets will be packaged in bottles containing 18 tablets.  
• 
20 mg film-coated tablets are red and round with 6 mm diameter 
• 
10 mg film-coated tablets are red and round with 5 mm diameter 
 
Tablet core components include active drug substance, microcrystalline cellulose, lactose 
monohydrate, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Film coating 
contains hydroxypropyl methylcellulose (hypromellose), macrogol, titanium dioxide, and ferric oxide 
red. 
 
9.1.4 
Storage: 
Store at or below 25 °C. Do not freeze.  
 
If a storage temperature excursion is identified, promptly return BAY 1895344 (elimusertib) to 25 
°C or below and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 

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9.1.5 
Stability: 
Shelf life stability studies are on-going. Dispense in original package. 
 
9.1.6 
Administration: See Treatment and Dose Modification sections of the protocol. 
 
Swallow tablets immediately following removal from package.  Take BAY 1895344 (elimusertib) one 
(1) hour before or two (2) hours after a meal with plenty of water. 
 
9.1.7 
Potential Drug Interactions: 
No formal drug interactions studies have been conducted with BAY 1895344 (elimusertib) in humans. 
 
In vitro, BAY 1895344 (elimusertib) is metabolized mainly by CYP3A4 and to a much lesser extent 
CYP1A1. BAY 1895344 (elimusertib) is not a P-gp or BCRP substrate.  Strong inhibitors and inducers 
of CYP3A4 should be avoided. 
 
BAY 1895344 (elimusertib) is a weak to moderate inhibitor of CYP3A4, 2C8, 2C9, and 2C19 in vitro. 
BAY 1895344 (elimusertib) had no significant inhibitory effect on CYP1A2, 2A6, 2B6, 2D6, and 2E1. 
In vitro, BAY 1895344 (elimusertib) was also shown to be an inducer of CYP3A4 and 2C19 but not 
1A2. BAY 1895344 (elimusertib) is predicted to be a moderate inducer toward sensitive CYP3A4 
substrates. CYP3A4 substrates with narrow therapeutic index should be avoided, and substrates of 
CYP2C8, 2C9, and 2C19 should be used with caution. 
 
BAY 1895344 (elimusertib) was identified as an in vitro inhibitor of BCRP, P-gp, BSEP, OATP1B1, 
and OATP1B3.  The risk for clinically relevant drug-drug interactions due to inhibition of BSEP is 
considered to be negligible but substrates of BCRP, P-gp, OATP1B1, and OATP1B3 should be used 
with caution. 
 
Because of pH dependent solubility, antacid drugs, H2-blockers, and proton pump inhibitors may 
affect absorption and exposure of BAY 1895344 (elimusertib). 
 
9.1.8 
Patient Care Implications: 
Based on the UV absorption properties of BAY 1895344 (elimusertib), patients should be instructed 
to use topical sun block and UV-blocking sunglasses on the days BAY 1895344 (elimusertib) is 
administered for 3 days after treatment with BAY 1895344 (elimusertib). Direct exposure of patients 
to sun light after administration should be avoided. 
 
Both male and female patients of reproductive potential should use highly effective contraceptive 
measures throughout the duration of the study and for 3 months + 2 days for males and 6 months + 
2 days for females after receiving the last dose of BAY 1895344 (elimusertib). Female patients must 
not breastfeed during treatment and until 4 months after last study drug administration. 
 
 

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Adverse events reported on BAY 1895344 trials, but for which there is insufficient evidence to suggest that there was 
a reasonable possibility that BAY 1895344 caused the adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
GASTROINTESTINAL DISORDERS - Abdominal pain; Dysphagia 
INFECTIONS AND INFESTATIONS - Shingles 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and procedural complications - 
Other (medication error) 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Lipase increased; 
Lymphocyte count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hypokalemia; Hypophosphatemia 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Presyncope 
PSYCHIATRIC DISORDERS - Irritability 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Epistaxis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Rash maculo-papular 
VASCULAR DISORDERS - Hypotension 
 
 
Note: BAY 1895344 in combination with other agents could cause an exacerbation of any adverse event currently known 
to be caused by the other agent, or the combination may result in events never previously associated with either agent. 
 
 
9.1.10 Agent Ordering and Agent Accountability: 
NCI supplied agents may be requested by the Principal Investigator (or their authorized designee) 
at each participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
agent be shipped directly to the institution where the patient is to be treated. PMB does not permit 
the transfer of agents between institutions (unless prior approval from PMB is obtained.) The CTEP 
assigned protocol number must be used for ordering all CTEP supplied investigational agents. The 
responsible investigator at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA form 1572 (Statement of Investigator), NIH BioSketch, 
Agent Shipment Form, If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Note: No starter supplies will be provided. Drug orders of BAY 1895344 should be placed 
with CTEP PBM after enrollment and treatment assignment to PEPN2112 with 
consideration for timing of processing and shipping to ensure receipt of drug supply prior to 
start of protocol therapy.  
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active person 
registration status.  For questions about drug orders, transfers, returns, or accountability, call or 
email PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to 
agent management.   
 
9.2 
Clinical Drug Request 
Active CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
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and the maintenance of an active person registration status, “active” account status and a “current” 
password. For questions about drug orders, transfers, returns, or accountability call or email PMB anytime. 
Refer to the PMB’s website for specific policies and guidelines related to agent management. 
 
9.3 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the receipt, dispensing and final disposition of all agents using the appropriate (Drug) Accountability 
Record form (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
9.3.1 
Investigator Brochure Availability: 
The current version(s) of the IB for the agent will be accessible to site investigators and research staff 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status, a “current” password and active person registration status. Questions about IB 
access may be directed to the PMB IB coordinator via email. 
 
9.3.2 
Useful Links and Contacts:  
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci.nih.gov/OAOP/. 
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
PMB email: PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) 
 
 

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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) Clinical (including physical examination or serum tumor markers) or radiographic evidence of 
progressive disease (See Section 12) 
b) Adverse Events requiring removal from protocol therapy (See Section 13). 
c) Refusal of protocol therapy by patient/parent/guardian 
d) Non-compliance that in the opinion of the investigator does not allow for ongoing participation. 
e) Completion of 26 cycles of therapy. 
f) Physician determines removal from protocol is in the patient’s best interest. 
g) Repeat eligibility studies are outside the parameters required for eligibility prior to the start of cycle 1 
BAY 1895344 (elimusertib) (See Section 4.0). 
h) Study is terminated by Sponsor. 
i) Pregnancy 
j) Development of secondary malignancy 
Patients who are removed from protocol therapy during Cycle 1 should continue to have the required 
observations in Section 8.1 until the originally planned end of the cycle or until all adverse events 
have resolved per Section 13.5 whichever happens LATER. The only exception is with documentation 
of the patient’s withdrawal of consent. Patients who are removed from protocol therapy in 
subsequent cycles should have the necessary observations to ensure adequate clinical care. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
Section 10.2). Ongoing adverse events, or adverse events that emerge after the patient is removed from 
protocol therapy, but within 30 days of the last dose of investigational agent, must be followed and reported 
via RAVE and CTEP-AERS (if applicable). Follow-up data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
a) The fifth anniversary of the date the patient was enrolled on this study. 
b) Withdrawal of consent for any required observations or data submission. 
c) The patient does not receive protocol treatment after study enrollment.  
d) Patient enrollment onto another COG study with therapeutic (anti-cancer) intent. 
e) Lost to follow-up 
f) Death. 
 
 

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11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS  
 
11.1 
Sample Size and Study Duration 
Dose escalation (Part A) will require a minimum of 4 DLT-evaluable patients and a maximum of 12. Once 
the MTD or recommended Phase 2 dose has been defined, up to 6 additional patients with recurrent or 
refractory solid tumors without restrictions on heme evaluability may be enrolled to acquire PK data in a 
representative number of young patients (i.e. patients < 12 years old). Therefore, a maximum of 23 patients 
is anticipated for Part A allowing for 2 dose levels, PK expansion, and 20% inevaluability. Review of the 
enrollment rate into previous COG early phase new agent studies indicates that 1-2 patients per month are 
available, which will permit completion of the study within 12-23 months.  
 
In the unlikely event that both dose levels are expanded to 12 patients each (see section 11.2.2), the absolute 
maximum number of patients enrolled in Part A will be 38 which would require up to 38 months accounting 
for 2 dose levels, PK expansion, and 20% inevaluability. 
 
The three disease-specific phase 2 cohort studies will require a minimum of 20 response-evaluable patients. 
The maximum number of patients will be 67 allowing for 20% inevaluability. This part of the study is 
expected to be completed within about 25 months assuming 1 patient per month per cohort is available. 
However, completion of enrollment to Part B3 (DDR) will not be required for termination of the study. 
 
Overall, this study will plan to enroll up to 90 patients within 48 months. 
 
11.2 
Definitions 
 
11.2.1 Evaluable for Adverse Events: 
Any patient who receives at least one dose of BAY 1895344 (elimusertib) or who experiences a 
dose-limiting toxicity is considered evaluable for Adverse Events. In addition, during Cycle 1, 
patients not experiencing a DLT must receive at least 75% of the prescribed dose per protocol 
guidelines and must have the appropriate toxicity monitoring studies performed to be considered 
evaluable for dose limiting toxicity. Patients who do not have DLT and are not considered evaluable 
for dose limiting toxicity in Part A will be replaced. 
 
11.2.2 Maximum Tolerated Dose: 
• 
The MTD will be the maximum dose at which fewer than one-third of patients experience DLT 
(See Section 5.5) during Cycle 1 of therapy.  
 
• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are different classes 
of Adverse Effects (eg, hepatotoxicity and myelosuppression), AND all of the following 
conditions are met, expansion of the cohort to 12 patients will be considered:  
 
• 
One of the DLTs does not appear to be dose-related 
• 
The Adverse Effects are readily reversible 
• 
The study chair, PEP-CTN statistician, PEP-CTN committee chair or vice chair, and IND 
sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting toxicities, the 
dose escalation can proceed. 
 
• 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will contribute towards the 
total number of DLTs observed at the RP2D/MTD during the dose escalation portion of the 

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study. If ≥ 1/3 of the cohort of patients at the RP2D/MTD (during the dose escalation plus the 
PK expansion) experience DLT then the MTD will be exceeded. 
• 
If required number of responses per the Simon two-stage design for expansion is not met for 
either the ARMS or EWS phase 2 cohorts whilst the PK expansion is still enrolling, the PK 
expansion will subsequently be closed to those patients.   
 
11.3 
Dose Escalation and Determination of MTD 
 
Rolling Six Design 
The rolling six phase 1 trial design will be used for the conduct of this study.40  Two to six patients can be 
concurrently enrolled onto a dose level, dependent upon (1) the number of patients enrolled at the current 
dose level, (2) the number of patients who have experienced DLT at the current dose level, and (3) the 
number of patients entered but with tolerability data pending at the current dose level. Accrual is suspended 
when a cohort of six has enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the cohort, the number 
of DLTs observed, and the number of participants at risk for developing a DLT (i.e., participants enrolled 
but who are not yet assessable for toxicity). For example, when three participants are enrolled onto a dose 
cohort, if toxicity data is available for all three when the fourth participant entered and there are no DLTs, 
the dose is escalated and the fourth participant is enrolled to the subsequent dose level. If data is not yet 
available for one or more of the first three participants and no DLT has been observed, or if one DLT has 
been observed, the new participant is entered at the same dose level. Lastly, if two or more DLTs have been 
observed, the dose level is de-escalated. This process is repeated for participants five and six. In place of 
suspending accrual after every three participants, accrual is only suspended when a cohort of six is filled. 
When participants are inevaluable for toxicity, they are replaced with the next available participant if 
escalation or de-escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose level (ii) at an 
escalated dose level, (iii) at a de-escalated dose level, or whether the study is suspended to accrual: 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data 
Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 

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6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
* If six patients already entered at next lower dose level, the MTD has been defined. 
**If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then the MTD has 
been exceeded and dose escalation will be stopped (see Section 11.2.2 for exception to rule). 
 
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported. 
 
11.4 
Pharmacokinetic and Correlative Studies and Response Analysis 
A descriptive analysis of pharmacokinetic (PK) parameters of BAY 1895344 (elimusertib) will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK 
parameters will be summarized with simple summary statistics, including means, medians, ranges, and 
standard deviations (if numbers and distribution permit). 
 
While the primary aim of this study is to evaluate the toxicity of BAY 1895344 (elimusertib), patients will 
have disease evaluations performed as indicated in Section 8.1. Disease response will be assessed according 
to RECIST criteria for patients with solid tumors, and will be reported descriptively. 
 
All these analyses will be descriptive and exploratory and hypothesis-generating in nature. 
 
11.5 
Study Design - Phase 2 
Part B will include three separate, Phase 2 cohort studies. The three disease cohorts will include B1) Ewing 
sarcoma, B2) PAX3-FOXO1 ARMS, and B3) disease agnostic DDR. Data collected from patients from the 
dose escalation portion (Part A) and PK expansion portion, treated at the MTD/RP2D and who meet 
eligibility criteria for Part B of the study will be counted in the Phase 2 evaluation. The best response of 
disease to BAY 1895344 (elimusertib) will be examined separately for each cohort.  
 
Parts B1 (Ewing sarcoma) and B2 (PAX3-FOXO1 Alveolar Rhabdomyosarcoma (ARMS)) will use the 
10+10 Simon’s optimal two stage design. 
 
The two-stage design is illustrated below: 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 10 
evaluable patients 
0 
Terminate the trial: conclude 
the agent is ineffective. 
1 or more 
Inconclusive result: Proceed to 
stage 2 
Stage 2: Enter 10 
additional evaluable 
patients 
2 or less 
Conclude the agent is 
ineffective. 
3 or more 
Conclude the agent is effective. 
 
We will consider BAY 1895344 (elimusertib) not of sufficient interest for further evaluation in a disease 
category if the true response rate is ≤5% and of sufficient activity if the true response rate is ≥25%. If BAY 
1895344 (elimusertib) has a true response rate 5%, the rule described above will identify it of sufficient 
activity for further study with probability 7% (type I error), and the trial will have an expected sample size 
of 14 with 60% probability of early termination. If BAY 1895344 (elimusertib) has a true response rate 

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25%, the rule described above will identify it of sufficient activity for further study with probability 88% 
(power). 
 
Part B3 (DNA Damage repair (DDR)) will use the 7+6 Simon’s two stage design if sufficient enrollment is 
observed in the study.  
 
The two stage design is illustrated below: 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 7 
evaluable patients 
0 
Terminate the trial: conclude 
agent is ineffective. 
1 or more 
Inconclusive result: Proceed to 
stage 2 
Stage 2: Enter 6 
additional evaluable 
patients 
1 or less 
Conclude the trial because the 
agent is ineffective. 
2 or more 
Conclude the trial because the 
agent is effective. 
 
We will consider BAY 1895344 (elimusertib) not of sufficient interest for further evaluation in a disease 
category if the true response rate is ≤5% and of sufficient activity if the true response rate is ≥25%. If BAY 
1895344 (elimusertib) has a true response rate 5%, the rule described above will identify it of sufficient 
activity for further study with probability 11% (type I error), and the trial will have an expected sample size 
of 8.8 patients with 70% probability of early termination. If BAY 1895344 (elimusertib) has a true response 
rate 25%, the rule described above will identify it of sufficient activity for further study with probability 
81% (power to reject the null hypothesis P=0.05). 
 
Response in all patients, regardless of age group, with solid tumors will be determined according to RECIST 
or appropriate disease-specific response criteria as defined in the protocol as either complete response (CR), 
partial response (PR), stable disease (SD), or progressive disease (PD) or as described in Section 12.0 for 
other categories or response assessment, and reported as final results.  
 
11.6 
Method of Analysis - Phase 2  
Response in Part B patients will be determined as defined in Section 12.0. A responder is defined as a 
patient who achieves a best confirmed response of PR or CR on the study. Response is defined relative to 
baseline disease. A report on the efficacy assessment will be posted on the completed cohorts as part of the 
semi-annual study committee meeting book report.  
 
The response rate will be estimated by the uniform minimum variance unbiased estimate41 with one-sided 
p-value and confidence interval.42  Each disease cohort will be separately analyzed without adjusting for 
multiple hypothesis tests. 
 
Toxicities for patients will be described separately. Every effort will be made to accrue the number of 
patients needed to evaluate efficacy according to the schema in Section 11.5. For strata not appropriately 
filled, descriptive statistics will be employed to describe outcomes. 
 
 

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11.11 Analysis of the Pharmacokinetic Parameters 
A descriptive analysis of pharmacokinetic (PK) parameters of BAY 1895344 (elimusertib) will be 
performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK 
parameters will be summarized with simple summary statistics, including means, medians, ranges, and 
standard deviations (if numbers and distribution permit). All these analyses will be descriptive and 
exploratory and hypotheses generating in nature. 
 
11.12 Analysis of Biological and Correlative Endpoints 
A descriptive analysis of biomarkers will assess associations with disease response. The parameters will be 
summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if 
numbers and distribution permit). All these analyses will be descriptive and exploratory and hypotheses 
generating in nature. 
 
12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP 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 v.5.0’ is understood to represent the most current version of CTCAE v.5.0 as 
referenced on the CTEP website. 
 
12.2 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 and Therapy Delivery Maps for the schedule of tumor evaluations. In addition 
to the scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle following 
initial documentation of objective response. 
  
See Appendix XIII – Response Criteria for Solid Tumors, for imaging guidelines on solid tumors 
(measurable versus evaluable disease) in addition to disease assessment and imaging guidelines for Ewing 
sarcoma, PAX3-FOXO1 ARMS, and DDR. 
   
Response and progression will be evaluated in this study using the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1).43  Key points are that 5 target lesions are identified and 
that changes in the largest diameter (unidimensional measurement) of the tumor lesions but the shortest 
diameter of malignant lymph nodes are used in the RECIST v 1.1 criteria. 
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for toxicity: 
All patients who experience a cycle 1 DLT or receive at least 75% of the planned dose 
will be evaluable for toxicity from the time of their first treatment with BAY 1895344 
(elimusertib).  Enrolled patients who have not received any treatment will not be 
considered evaluable for toxicity. 
 
12.2.1.2 Evaluable for objective response: 
All patients who receive at least one dose of BAY 1895344 (elimusertib) will be 
evaluable for response. Evaluable patients who demonstrate a complete or partial 
response confirmed by central review before receiving non-protocol anti-cancer therapy 
will be considered a responder. All other evaluable patients will be considered non-

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13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are done to ensure the 
safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. 
Adverse events are reported in a routine manner at scheduled times during a trial. (Please follow directions for 
routine reporting provided in the Case Report Forms for this protocol). Additionally, certain adverse events must 
be reported in an expedited manner to allow for optimal monitoring of patient safety and care. The following 
sections provide information about expedited reporting. 
 
Reporting requirements may include the following considerations: 1) whether the patient has received an 
investigational or commercial agent; 2) whether the adverse event is considered serious; 3) the adverse (severity); 
and 4) whether or not hospitalization or prolongation of hospitalization was associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug Application (IND). In 
some instances, the investigational agent may be available commercially, but is actually being tested for indications 
not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a commercial source. 
The NCI, rather than a commercial distributor, may on some occasions distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Step 2:  Grade the adverse event using the NCI CTCAE v.5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific adverse 
events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements. 
 
NOTE: This includes all events that occur within 30 days of the last dose of protocol treatment. 
Any event that occurs more than 30 days after the last dose of treatment and is attributed 
(possibly, probably, or definitely) to the agent(s) must also be reported according to the 
instructions in the table below. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 
 
 

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13.3 
Expedited Reporting Methods 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event Expedited Reporting 
System (CTEP-AERS) that can be found at https://ctepcore.nci.nih.gov/ctepaers/pages/task. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS Web-based 
application located at https://ctepcore.nci.nih.gov/ctepaers/pages/task.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be made 
to the NCI for agents supplied under a CTEP IND by telephone call to (301) 897-7497.  
 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned in must 
be entered into the electronic CTEP-AERS system by the original submitter of the report at the site. 
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 1) 
whether the patient has received at least one dose of an investigational agent on this study; 2) the 
characteristics of the adverse event including the grade (severity), the relationship to the study 
therapy (attribution), and the prior experience (expectedness) of the adverse event; 3) the phase (1, 
2, or 3) of the trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.  
 
Email supporting documentation to the PEP-CTN Study Assigned Research Coordinator. 
ALWAYS include the ticket number on all faxed documents. 
 
For COG held IND studies, only email the Research Coordinator; do not fax CTEP. 
 
13.4 
Specific Examples for Expedited Reporting 
13.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug: 
Any Serious Adverse Event that occurs more than 30 days after the last administration of the 
investigational agent/intervention and has an attribution of a possible, probable, or definite 
relationship to the study therapy must be reported according to the CTEP-AERS reporting table in 
this protocol. 
 
13.4.2 Persistent or Significant Disabilities/Incapacities: 
Any AE that results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions (formerly referred to as disabilities), congenital anomalies or birth 
defects, must be reported via CTEP-AERS if it occurs at any time following treatment with an 
agent under a NCI or non-NCI IND/IDE since these are considered serious AEs. 
 
13.4.3 Reportable Categories of Death:  
 
• 
Death attributable to a CTCAE v5.0 term.  
 
• 
Death Neonatal: Newborn death occurring during the first 28 days after birth. 
 
• 
Sudden Death NOS: A sudden (defined as instant or within one hour of the onset of symptoms) 
or an unobserved cessation of life that cannot be attributed to a CTCAE term associated with 
Grade 5.  
 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
 

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• 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” in the 
system organ class (SOC). “General disorder and administration site conditions”. Evidence that 
the death was a manifestation of underlying disease (eg, radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
 
13.4.3 Secondary Malignancy: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment 
with investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial 
neoplasm is not considered a secondary malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with an agent under 
an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy (eg, acute myelocytic leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must also be reported 
via the routine reporting mechanisms in the following section.  
 
13.4.3.1 Reporting Secondary AML/MDS 
All cases of AML and MDS that occur in patients following their chemotherapy for 
cancer must be reported via CTEP-AERS and included as part of the second malignant 
neoplasm reporting requirements for this protocol (see data submission packet). Submit 
the completed CTEP-AERS report within 14 days of an AML/MDS diagnosis occurring 
after protocol treatment for cancer. 
 
13.4.4 Second Malignancy: 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  
 
13.4.5 Pregnancy, Pregnancy Loss, and Death Neonatal: 
Note: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Death 
Neonatal”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportForm.
pdf, should be completed and emailed to the PEP-CTN Study Assigned Research Coordinator along 
with any additional medical information. The potential risk of exposure of the fetus to the 
investigational agent should be documented in the “Description of Event” section of the CTEP-
AERS report. 
 
13.4.5.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to agents 
that may be teratogenic. For this reason, pregnancy needs to be reported in an expedited 
manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and perinatal 

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conditions - Other (pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
Pregnancy needs to be followed until the outcome is known if the baby is born with a 
birth defect or anomaly, then a second CTEP-AERS report is required. 
 
13.4.5.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero” Any pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy, loss” under the “Pregnancy, 
puerperium and perinatal conditions” SOC. Do NOT report a pregnancy loss as a 
Grade 5 event since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
13.4.5.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during the first 28 days 
after birth” should be reported expeditiously, as Grade 4 “Death neonatal” under the 
“General disorders and administration” SOC, when the death is the result of a 
patient pregnancy or pregnancy in partners of men on study. Do NOT report a 
neonatal death resulting from a patient pregnancy or pregnancy in partners of men on 
study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event as a patient 
death.  
 
13.4.6 Syndrome Reporting: 
Unless otherwise specified in this protocol, syndromes should be reported as a single event using 
the CTCAE term for the composite syndrome, and not as the individual events that make up the 
syndrome. For example, Tumor Lysis Syndrome should be reported under the composite definition 
rather than reporting the component events (hyperkalemia, hyperphosphatemia, hypocalcemia, 
hyperuricemia) separately. 
 
 
13.5 
Definition of Onset and Resolution of Adverse Events 
Note: These guidelines below are for reporting adverse events on the COG PEP-CTN case report forms 
and do not alter the guidelines for CTEP-AERS reporting. 
 
13.5.1 If an adverse event occurs more than once in a course (cycle) of therapy only the most severe grade 
of the event should be reported. 
 
13.5.2 If an adverse event progresses through several grades during one course of therapy, only the most 
severe grade should be reported. 
 
13.5.3 The duration of the AE is defined as the duration of the highest (most severe) grade of the Adverse 
Effects. 
 
13.5.4 The resolution date of the AE is defined as the date at which the AE returns to baseline or less than 
or equal to Grade 1, whichever level is higher (note that the resolution date may therefore be 
different from the date at which the grade of the AE decreased from its highest grade). If the AE 
does not return to baseline the resolution date should be recorded as “ongoing”. 
 
13.5.5 An adverse event that persists from one course to another should only be reported once unless the 
grade becomes more severe in a subsequent course. An adverse event which resolves and then 
recurs during a different course, must be reported each course it recurs.  
 

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13.6 
Other Recipients of Adverse Event Reports 
 
13.6.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 9.1.10) should be reported 
at the end of each cycle using the forms provided in the CRF packet. 
 
13.6.2 COG will forward reports and supporting documentation to the Study Chair, to the FDA (when 
COG holds the IND) and to the pharmaceutical company (for industry sponsored trials). 
 
13.6.3 Adverse events determined to be reportable must also be reported according to the local policy and 
procedures to the Institutional Review Board responsible for oversight of the patient. 
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories: 
 
1. Non-computerized Information: Therapy Delivery Maps (TDMs), Pathology Reports, Surgical 
Reports. These forms are uploaded into RAVE. 
 
2. Reference Labs, Biopathology Reviews, and Imaging Center data: These data accompany submissions 
to these centers, which forward their data electronically to the PEP-CTN Operations and Data/Statistics 
Center. 
 
 
3. Computerized Information Electronically Submitted: All other data will be entered in RAVE with the 
aid of schedules and worksheets (essentially paper copies of the OPEN and RAVE screens) provided 
in the case report form (CRF) packet. 
 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN  
 
Data Mapping Utility (DMU) Reporting Complete 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative protocol- and 
patient-specific data will be submitted weekly to CTEP electronically via the DMU.  DMU Complete 
reporting consists of Patient Demographics, Baseline Abnormalities, On/Off Treatment/Study Status, 
Treatment/Course/Dosing information, Adverse Events, Late Adverse Events, and Response data as 
applicable.  More information on the DMU is available on the CTEP Website: 
 https://ctep.cancer.gov/protocolDevelopment/dmu.htm. DMU reporting is not a responsibility of 
institutions participating in this trial. 
 
14.3 
CRADA/CTA/CSA 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the 
following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 

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1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the NCI. If a copy of this 
protocol is requested by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
investigational Agent(s), each the subject of different collaborative agreements, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as “Multi-Party Data”): 
 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NCI, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI’s 
participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by 
any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational Agent. 
 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made 
available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) Additionally, all Clinical 
Data and Results and Raw Data will be collected , used and disclosed consistent with all applicable 
federal statutes and regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who 
will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for 
other studies) of Collaborator’s wish to contact them. 
 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and 
policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 
 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for immediate 
delivery to Collaborator(s) for advisory review and comment prior to submission for publication. 
Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right 
to request that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual property 

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rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, 
abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript 
or other form of public disclosure shall contain any of Collaborator’s confidential/proprietary 
information. 
 
14.4 
Monitoring 
On-site, retrospective source data verification is completed by Theradex on an annual basis for 100% of 
COG PEP-CTN patients enrolled in early phase clinical trials. 
 
This study will additionally include central monitoring as part of data review. Source documents will be 
uploaded via CTSU’s Source Document Portal. (See Appendix II for details). 
 
14.5 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the Data and Safety Monitoring 
Committee. 
 
14.5.1 Data and Safety Monitoring Committee: 
This study will be monitored in accordance with the Children’s Oncology Group PEP-CTN policy 
for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of the COG PEP-CTN 
Data and Safety Monitoring Committee is to protect the interests of patients and the scientific 
integrity for all Phase 1 and 2 studies. The DSMC consists of a chair; a statistician external to COG; 
one external member; one consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months to review current 
study results, as well as data available to the DSMC from other related studies. Approximately 6 
weeks before each meeting of the Phase 1 and 2 DSMC, study chairs will be responsible for 
working with the study statistician to prepare study reports for review by the DSMC. The DSMC 
will provide recommendations to the PEP-CTN Chair and the Group Chair for each study reviewed 
to change the study or to continue the study unchanged. Data and Safety Committee reports for 
institutional review boards can be prepared using the public data monitoring report as posted on 
the COG member’s Web site. 
 
14.5.2 Monitoring by the Study Chair and the Steering Committee: 
The study chair will monitor the study regularly and enter evaluations of patients’ eligibility, 
evaluability, and dose limiting toxicities into the study database. In addition, study data and the 
study chair’s evaluations will be reviewed by the PEP-CTN Chair, Vice Chair and Statistician on 
a weekly conference call. 
 

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Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using 
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Yap TA, Tan DSP, Terbuch A, et al. First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related 
(ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors. Cancer discovery. 2021;11(1):80-91. 
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Bono JSD, Tan DSP, Caldwell R, et al. First-in-human trial of the oral ataxia telangiectasia and Rad3-related (ATR) 
inhibitor BAY 1895344 in patients (pts) with advanced solid tumors. Journal of Clinical Oncology 2019;37:3007. 
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Wengner AM, Siemeister G, Lucking U, et al. The novel ATR inhibitor BAY 1895344 is efficacious as 
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Henssen AG, Koche R, Zhuang J, et al. PGBD5 promotes site-specific oncogenic mutations in human tumors. 
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Gorthi A, Romero JC, Loranc E, et al. EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair 
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Stewart SA, Weinberg RA. Telomeres: cancer to human aging. Annu Rev Cell Dev Biol. 2006;22:531-557. 
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Heaphy CM, de Wilde RF, Jiao Y, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 
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Henson JD, Cao Y, Huschtscha LI, et al. DNA C-circles are specific and quantifiable markers of alternative-
lengthening-of-telomeres activity. Nat Biotechnol. 2009;27(12):1181-1185. 
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Koppenhafer SL, Goss KL, Terry WW, Gordon DJ. Inhibition of the ATR-CHK1 Pathway in Ewing Sarcoma Cells 
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MCR. 2019. 
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Nieto-Soler M, Morgado-Palacin I, Lafarga V, et al. Efficacy of ATR inhibitors as single agents in Ewing sarcoma. 
Oncotarget. 2016;7(37):58759-58767. 
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Henssen AG, Kentsis A. Emerging functions of DNA transposases and oncogenic mutators in childhood cancer 
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Gorthi A, Bishop AJR. Ewing sarcoma fusion oncogene: At the crossroads of transcription and DNA damage 
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Stewart E, Goshorn R, Bradley C, et al. Targeting the DNA repair pathway in Ewing sarcoma. Cell reports. 
2014;9(3):829-841. 
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Yang W, Soares J, Greninger P, et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic 
biomarker discovery in cancer cells. Nucleic acids research. 2013;41(Database issue):D955-961. 
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García HD, Bei Y, von Stebut J, et al. Exploiting a PAX3-FOXO1-induced synthetic lethal ATR dependency for 
rhabdomyosarcoma therapy. bioRxiv. 2020:2020.2012.2004.411413. 
36. 
Wengner AM, Siemeister G, Lucking U, et al. The Novel ATR Inhibitor BAY 1895344 Is Efficacious as 
Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical 
Cancer Models. Molecular cancer therapeutics. 2020;19(1):26-38. 
37. 
White D, Rafalska-Metcalf IU, Ivanov AV, et al. The ATM substrate KAP1 controls DNA repair in 
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38. 
Bayer AG. BAY 1895344 Investigator's Brochure, Version 5.0. In: Bayer AG; 2019. 
39. 
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr. 
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40. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of pediatric phase I trials: the 
rolling six design. J Clin Oncol. 2008;26(2):190-195. 
41. 
Jung SH, Kim KM. On the estimation of the binomial probability in multistage clinical trials. Stat Med. 
2004;23(6):881-896. 
42. 
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med. 2008;27(16):3145-3154. 
43. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST 
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Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. 
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Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
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3068. 
 
 
 

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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all individuals 
contributing to NCI-sponsored trials to register and to renew their registration annually. To register, all individuals 
must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator (IVR), Non-Physician 
Investigator (NPIVR), or Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications such as the Roster 
Update Management System (RUMS), OPEN, Rave, acting as a primary site contact, or with consenting 
privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited access to NCI-
supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and Cancer 
Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs must list all clinical practice 
sites and Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment 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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Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
IRB Approval  
U.S. sites participating in the PEP-CTN network are required to use the NCI CIRB as of 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 with the NCI CIRB must submit the Study Specific Worksheet for Local Context (SSW) to the 
CIRB using IRBManager to indicate their intent to open the study locally. The NCI CIRB’s approval of the SSW is 
automatically communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals across their 
Signatory Network. Site preferences can be set at the network or protocol level. Questions about establishing site 
preferences can be addressed to the CTSU Regulatory Office by email or 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 in order for the processing of the IRB/REB approval record to be completed: 
• 
Holds an Active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval and on at least one participating roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the Registration and 
Credential Repository (RCR) profile; 
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating Organization (PO);  
• 
An Active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory Institution (US sites 
only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 

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Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory Submission Portal on 
the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the Regulatory section 
and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should alert the CTSU 
Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or CTSURegHelp@coccg.org in order 
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. 
 
Requirements for PEPN2112 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, and/or Protocol Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form. 
 
Delegation of Tasks Log 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL application in the 
Delegation Log section on the CTSU members’ website. 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 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 include a Master Task List, which describes DTL task 
assignments, CI signature, and CTEP registration requirements. 
 
Data Submission / Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this trial/study. Access to 
the trial in Rave is controlled through the CTEP-IAM system and role assignments.  
 
Requirements to access Rave via iMedidata: 

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• 
A valid CTEP-IAM account; 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 an Non-Physician Investigator (NPIVR) or Investigator 
(IVR); and 
o 
Rave Read Only 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. 
 
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 Regulatory Support System (RSS), all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site staff must either click on the link in email or log in to iMedata via the CTSU members’ website 
under Data Management > Rave home and click accept to the invitation in the the upper right-corner of the 
iMedidata screen. Site staff will not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) and can be accessed by 
clicking on the link in the upper right corner of the iMedidata screen. If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies pane located in the 
center of the iMedidata screen. Once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the eLearning link under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in RSS will receive a separate invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website in the Data Management section under the Rave resource 
materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave section at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
.   
Rave CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
integration enables evaluation of post-baseline Adverse Events (AE) entered in Rave to determine whether 
they require expedited reporting, and facilitates entry in CTEP-AERS for those AEs requiring expedited 
reporting.    
All AEs that occur after baseline are collected in Rave using the Adverse Event form, which is available 
for entry at each treatment or reporting period, and used to collect AEs that start during the period or persist 
from the previous reporting period. The Clinical Research Associate (CRA) will enter AEs that occur prior 
to the start of treatment on a baseline form that is not included in the Rave-CTEP-AERS integration. 
Baseline AEs must begin and end on the baseline Adverse Events form and should not be included on the 
Adverse Events form that is available at treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the following on the 
Adverse Event form in Rave: 
• 
The reporting period (course/cycle) is correct; and 
• 
AEs are recorded and complete (no missing fields) and the form is query free. 

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The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA modifies an AE, 
it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Rave, the Rave CRA submits the AE for rules evaluation by completing 
the Expedited Reporting Evaluation form in Rave. Both NCI and protocol-specific reporting rules evaluate 
the AEs submitted for expedited reporting. A report is initiated in CTEP-AERS using information entered 
in Rave for AEs that meet reporting requirements. The CRA completes the report by accessing CTEP-
AERS via a direct link on the Rave Expedited Reporting Evaluation form. 
In the rare occurrence, that Internet connectivity is lost; a 24-hour notification is to be made to CTEP by 
telephone at 301-897-7497. Once internet connectivity is restored, the 24-hour notification that was phoned 
in must be entered electronically into CTEP-AERS using the direct link from Medidata Rave... 
Additional information about the CTEP-AERS integration is available on the CTSU website: 
• 
Study specific documents: Protocols > Documents> Education and Promotion; and   
• 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU Operations 
Information> User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
• 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf. 
 
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. Review 
the DQP modules on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. Staff 
that have Rave study access can access the Rave study data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, DQP Queries, 
DQP Form Status and DQP Reports modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on the DQP. A 
protocol must have the Calendar functionality implemented in Rave by the Lead Protocol Organization 
(LPO) for delinquent form details and reports to be available on the DQP. Site staff should contact the LPO 
Data Manager for their protocol regarding questions about Rave Calendaring functionality.   
 
Central Monitoring 
 
Central Monitoring (CM) Review is required for this protocol. CM allows Lead Protocol Organizations (LPOs) to 
remotely compare data entered in Rave to source documentation to ensure that sites are adhering to the protocol 
and central monitoring plan as well as accurately transcribing data from patients’ charts (i.e., source data 
verification).  

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Sites can upload source documents required for CM Review as documented in the central monitoring plan using 
the Source Document Portal (SDP). This application is available on the CTSU members’ website under Auditing 
& Monitoring and may also be accessed using a direct link within Rave on the CM Alert form. Site staff with the 
CRA or Investigator roles in Rave can view and upload source documents. Prior to saving source documents on the 
SDP, each site is responsible for removing or redacting any Personally Identifiable Information (PII) (note that 
functionality to do this redaction exists within the SDP itself). Designated LPO staff will review each document 
after it has been loaded on the SDP to ensure the appropriate documents have been uploaded and to ensure PII is 
redacted. 
Additional information on the SDP is available on the CTSU members’ website under Auditing & Monitoring > 
Source Document Portal in the Help Topics button or by contacting the CTSU Help Desk (1-888-823-5923 or 
ctsucontact@westat.com).  
 

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Labs/reports 
documenting 
protocol 
specific CTEP-
AERS 
reportable 
events 
13.0 
Has an Adverse Event 
Expedited Report been 
submitted? 
Conditional: If 
response is YES, CM 
is required 
E.g., hospital admission 
report, laboratory reports, 
etc. 
Relevant Document Cycle 1 
Cycle 3 
 
Addressing Monitoring Findings 
In the event that this monitoring identifies unacceptable procedures or significant deviations from protocol procedures, then the site will need to submit a corrective 
action plan to COGRegComp@childrensoncologygroup.org within two weeks. 
 
In the event of significant repeated major deviations from the protocol, COGQA, in consultation with the study chair, may recommend that COG leadership suspend 
accrual at the site. 
 

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APPENDIX III: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is important to regularly consult 
frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate Inhibitors 
Strong Inducers 
Moderate Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodipine 
aprepitant/fosaprepitant 
atorvastatin 
avanafil5 
axitinib 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
colchicine5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
ebastine5 
eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
felodipine5 
fentanyl4 
gefitinib 
atazanavir 
boceprevir 
clarithromycin 
ceritinib 
cobicistat 
danoprevir/ritonavir 
darunavir 
delavirdine 
elvitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lefamulin 
letermovir 
mifepristone 
netupitant 
nilotinib 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
modafinil 
nafcillin 
rifabutin 
rifapentin 
 
 
 

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CYP3A4 substrates  
Strong Inhibitors1 
Moderate Inhibitors 
Strong Inducers 
Moderate Inducers 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
lomitapide5 
lorlatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
naloxegol5 
nefazodone 
nilotinib 
nisoldipine5 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
tadalafil5 
telaprevir 
temsirolimus 
teniposide 
tetracycline 

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CYP3A4 substrates  
Strong Inhibitors1 
Moderate Inhibitors 
Strong Inducers 
Moderate Inducers 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may inhibit CYP 3A4 
isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.2.2.1 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is concentration-, dose-, and 
preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 
 
 
 
 

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APPENDIX IV: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
Grade 1: 
> ULN- ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN 
Grade 3: 
> 3.0 x ULN -10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline. 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for SGOT is 50 U/L regardless of baseline. 
Grade 1: 
> 50 U/L - ≤ 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN -20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 
 

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APPENDIX VII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
A Phase 1/ 2 Study of BAY 1895344 (elimusertib) in Pediatric Patients with Relapsed or Refractory Solid 
Tumors  
  
1. We have been talking with you about your cancer.  You have had treatment for the cancer already but the 
cancer did not go away or it came back after treatment. 
 
2. We are asking you to take part in a research study because other treatments did not get rid of the cancer. 
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 cancer that you have. We will do this by 
trying a new medicine to treat your cancer. 
 
3. Children who are part of this study will be treated with a cancer-fighting medicine called BAY 1895344 
(elimusertib). You will have some tests and check-ups done more often than if you weren’t part of the 
study. Some of these tests will require extra needle sticks for blood. The doctors want to see if BAY 
1895344 (elimusertib) will make children with your type of cancer get better. We don’t know if BAY 
1895344 (elimusertib) will work well to get rid of your cancer. That is why we are doing this study.  
 
4. 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 of being part of this study is that BAY 1895344 
(elimusertib) may cause your cancer to stop growing or to shrink for a period of time but we don’t know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things are 
called “risks.” The risks to you from this study are that you may have more problems, or side effects, 
from BAY 1895344 (elimusertib) than other treatments. Other things may happen to you that we don’t 
yet know about. 
 
6. You and your family can choose to be part of this study or not. You and your family can also decide to 
stop being in this study at any time once you start. There may be other treatments for your illness that 
your doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood and tumor tissue. We want to see if there are 
ways to tell how the cancer will respond to treatment. The blood samples would be taken when other 
standard blood tests are being performed and we are asking for extra tumor tissue already taken and 
stored during your diagnosis or removed with procedures that happen while you are on the study, so 
there would be no extra procedures. You and your family can still take part in this study even if you 
don't allow us to collect the extra blood or tumor tissue samples for research. 
 
 
 
 
 

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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
A Phase 1/ 2 Study of BAY 1895344 (elimusertib) in Pediatric Patients with Relapsed or Refractory Solid Tumors  
  
1. We have been talking with you about your cancer.  You have had treatment for the cancer already but 
the cancer did not go away or it came back after treatment. 
  
2. We are asking you to take part in a research study because other treatments did not get rid of the cancer. 
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 cancer that you have. We will do this by 
trying a new medicine to treat your cancer. 
 
3. Children and teens who are part of this study will be treated with a cancer-fighting medicine called BAY 
1895344 (elimusertib). You will also have some tests and exams done more often while you are in this 
study. Some of these tests will require extra needle sticks for blood tests. The doctors want to see if 
BAY 1895344 (elimusertib) will make children with your type of cancer get better. We don’t know if 
BAY 1895344 (elimusertib) will work well to get rid of your cancer. That is why we are doing this 
study.  
 
4. 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 of being part of this study is that BAY 1895344 
(elimusertib) may cause your cancer to stop growing or to shrink for a period of time but we don’t know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things are 
called “risks.” The risks to you from this study are that you may have more problems, or side effects, 
from BAY 1895344 (elimusertib) than other treatments. Other things may happen to you that we don’t 
yet know about. 
 
6. You and your family can choose to be part of this study or not. You and your family can also decide to 
stop being in this study at any time once you start. There may be other treatments for your illness that 
your doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional blood and tumor tissue. We want to see if there are 
ways to tell how the cancer will respond to treatment. The blood samples would be taken when other 
standard blood tests are being performed and we are asking for extra tumor tissue already taken and 
stored during your diagnosis or removed with procedures that happen while you are on the study, so 
there would be no extra procedures. You and your family can still be treated on this study even if you 
don't allow us to collect the extra blood or tumor tissue samples for research. 
 
 
 

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Priority Biomark
er Name  
Assay 
(CLIA
: Y/N) 
Use in the Trial 
(Integral, 
Integrated, 
or 
Exploratory) 
AND Purpose  
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional Assay 
Laboratory 
and Lab PI c 
2 
Tumor 
Whole 
Genome 
Sequenci
ng 
Whole 
Geno
me 
Seque
ncing 
CLIA: 
N 
Exploratory  
Correlative 
See section 8.3.1 
for purpose. 
Frozen 
Tumor  
Pre-dose, 
archival 
tumor tissue, 
at 
relapse, 
post 
treatment 
study 
O 
Dr. 
Alex 
Kentsis 
(MSKCC, New York 
City, NY) 
kentsisa@ mskcc.org 
3* 
pH2AX, 
pKAP1 
and 
pATR 
IHC 
CLIA: 
N 
Exploratory 
Correlative 
See section 8.3.3 
for purpose 
FFPE 
Tumor 
Pre-dose, 
archival 
tumor tissue 
O 
Dr. 
Alex 
Kentsis 
(MSKCC, New York 
City, NY) 
kentsisa@ mskcc.org  
4* 
 
R-loops 
PGBD5 
IHC 
CLIA: 
N 
Exploratory 
Correlative 
See section 8.3.2 
for purpose 
FFPE 
Tumor  
Pre-dose, 
archival 
tumor tissue 
O 
Dr. 
Alex 
Kentsis 
(MSKCC, New York 
City, NY) 
kentsisa@ mskcc.org  
5 
ALT 
RT-
PCR 
for 
TERT 
and C-
circle 
assay 
CLIA: 
N 
Exploratory 
Correlative 
 
See section 8.3.1 
for purpose 
FFPE 
Tumor  
Pre-dose 
archival 
tumor tissue, 
post-dose 
(Analyzed 
with 
WGS 
tumor tissue) 
O 
Dr. Charles Patrick 
Reynolds 
(COGCCXR, 
Lubbock, TX) 
patrick.reynolds@ttu
hsc.edu 
6. 
Archival 
Tumor 
Tissue for 
Biobanki
ng 
Archiv
al 
Tumor 
Tissue 
CLIA: 
Y 
Exploratory 
Correlative 
See Section 8.3.6 
FFPE 
Tumor 
or 
slides 
Pre-dose 
archival 
tumor tissue 
O 
Biopathology Center 
Nationwide 
Children’s Hospital 
BPCBank@nationwi
dechildrens.org 
 
Blood-based Biomarkers 
1 
ALT 
ctDNA 
CLIA: 
N 
Exploratory 
Correlative 
See section 8.3.4 
for purpose 
Blood (pre-
dose) 
Pre-Dose 
O 
Dr. Charles Patrick 
Reynolds 
(COGCCXR, 
Lubbock, TX) 
patrick.reynolds@ttu
hsc.edu 

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Priority Biomark
er Name  
Assay 
(CLIA
: Y/N) 
Use in the Trial 
(Integral, 
Integrated, 
or 
Exploratory) 
AND Purpose  
Specimens 
Tested 
Collection 
Time Points 
Mandatory 
or Optional Assay 
Laboratory 
and Lab PI c 
2 
ALT 
RT-
PCR 
for 
TERT 
and C-
circle 
assay 
CLIA: 
N 
Exploratory 
Correlative 
 
See section 8.3.1 
for purpose 
Blood (pre-
dose) 
Pre-Dose 
(Analyzed 
with 
WGS 
blood 
samples) 
O 
Dr. Charles Patrick 
Reynolds 
(COGCCXR, 
Lubbock, TX) 
patrick.reynolds@ttu
hsc.edu 
2 
Tumor 
Whole 
Genome 
Sequenci
ng 
Whole 
Geno
me 
Seque
ncing 
CLIA: 
N 
Exploratory  
Correlative 
See section 8.3.1 
for purpose. 
Blood (pre-
dose) 
Pre-Dose 
O 
Dr. 
Alex 
Kentsis 
(MSKCC, New York 
City, NY) 
kentsisa@ mskcc.org 
3. 
Pharmaco
kinetics 
Pharm
acokin
etics 
CLIA: 
Y 
Integrated 
Correlative 
See section 8.5.1 
for purpose 
Blood 
Part A: 
Cycle 1, Day 
1; 
Cycle 1, Day 
3; 
Cycle 1, Day 
10 
Part B: 
Cycle 1, Day 
1; 
Cycle 1, Day 
3; 
Cycle 1, Day 
10 
M 
Dr. Joel Reid 
Pharmacology Shared 
Resource 
reid@mayo.edu 
4.  
Pharmaco
kinetics 
Pharm
acokin
etics 
CLIA: 
Y 
Exploratory 
Correlative 
 
Blood 
Part A: 
Cycle 1, Day 
1; 
Cycle, 
1, 
Day 10 
O 
Dr. Joel Reid 
Pharmacology Shared 
Resource 
reid@mayo.edu 
* Will prioritize pH2AX, pKAP1 and pATR over R-loops and PGBD5 if there are pre-/post- matched samples.  If not, will 
prioritize R-Loops and PGBD5. 
 

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13 
Cycle 1, Day 10 
8 hours post-dose (± 30 minutes) 
___/___/___ 
|
|
| : |
|
| 
14 
Cycle 1, Day 
10* 
12 hours post-dose (± 30 minutes) 
___/___/___ 
|__|__| : |__|__| 
 
 
BAY 1895344 
(elimusertib) 
BID Dose on  
Cycle 1, Day 10 
 
Date:___/___/___ 
Time Dose Given:               Dose Given: ___________ mg 
|__|__| : |__|__| 
*12-hour PK collection on cycle 1, day 1 and cycle 10, day 1 is optional, and if obtained, should be drawn before the PM dose. 
 
One copy of this PK Form should be uploaded into RAVE. A second copy should be sent with the samples to the address listed in 
Section 8.5.2, in addition to detailed guidelines for packaging and shipping PK samples. 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this form below: 
 
Signature: _________________________________________                        Date:___________________                                             
(site personnel responsible for collection of samples
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX XII: RESPONSE CRITERIA FOR LYMPHOMA 
 
Response Criteria for Non-Hodgkin Lymphoma 
Response and progression will be evaluated in this study using the new international criteria proposed by the revised 
Response Evaluation Criteria in Pediatric Non-Hodgkin Lymphoma Criteria44, with modification from the Lugano 
classification.45 
 
Disease Parameters 
 
Measurable disease: A measurable node must have an LDi (longest diameter) greater than 1.5 cm. A measurable extranodal 
lesion should have an LDi greater than 1.0 cm. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Non-measured disease: All other lesions (including nodal, extranodal, and assessable disease) should be followed as 
nonmeasured disease (eg, cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial effusions, ascites). 
 
Target lesions: For patients staged with CT, up to six of the largest target nodes, nodal masses, or other lymphomatous 
lesions that are measurable in two diameters (longest diameter [LDi] and shortest diameter) should be identified from 
different body regions representative of the patient’s overall disease burden and include mediastinal and retroperitoneal 
disease, if involved. 
 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than 2 weeks prior to the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and reported lesion 
at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules and palpable 
lymph nodes) and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Conventional CT and MRI: The major response designations will be established by CT or MRI of involved sites in 
conjunction with morphologic evaluation of bone marrow (BM) if involved at diagnosis. With growing concerns about the 
risks of cumulative ionizing radiation exposure to children from CT, MRI could be considered as an alternative to CT for 
evaluating non-pulmonary disease sites. eg, assessment of abdominal/pelvic disease. As with CT, if an MRI is performed, 
the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions 
should be measured/assessed on the same pulse sequence. It is beyond the scope of the response guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should 
be used and the image acquisition protocol should be followed as closely as possible to prior scans. Pulse sequences should 
include at a minimum, axial and coronal fat-saturated FRFSE-T2, coronal T1 and axial and coronal post-gadolinium fat-
saturated T1 weighted imaging. Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal 
diagnostic CT quality. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for International 
Pediatric Non-Hodgkin Lymphoma Response Criteria measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional 
data, which may bias an investigator if it is not routinely or serially performed.   

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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. 
Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment 
to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If 
there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers: There will be no use of tumor markers to assess response in the protocol. EBV qPCR of peripheral blood 
PBMCs will be performed centrally to measure the presence of active viral replication and disease activity but results will 
not be used to stratify assignment to treatment arms. 
 
FDG-PET: For patients with a positive PET scan at diagnosis, PET can be used to follow response in addition to a CT scan 
using the International Pediatric Non-Hodgkin Lymphoma Response Criteria. 
 
 
Response Criteria 
 
Evaluation of Measurable Disease 
 
• 
Complete Response (CR): Disappearance of all disease. CT or MRI should be free of residual mass or evidence 
of new disease. FDG-PET should be negative. 
 
• 
CR unconfirmed (Cru): Residual mass is negative by FDG-PET; no new lesions by imaging examination; no new 
and/or progressive disease elsewhere 
 
• 
Partial Response (PR): 50% decrease in SPD (the sum of the products of the largest diameter and the perpendicular 
diameter for a tumor mass) on CT or MRI; FDG-PET may be positive (Deauville score or 4 or 5 with reduced 
lesional uptake compared with baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in percentage of lymphoma cells 
 
• 
Progressive Disease (PD): For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on FDG-
PET with increase in lesional uptake from baseline, or development of new morphologic evidence of disease in BM 
 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
  
Evaluation of Non-measured Lesions (CT-based response, PET/CT based response not applicable) 
 
• 
Complete Response (CR): Absent non-measured lesions.  
 
• 
Partial response (PR): Absent/normal, regressed, lesions, but no increase. 
 
• 
Stable Disease (SD): No increase consistent with progression 
 
• 
Progressive Disease (PD): New or clear progression of preexisting non-measured lesions. 
 
 

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Evaluation of organ enlargement 
 
• 
Complete Response (CR): Regress to normal  
 
• 
Partial response (PR): Spleen must have regressed by > 50% in length beyond normal 
 
• 
Stable Disease (SD): No increase consistent with progression 
 
• 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length must increase by 50% of the extent 
of its prior increase beyond baseline. If no prior splenomegaly, must increase by at least 2 cm from baseline.  
  
New or recurrent splenomegaly 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are 
met.  
 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. 
 
Response Review 
Response will be as per institutional evaluations. 
 
Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of analysis of treatment effect. Best response 
is determined as outlined in Section 12.3 from a sequence of overall response assessments. 
 
Response Criteria for Hodgkin Lymphoma 
 
Baseline Imaging Lesion Evaluation at Diagnosis 
Imaging guidelines and response criteria have been revised from previous COG protocols, including AHOD0031, 
AHOD0431, AHOD0831, CCG 5942, CCG 59704, POG 9425, and POG 9426 and incorporate International Lymphoma 
Working Group’s revised recommendations and the Euro net consortium guidelines for malignant lymphoma.  
 
Note: The determination of RRL or SRL and CR will be based on interim and end-of-therapy FDG-PET response, 
and will not be based on size change on CT, with the exception of macronodular splenic involvement. CT-based size 
criteria will still be used in the determination of PD and in cases of macronodular splenic involvement. As such, diagnostic 
quality contrast-enhanced CT imaging will still be required for staging and at the time of interim and end of therapy response 
assessment. This will also facilitate comparison with prior COG studies, and allow the importance of CT imaging to be 
prospectively assessed within the context of the proposed PET response criteria. 
 
Staging Considerations  
Measurable disease indicates the presence of at least one measurable lesion. Superficial lesions (eg, palpable 
lymphadenopathy) measurable only by clinical exam or ultrasound are operator dependent and are not admissible as target 

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lesions. A measurable lesion by CT is a lesion that can be accurately measured in 2 orthogonal dimensions. For extranodal 
sites, this typically involves lesions of at least 1 cm diameter. Lymph nodes are considered abnormal if the long axis is > 
2.0 cm, regardless of the short axis. Lymph nodes with a long axis measuring between 1.0-2.0 cm are only considered 
abnormal if they are part of a conglomerate of nodes and are FDG-PET positive. 
 
Evaluable disease 
Non-measurable evaluable lesions include permeative bone lesions, malignant ascites, malignant pleural/pericardial 
effusions, pulmonary or cutaneous lymphangitic spread, and lesions too small to accurately measure in 2 dimensions by 
CT. All non-target and non-measurable assessable lesions will be recorded at baseline and noted on follow-up. 
 
Lymph node involvement 
Any lymph node is considered involved if and only if it is FDG-PET positive. 
 
FDG-PET positive is defined as: 
a. For moderately sized ( ≥ 2 cm in greatest transverse diameter by CT) regardless of their location, mild and 
diffusely increased FDG uptake with intensity higher than that of mediastinal blood pool structures should be 
considered positive. When possible use the ascending aorta or aortic arch for reference mediastinal blood pool.  
 
b. For smaller masses or normal sized lymph nodes (< 2 cm in greatest transverse diameter by CT), any FDG 
uptake more than that of surrounding background activity should be considered positive.  
 
Bulk Disease (See Appendix XII, subsection C) 
 
Extra nodal involvement 
• 
Extra-lymphatic structures contiguous with sites of lymph node involvement are considered E-lesions (particularly 
lung). Exception: liver and/or bone marrow involvement is considered Stage 4. 
 
• 
Pleural and pericardial effusions alone are not considered E-lesions. 
 
• 
Pleural, pericardial, or chest wall infiltration by an adjacent nodal lesion that is PET positive is considered an E-lesion. 
 
Organ involvement 
 
Lung 
Lung involvement is assumed if there is at least one intrapulmonary focus that is >1 cm and is PET positive or 3 or more 
lesions between 0.5 and 1 cm regardless of FDG-PET activity. Solitary lung nodules that are < 1 cm in transverse diameter, 
but are FDG avid, are also considered disease. 
 
FDG-PET positive is defined as: 
a. For lung nodules that are ≥ 1 cm in greatest transverse diameter by CT, FDG uptake exceeding that of 
mediastinal blood pool structures should be considered positive. When possible use the ascending aorta or aortic 
arch for reference mediastinal blood pool. 
b. For lung nodules < 1 cm in greatest transverse diameter by CT, due to partial volume averaging effects, any 
uptake is considered positive. 
 
Visceral organs (liver, spleen, kidney) 
Any focal mass lesion large enough to characterize is considered due to lymphomatous involvement unless the imaging 
characteristics indicate an alternative nature (eg, cyst, hemangioma, abscess, etc.). Ultrasound or MRI may be utilized if 
clarification is necessary. Focal splenic lesions seen on an appropriately timed IV contrast enhanced CT scan can be 
considered positive if they are PET positive; small lesions below limits of detection by PET/CT must be confirmed by 
ultrasound or MRI. Splenomegaly without focal lesions does not indicate splenic involvement with disease. 
 

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Hepatic and Splenic Lesions: 
FDG-PET positive is defined as: 
a. For hepatic or splenic lesions ≥ 1.5 cm on CT, FDG uptake greater than or equal to that of normal liver or spleen 
parenchyma, respectively, should be considered positive. 
b. For hepatic or splenic lesions < 1.5 cm on CT, FDG uptake greater than that of normal liver or spleen 
parenchyma, respectively, should be considered positive. 
c. In the absence of focal splenic involvement at diagnosis, diffusely increased splenic FDG uptake greater than 
normal liver parenchymal FDG uptake but in the absence of lesions seen on CT will not be considered evidence 
of involvement.  
 
Bone and bone marrow involvement  
Focal bone lesions that are permeative, sclerotic, or both and are PET positive are considered involved. A bone focus of 
PET positivity outside the regions included in pre-study diagnostic CT evaluation should be assessed on the attenuation 
correction CT. Alternatively this can be evaluated individually by dedicated regional CT or preferably MRI. If there are 
three or more PET positive bony foci with no CT or MRI correlate these likely represent bone marrow involvement and are 
sufficient to establish Stage IV disease. As part of the Imaging aim, these will be recorded and will be correlated with bone 
marrow biopsy results at a later time. For this reason bone marrow biopsy results (required in children < 18 years of age; 
optional in patients who are ≥ 18 years of age) should be recorded on all patients when they are performed. 
 
Bone Marrow FDG Uptake: 
FDG-PET positive is defined as: 
a. Three or more FDG-PET positive lesions in bone marrow. Suggest MRI correlation for confirmation of these 
FDG-PET positive marrow foci if possible. Diffusely increased bone marrow FDG uptake, regardless of level 
of uptake – including more intense than liver, is not considered positive.  
b. A negative bone marrow FDG-PET does not exclude bone marrow involvement or preclude a bone marrow 
biopsy/aspirate assessment. 
 
CLINICAL AND STAGING CRITERIA FOR HODGKIN LYMPHOMA 
A. Stage  
 
(See the diagram below for definitions of regions). 
 
Stage I: 
Involvement of single lymph node region (I) or localized involvement of a single extralymphatic organ or site 
(IE). 
 
Stage II: 
Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized contiguous 
involvement of a single extralymphatic organ or site and its regional lymph node(s) with involvement of 1 or 
more lymph node regions on the same side of the diaphragm (IIE). 
 
Stage III: 
Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by 
localized contiguous involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (IIIS), 
or both (IIIE+S). 
 
Stage IV: 
Disseminated (multifocal) involvement of 1 or more extralymphatic organs or tissues, with or without 
associated lymph node involvement, or isolated extralymphatic organ involvement with distant (non-regional) 
nodal involvement. 
 
B. Symptoms and Presentations 
"A" Symptoms: Lack of "B" symptoms. 
 
"B" Symptoms: At least one of the following: 
• 
Unexplained weight loss > 10% in the preceding 6 months; 

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• 
Unexplained recurrent fever ≥ 38°C in the preceding month; or 
• 
Recurrent drenching sweats in the preceding month. 
 
C. Bulk disease 
Each of the following presentations are considered "bulk" disease: 
 
• 
Large mediastinal Adenopathy (LMA):  
Mediastinal Bulk (LMA) = transverse tumor diameter > 1/3 the thoracic diameter at the dome of the diaphragm 
on a 6 foot PA upright CXR. A portable exam is not acceptable for measuring LMA and if this is the only 
exam available at the treating institution, a repeat exam must be performed prior to establishing bulk as it is a 
criterion for targeting subsequent radiotherapy.  
 
The hilum is technically not part of the anterior mediastinum, but if the hilar adenopathy is confluent with the 
anterior mediastinal adenopathy, it may be included in the transverse measurement. 
 
• 
Large extra-mediastinal nodal aggregate:  
Extra-mediastinal bulk is defined as a continuous aggregate of nodal tissue outside the mediastinum that 
measures > 6 cm in transverse dimension on axial CT or longest dimension on coronal or sagittal reformatted 
CT. This would not include a contiguous chain of small nodes. 
 
D.  Splenic lesions:  
Splenomegaly without focal lesions does not indicate splenic involvement with disease. Focal splenic lesions seen 
on an appropriately timed IV contrast enhanced CT scan can be considered positive if they are PET positive; small 
lesions below limits of detection by PET/CT must be confirmed by ultrasound or MRI, and are also considered 
positive. Diffusely increased splenic FDG uptake greater than normal liver parenchymal FDG uptake but in the 
absence of lesions seen on CT will not be considered evidence of involvement at diagnosis. 
 
E.  E-Lesions Defined:  
Extra-lymphatic structures contiguous with sites of lymph node involvement are considered E-lesions (particularly 
lung). Pleural, pericardial, or chest wall infiltration by an adjacent nodal lesion that is PET positive would be 
considered an E-lesion. Liver and/or bone marrow involvement is not considered an E lesion, but rather considered 
Stage IV. Pleural and pericardial effusions alone are not considered E-lesions. 
 
F. Regions of Nodal Involvement 
 
Peripheral Upper Regions (indicate laterality: right or left) 
• 
Neck: cervical (upper, lower/supraclavicular), occipital, and pre-auricular 
• 
Infraclavicular 
• 
Axilla 
• 
Pectoral 
• 
Epitrochlear   
• 
Brachial 
 
Central Regions 
• 
Waldeyer's ring (including base of tongue) 
• 
Mediastinum (anterior; hilar; cardiophrenic; subcarinal) 
• 
Hilar 
• 
Mesenteric 
• 
Paraaortic (including retrocrural, portal and celiac) 
• 
Splenic/splenic hilar 
 

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Peripheral Lower Regions (indicate laterality: right or left) 
• 
Iliac 
• 
Inguinal 
• 
Femoral  
• 
Popliteal 
 
Other Non-Nodal Sites 
• 
Lung (right, left or bilateral) 
• 
Bone  
• 
Bone marrow 
 
 

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APPENDIX XIII: RESPONSE CRITERIA FOR SOLID TUMORS 
 
Disease Parameters 
 
• 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
NOTE: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the conditions under which such lesions should be considered must be 
defined in the protocol. 
 
• 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm 
in short axis when assessed by CT scan (CT scan slice thickness no greater than 5 mm). At baseline and in follow-
up, only the short axis will be measured and followed. 
 
• 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant 
lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. “Cystic lesions” thought to 
represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described 
above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. 
 
• 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be selected. A sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
• 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
Methods for Evaluation for Patients with Solids Tumors and Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion 
at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 

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• 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules and 
palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
• 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (eg, for body 
scans). Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  
 
• 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of 
optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially performed.   
 
• 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response.  
 
• 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (eg, residual lesions in tumor types, such as germ cell tumors, where known residual 
benign tumors can remain). 
 
Cytology should be obtained if an effusion appears or worsens during treatment when the measurable tumor has 
met criteria for response or stable disease. 
 
• 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate 
the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' 
disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is 
not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if 
there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
 
Note: A “positive” FDG-PET scan lesion means one that is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
 
 
 

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Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
Evaluation of Target Lesions: 
  
• 
Complete Response (CR): Disappearance of all target and non-target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. If immunocytology is available, no 
disease must be detected by that methodology. Normalization of urinary catecholamines or other tumor markers if 
elevated at study enrollment (for patients with neuroblastoma).  
 
• 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference 
the baseline sum diameters 
  
• 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progressions). Note: In presence of SD or PR in target disease but 
unequivocal progression in non-target or non-measurable disease, the patient has PD if there is an overall level of 
substantial worsening in non-target disease such that the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy 
  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study 
 
Evaluation of Non-Target Lesions 
  
• 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis) 
  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. 
  
• 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits 
  
• 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. Unequivocal progression should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase. 
  
Overall Response Assessment - Solid Tumors 
  
Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation 
CR 
Not 
evaluated 
No 
PR 

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PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
≥ 28 days from baseline 
PD 
Any 
Yes 
or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes 
or 
No 
PD 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
**In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression 
at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after 
discontinuation of treatment. 
 
Overall Best Response Assessment – Solid Tumors 
Each patient will be classified according to his “best response” for the purposes of analysis of treatment effect. Best response 
is determined as outlined in Section 12.3 from a sequence of overall response assessments. 
 
• 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured in at least one dimension. 
Such lesions may be evaluable by nuclear medicine techniques, immunocytochemistry techniques, tumor 
markers or other reliable measures.  
 
Complete Response 
Disappearance of all evaluable disease. 
 
Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), or Progressive Disease. 
 
Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or radiographic progression. 
 
 
 

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APPENDIX XIV:  PATIENT INSTRUCTIONS FOR SUN PROTECTION 
 
Guidelines for Sun Protection 
 
The following precautions should be taken for at least 3 days after each dose of BAY 1895344 (elimusertib): 
 
• 
You should avoid sun exposure in the post-dose period after leaving the clinic 
• 
You should not purposefully engage in skin tanning 
• 
Avoid being outside during daylight hours for more than 15 minutes (even on cloudy days) 
• 
Sun exposure should be particularly avoided during the hours of 10am and 4pm, or in areas where reflection of 
sunlight from snow, water, or sand might intensify exposure 
• 
Special arrangements for children should be made at school to ensure that they are not exposed to sunlight from 
an open window, that they are not exposed to any unfiltered (bare) fluorescent light bulbs, and that they are not 
permitted outside for gym, recess, fire drills, or other activities unless they are under ultraviolet light-blocking 
shelters and away from reflective surfaces such as snow, sand or water 
• 
You should wear protective clothing (e.g. long-sleeved shirt, full-length pants, wide-brimmed hat) to minimize 
sun exposure. Two layers of clothing protect more than one layer. Tightly woven fabrics generally give more 
sun protection than loose weaves. 
o Wear clothing that you can’t see the light through. Some companies make light-weight clothing 
specifically designed to provide a high degree of sun protection. 
• 
Long hair styles help protect the neck and ears. Any skin not covered by clothing or hair should be protected 
by sunscreen 
• 
You should apply sunscreen to any potentially sun-exposed skin, even on cloudy days. Sunscreen should have 
a sun protection factor (SPF) of 50 or higher and should provide broad-spectrum protection from both ultraviolet 
A (UVA) and ultraviolet B (UVB) rays 
o Sunscreen should be applied at least 30 minutes before going out in the sun 
o Sunscreen may also be used indoors to protect against unrecognized sources of ultraviolet light 
• 
You should apply a sun-protective lip balm. The lip balm should have an sun protection factor (SPF) of 30 or 
higher and should provide broad-spectrum protection from both ultraviolet A (UVA) and ultraviolet B (UVB) 
rays 
• 
You should wear sunglasses or clip-ons when in ambient external light that provide full protect against UV 
light. Glasses with side-shields protect the eyelids and skin around the eyes. When selecting appropriate 
sunglasses or clip-ons, look for a label or sticker that indicates one or more of the following: 
o Lenses block 99% or 100% of UVB and UVA rays 
o Lenses meet American National Standards Institute (ANSI) Z80.3 blocking requirements or 
Australian/New Zealand Standard for Sunglasses and Fashion Spectacles, AS/NZS 1067 
o Lenses provide UV 400 protection (providing protection against light rays with wavelengths as high as 
400 nanometers, which covers the entire UV spectrum) 
 
 
 
 

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APPENDIX XV: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions with Other 
Drugs and Herbal Supplements  
 
Patient 
Name: 
      
 
Diagnosis:  
      
Trial #: 
PEPN2112 
Study 
Doctor: 
      
 
Study Doctor 
Phone #:  
      
Study 
Drug(s): 
BAY 1895344 
(elimusertib) 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, pharmacists), 
and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
BAY 1895344 (elimusertib) interacts with certain specific enzyme(s) in your liver or other tissues like the gut, 
and certain transport proteins that help move drugs in and out of cell. 
 
 
Explanation 
CYP 
isoenzymes 
The enzymes in question are CYP3A4, 2C8, 2C9, and 2C19. BAY 
1895344 (elimusertib) is broken down by CYP3A4 and may be affected by 
other drugs that inhibit or induce this enzyme. Strong inhibitors and 
inducers of CYP3A4 should be avoided. BAY 1895344 (elimusertib) 
weakly to moderately inhibits CYP3A4, CYP2C8 2C9, and 2C19.  BAY 
1895344 (elimusertib) induces CYP3A4 and 2C19. Substrates of CYP3A4 
with narrow therapeutic window should be avoided. Other drugs that are 
broken down by CYP2C8, 2C9, and 2C19 may be affected when used at 
the same time. 
Transport 
proteins 
The proteins in question are P-gp, BCRP, OATP1B1, and OATP1B3. 
BAY 1895344 (elimusertib) inhibits these transport proteins and may affect 
other drugs that require them to move in and out of the cells.  
 
 
These are the things that you need to know: 
The study drug BAY 1895344 (elimusertib) may interact with other drugs which can cause side effects. For this reason, it 
is very important to tell your doctors about all your medicines, including: (a) medicines you are taking before this clinical 
trial, (b) medicines you start or stop taking during this study, (c) medicines you buy without a prescription (over-the-
counter remedy), (d) herbals or supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or an 
updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered strong inhibitors and inducers of CYP3A4, substrates of CYP3A4 
with narrow therapeutic window, substrates of CYP2C8, 2C9, 2C19, BCRP, P-gp, OATP1B1, and OATP1B3. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain ingredients that could 
interact with your study drug.  Speak to your doctors or pharmacist to determine if there could be any side effects.  
• Make sure your doctor knows to avoid certain prescription medications.  

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• No grapefruit juice, Seville oranges, or grapefruit can be consumed while on BAY 1895344 (elimusertib). 
• Antacids, H2 receptor antagonists, and proton pump inhibitors should be used with caution. 
• Avoid prolonged exposure to the sun and wear protective clothing and sunscreen when out in the sun. 
• Your regular health care provider should check a frequently updated medical reference or call your study doctor 
before prescribing any new medicine or discontinuing any medicine.   
 
 
 
Version Nov/2019 
 
(Next page: Patient Drug Interaction Wallet Card)