NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of BVD-523FB (Ulixertinib) in Patients With Tumors Harboring Activating MAPK Pathway Mutations
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Recurrent Ependymal Tumor, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Histiocytic and Dendritic Cell Neoplasm, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Primary Malignant Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Glioma, Refractory Hepatoblastoma, Refractory Histiocytic and Dendritic Cell Neoplasm, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Primary Malignant Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Wilms Tumor
Sponsor: National Cancer Institute (NCI)

 
Group Chair 
Douglas Hawkins, M.D. 
dhawkins@seattlechildrens.org  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
      December 9, 2020 
 
 
Martha Kruhm, M.S., RAC  
 
Protocol and Information Office (PIO) Head  
 
National Cancer Institute  
 
Executive Plaza North Room 730  
 
Bethesda, MD 20892 
 
      Dear Ms. Kruhm, 
 
APEC1621J, NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - 
Phase 2 Subprotocol of BVD-523FB (ulixertinib) in Patients with Tumors Harboring 
Activating MAPK Pathway Mutations. A dose modification table for diarrhea has been 
added along with an additional appendix for the treatment of diarrhea. In addition, there 
have been various administrative changes added to this amendment. These changes are 
outlined in a point-by-point summary below. No changes have been made to the informed 
consent document.  
 
Please contact us if you have further questions.  
 
Sincerely, 
 
Samuel Baird, MPH, Protocol Coordinator for 
Kieuhoa T. Vo, MD MAS, APEC1621J Study Chair 
Douglas Hawkins, M.D., Chair, Children’s Oncology Group 
 

                                                           
 
          APEC1621J 
 
 
 ii 
SUMMARY OF CHANGES 
The following specific revisions have been made to the protocol and informed consent document. 
Additions are in boldfaced font and deletions in strikethrough font. 
I. 
Protocol Changes made by the Principal Investigator: 
# 
Section 
Page(s) 
Comments 
1. 
throughout 
- 
The amendment # and version date have been updated.  
2. 
Contact 
Information 
2 
Included updated, templated language for contact information from 
NCTN protocol template, based on recommendation received from 
CTEP 3/25/2020. 
3. 
Table of 
Contents 
3-5 
Updated for repagination  
4. 
Study 
Committee 
6 
• 
Replaced Dr. Peter C. Adamson with Dr. Douglas Hawkins 
• 
Updated Dr. Fox’s info 
5. 
COG 
Operations 
Staff 
7 
• 
Removed 222 East Huntington Dr. Suite 100 from all COG 
staff info. 
• 
Removed Nita Tawdros as scientific writer and replaced with 
Samuel Baird. 
• 
Removed Jonathan Bennett as RC and replaced with Bumjin 
Lee. 
6. 
6.4 
27-29 
Section 6.4 
Dose Modifications for GI Toxicities (Nausea, 
Vomiting, Dehydration) was added. 
7. 
8.4.5 
36 
Deleted,  
 
Each sample must be labeled with the patient’s study registration 
number, the study I.D# (APEC1621J), and the date and time the 
sample was drawn.  Data should be recorded on the 
Pharmacokinetic Study Form, which must accompany the 
sample(s).” 
 
And replaced with… 
 
“Each tube must be labeled with the patient’s study 
registration number, the study I.D (APEC1621J), and the date 
and time the sample was drawn.  Data should be recorded on 
the appropriate transmittal form found in RAVE. 
 
8. 
8.4.6 
36 
Updated PK sample shipment contact info for Covance. 
9. 
9.1.3 
38 
Added, “size 0” to clarify capsule size for participating sites.  
10. Appendix IX 
94-99 
Added updated templated language from newest NCTN protocol 
template. 
11. 
Appendix 
XIII 
105 
Added Appendix for the treatment of diarrhea.  

                                               
 
 
             APEC1621J                           
Version Date: 12/09/2020 
 
Page 1 
 
Activated:10/01/2018 
 
Version Date: 12/09/2020 
 
Closed: 
 
Amendment# 3 
 
 
 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
APEC1621J 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF BVD-523FB (ULIXERTINIB) IN PATIENTS WITH TUMORS 
HARBORING ACTIVATING MAPK PATHWAY MUTATIONS 
 
 
Open to COG Member Institutions in the USA  
 
 
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 
  Kieuhoa T. Vo, MD MAS 
                                                                       UCSF Medical Center Mission Bay 
                                                                                           550 16th Street, 4th floor, Box 0434     
                                                                  San Francisco, CA, 94158 
                                                                  Phone: (415) 476-3831 
                                                                  Fax: (415) 353-2657 
                                                                  Email: kieuhoa.vo@ucsf.edu 
 
 
 
 
 
 

                                               
 
 
             APEC1621J                           
Version Date: 12/09/2020 
 
Page 2 
 
CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN) which can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
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. 
 
 
 
 
 
 
 
 
 
 
 
 

                                               
 
 
             APEC1621J                           
Version Date: 12/09/2020 
 
Page 3 
TABLE OF CONTENTS 
SECTION 
PAGE 
 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
6 
STUDY COMMITTEE, CONT. 
7 
COG OPERATIONS STAFF 
7 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
 
Primary Aims 
9 
 
Secondary Aims 
9 
 
Exploratory Aims 
9 
2.0 
BACKGROUND 
9 
 
Introduction/Rationale for Development 
9 
 
Preclinical Studies 
11 
 
Adult Studies 
13 
 
Pediatric Studies 
16 
 
Overview of Proposed Pediatric Study 
16 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
17 
 
Genetic Screening Procedures for Eligibility 
17 
 
IRB Approval 
17 
 
Informed Consent/Assent 
18 
 
Screening Procedures 
18 
 
Eligibility Checklist 
18 
 
Study Enrollment 
18 
 
Institutional Pathology Report 
19 
 
Dose Assignment 
19 
4.0 
PATIENT ELIGIBILITY 
19 
 
Inclusion Criteria 
19 
 
Exclusion Criteria 
22 
5.0 
TREATMENT PROGRAM 
24 
 
Overview of Treatment Plan 
24 
 
Criteria for Starting Subsequent Cycles 
25 
 
Grading of Adverse Events 
25 
 
Definition of Dose-Limiting Toxicity (DLT) 
25 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
26 
 
Dose Modifications for Hematological Toxicity 
26 
 
Dose Modifications for Non-Hematological Toxicity 
26 
 
Dose Modifications for Visual Disturbances 
27 
 
Dose Modifications for GI Toxicities (Nausea, Vomiting, Dehydration) 
27 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
29 
 
Concurrent Anticancer Therapy 
29 
 
Investigational Agents 
29 
 
Supportive Care 
29 

                                               
 
 
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Version Date: 12/09/2020 
 
Page 4 
 
Growth Factors 
30 
 
Concomitant Medications 
30 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
30 
 
Required Clinical, Laboratory and Disease Evaluation 
30 
 
Monitoring for Specific Toxicities 
32 
 
Radiology Studies 
32 
 
Pharmacology (optional) 
34 
 
Circulating Tumor DNA Study (optional) 
36 
9.0 
AGENT INFORMATION 
37 
 
BVD-523FB (ulixertinib) 
38 
NSC# 799018 IND# 134661 
38 
 
Agent Ordering and Agent Accountability 
43 
 
Clinical Drug Request and Investigator Brochure Availability 
43 
 
Agent Inventory Records 
43 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
44 
 
Criteria for Removal from Protocol Therapy 
44 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
45 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
45 
 
Sample Size and Study Duration 
45 
 
Dosing Considerations 
45 
 
Study Design 
47 
 
Methods of Analysis 
47 
 
Evaluability for Response 
48 
 
Evaluability for Toxicity 
48 
 
Progression free survival (PFS) 
48 
 
Correlative Studies 
48 
 
Gender and Minority Accrual Estimates 
49 
12.0 
EVALUATION CRITERIA 
49 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
49 
 
Progression-Free Survival 
49 
 
Response Criteria for Patients with Solid Tumors 
49 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
53 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
55 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
57 
 
Response Criteria for Patients with CNS Tumors 
58 
 
Response Criteria for Patients with non- Hodgkin Lymphoma/Histiocytosis 
60 
 
Best Response 
61 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
63 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
63 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
64 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
 
65 
 
Definition of Onset and Resolution of Adverse Events 
66 
 
Other Recipients of Adverse Event Reports 
66 
 
Specific Examples for Expedited Reporting 
66 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
68 

                                               
 
 
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Version Date: 12/09/2020 
 
Page 5 
 
Categories of Research Records 
68 
 
CDUS 
69 
 
CRADA/CTA/CSA 
69 
 
Data and Safety Monitoring Plan 
71 
REFERENCES 
72 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
74 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
75 
APPENDIX III:  MEDICATION DIARY FOR BVD-523FB (ULIXERTINIB) 
77 
APPENDIX IV CORRELATIVE STUDIES 
80 
APPENDIX V: BVD-523FB (ULIXERTINIB) DOSING NOMOGRAM 
81 
APPENDIX VI: APEC1621J THERAPY DELIVERY MAP 
82 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621J EXPANSION COHORTS 
86 
APPENDIX VIII: APEC1621J ACTIONABLE MUTATIONS OF INTEREST 
87 
APPENDIX IX: CTEP AND CTSU REGISTRATION PROCEDURES 
94 
IRB Approval 
95 
Additional Requirements 
95 
Downloading Site Registration Documents 
96 
Submitting Regulatory Documents 
96 
Rave CTEP-AERS Integration 
97 
Data Quality Portal 
98 
Central Monitoring 
98 
APPENDIX X: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
100 
APPENDIX XI: TOXICITY-SPECIFIC GRADING 
102 
APPENDIX XII: YOUTH INFORMATION SHEETS 
103 
APPENDIX XIII:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
105 
 

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Page 6 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY VICE CHAIR 
Kieuhoa T. Vo, MD MAS  
Amit Jayant Sabnis, MD 
UCSF Medical Center Mission Bay 
UCSF Medical Center Mission Bay 
550 16th Street, 4th floor, Box 0434 
550 16th Street, 4th floor, Box 0434 
San Francisco, CA, 94158 
San Francisco, CA, 94158 
Phone: (415) 476-3831 
Phone: (415) 476-3831 
Fax: (415) 353-2657 
Fax: (415)-502-4372 
Email: kieuhoa.vo@ucsf.edu 
Email: amit.sabnis@ucsf.edu 
 
Will Parsons, MD, PhD 
Nita Seibel, MD 
Baylor College of Medicine 
National Cancer Institute 
1102 Bates, Suite 1030.15 
9609 Medical Center Drive, MSC 9739 
Houston, TX 77030 
Rockville, MD 20892 
Phone: (832) 824-4643 
Phone:  (240) 276-6560 
Email: dwparson@txch.org 
Fax:  (240) 276-7892 
Baylor College of Medicine 
E-mail: seibelnl@mail.nih.gov  
 
 
Todd Alonzo, PhD 
Douglas Hawkins, MD 
Study Statistician  
Seattle Children’s Hopsital 
COG Statistics and Data Center- Monrovia 
1900 9th Ave  
222 East Huntington Dr., Suite 100 
Seattle, WA 98101 
Monrovia, CA 91016 
Phone:  (206) 884-1107 
Phone: (626) 241-1522 
Fax:  (206) 987-3946 
Fax: (626) 445-4334 
Email: dhawkins@seattlechildrens.org 
Email: talonzo@childrensoncologygroup.org 
 
 
Stacey Berg, MD 
Joel Reid, PhD. 
Study Design and Logistics 
Study Pharmacologist 
Baylor College of Medicine 
Mayo Clinic 
Pediatric Oncology  
Guggenheim 17-37 
6621 Fannin Street 
200 First St SW 
MC3-3320 
Rochester, MN 55905 
Houston, TX 77030 
Phone: (507) 284-0822 
Phone: (832) 824-4588 
Fax: (507) 284-3906 
Fax:  (832) 825-4039 
E-mail: reid.joel@mayo.edu  
Email: sberg@txch.org 
 
 
Jin Piao, PhD 
Elizabeth Fox, MD 
Study Statistician 
Study Design and Logistics 
COG Statistics and Data Center- Monrovia 
Saint Jude Children's Research Hospital 
222 East Huntington Dr., Suite 100 
Pediatric Hematology/Oncology 
Monrovia, CA 91016 
262 Danny Thomas Place, MS 281  
Phone: (626) 241-1572 
Memphis, TN 38105 
Fax: (626) 445-4334 
Phone: (901) 595-3300 
Email: jpiao@childrensoncologygroup.org 
Fax:  (901) 595-7031 
 
Email: elizabeth.fox@stjude.org 
 
 
 
 
 

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Version Date: 12/09/2020 
 
Page 7 
STUDY COMMITTEE, CONT. 
Study CRA 
STUDY PHARMACIST 
TBD  
Micha Koentz, PharmD 
 
Cook Children's Medical Center 
 
801 7th Ave 
 
Fort Worth, TX 76104 
 
Phone: (682) 885-6236 
 
E-mail: micha.koentz@cookchildrens.org 
 
 
 
COG OPERATIONS STAFF 
Bumjin Lee, MS 
Lauren Saguilig, MS 
Research Coordinator 
Master Statistician  
Monrovia, CA 91016 
Monrovia, CA  91016 
Phone (626) 241- 1606 
Fax (626) 445-4334 
Email: blee@childrensoncologygroup.org 
Email: lsaguilig@childrensoncologygroup.org 
 
 
 
  
Samuel Baird, MPH 
Senior Scientific Writer/Protocol Coordinator 
 
Children’s Oncology Group – Operations Center 
 
Monrovia, CA  91016 
 
Phone: (626) 241-1619 
 
Email: sbaird@childrensoncologygroup.org 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
http:members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agent : 
BVD-523FB (ulixertinib) 
 
(NSC#799018) 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 8.4.6 AND 8.5.6 FOR SPECIMEN SHIPPING ADDRESSES 
 
 

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APEC1621J 
                                                                                                                                                         
 
Version Date: 12/09/2020 
 
Page 8 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about 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 
This subprotocol is a component of the Pediatric MATCH trial APEC1621. The APEC1621SC screening 
protocol details the assay used for the integral genomic profiling which will determine eligibility for this 
subprotocol. This is a phase 2 trial of BVD-523FB (ulixertinib) in children with relapsed or refractory solid 
tumors (including Non-Hodgkin lymphomas, histiocytoses and CNS tumors) harboring specified activating 
mutations of the MAPK pathway. BVD-523FB (ulixertinib) is a novel, reversible, ATP-competitive 
ERK1/2 inhibitor with high potency and ERK1/2 selectivity. BVD-523FB (ulixertinib) will be given at the 
dose determined by the dose escalation table (or at the established MTD/RP2D once dose escalation phase 
has been completed) twice daily continuously for 28-day cycles. The primary endpoint will be objective 
response rate as determined by RECIST. Progression free survival (PFS) will be assessed as a secondary 
endpoint. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-28 
BVD-523FB (ulixertinib) 
Day 28 
Evaluation 
 
 
Patients will receive BVD-523FB (ulixertinib) at a dose determined by the dose escalation table (Section 
5.1.1) (or at the established MTD/RP2D once dose escalation phase has been completed) will be 
administered twice daily per nomogram by mouth on an empty stomach. One treatment cycle is 28 days. 
Evaluations will occur every other cycle x 3, then every 3 cycles.  
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy (section 6.0). Therapy may otherwise continue for up to 2 years 
provided the patient meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any 
of the criteria for removal from protocol therapy criteria (Section 10.0).  
 
 
 
 
 

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Version Date: 12/09/2020 
 
Page 9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
Primary Aims 
 
1.1.1 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with BVD-523FB (ulixertinib) with 
advanced solid tumors (including CNS tumors), Non-Hodgkin lymphomas or 
histiocytic disorders that harbor activating genetic alterations in the MAPK 
pathway. 
 
 
Secondary Aims 
 
1.2.1 
To estimate the progression free survival in pediatric patients treated with BVD-
523FB (ulixertinib) with advanced solid tumors (including CNS tumors), Non-
Hodgkin lymphomas or histiocytic disorders that harbor activating genetic 
alterations in the MAPK pathway. 
 
1.2.2 
To obtain information about the tolerability of BVD-523FB (ulixertinib) in 
children and adolescents with relapsed or refractory cancer. 
 
1.2.3 
To provide preliminary estimates of the pharmacokinetics of BVD-523FB 
(ulixertinib) in children and adolescents with relapsed or refractory cancer. 
 
 
Exploratory Aims 
 
1.3.1 
To evaluate other biomarkers as predictors of response to BVD-523FB 
(ulixertinib) and specifically, whether tumors that harbor different mutations or 
fusions will demonstrate differential response to BVD-523FB (ulixertinib) 
treatment.  
 
1.3.2 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA. 
 
2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
A critical hallmark of cancer is the activation of cell-growth signaling cascades 
independent of appropriate growth stimuli. A canonical example of a cell growth control 
circuit is the mitogen-activated protein kinase, or MAPK, pathway. The RAS–RAF–MEK–
ERK pathway, also known as the classical MAPK pathway, is responsible for controlling 
multiple key physiological processes, making it an attractive therapeutic target in cancer.1 
Here, surface receptors activated by growth ligands signal via downstream effectors in a 
linear relay system: RAS family GTPases activate RAF family protein kinases, which in 
turn trigger a phosphorylation cascade involving MEK and ERK family kinases. ERK 
kinases activate an array of direct effectors that ultimately translate growth signaling into 
essential cellular functions including cell division and cell survival.  
 
Aberrant activation of the MAPK pathway is frequently observed in cancer. Often, 
components of the MAPK pathway undergo direct genetic mutation, causing constitutive 
activation of the signaling cascade in the absence of appropriate ligands. This commonly 

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Page 10 
occurs through gain-of-function mutations in genes encoding RAS and RAF family 
members as well as by loss of NF1. Among the malignances seen in pediatric and young 
adult population with known MAPK pathway aberrations include: hematological and 
lymphoid malignancies (activating N/K RAS mutations, 20%), rhabdomyosarcoma 
(activating BRAF, NRAS and PTPN11 mutations 20%), low grade glioma (activating 
mutation or fusion in BRAF 70-100%), as well as in glioblastoma multiforme (loss of NF-
1, 15%), neuroblastoma (activating mutations in NRAS, PTPN11, 2.9-3.6%) malignant 
peripheral nerve sheath tumors (NF1 loss 40-88%) and melanoma (activating mutation in 
BRAF, 86%).2-6   
 
There are several pre-clinical studies demonstrating the efficacy of inhibitors of MAPK 
pathway aberrations in pediatric tumors. For example, MEK/ERK inhibitor UO126 has 
shown to inhibit growth of rhabdomyosarcoma both as a single agent in vivo and in vitro 
as well as in combination with dual PI3K/mTOR inhibitor PI103.7,8 In addition, in vitro 
and in vivo synergy has also been seen between inhibitors of TORC1/2 (AZD8055), and 
MEK (AZD6244) in embryonal rhabdomyosarcoma.9 Pre-clinical data also support 
potential activity for MEK inhibitors against neuroblastoma with MAPK gene mutations.6 
Lastly, NF-1 deficiency has shown to be predictive of sensitivity to MEK inhibitors in vitro 
in glioblastoma multiforme.10 In preclinical studies, some MAP2K1 mutations are sensitive 
to MEK inhibition.11,12  
 
There is clinical evidence supporting diverse alterations in multiple MAPK genes as 
biomarkers for response to RAF and MEK inhibitors. These examples include: activating 
RAS gene mutations (NRAS/KRAS/HRAS); activating BRAF mutations (V600E and 
others) and fusions; GNAQ and GNA11 activating mutations; inactivating mutations in 
PTPN11 and loss of NF1 through inactivating mutations or insertion/deletion.13  
 
The US Food and Drug Administration (FDA) has approved two selective BRAF 
inhibitors, vemurafenib and dabrafenib, as monotherapies for patients with BRAFV600-
mutant metastatic melanoma. Though response rates can be as high as 50%, duration of 
response is often measured in months, not years. MEK inhibitors have shown clinical 
responses in patients with BRAF mutated melanoma refractory to BRAF inhibitors leading 
to FDA approval of trametinib for refractory melanoma both as a single agent as well as in 
combination with BRAF inhibitor dabrafenib.14,15 In addition, first-line use of trametinib 
administered in combination with dabrafenib offers an even greater improvement in overall 
survival compared with vemurafenib monotherapy, without increased overall toxicity, 
highlighting the potential usefulness of simultaneously targeting multiple stages of the 
MAPK signaling pathway.16  
 
Similarly, MEK inhibitors have also shown clinical responses (20% with PR) in melanoma 
with NRAS mutated melanomas.17 In patients with KRAS mutant lung cancers MEK 
inhibitors combined with gemcitabine improves response rate and event-free survival.18 
There is pre-clinical evidence for activity of MEK inhibitors in NF1 deficient 
neurofibromas and melanomas and a phase 1 trial of selumetinib (AZD6244) demonstrated 
clinical responses in 17/24 (17%) pediatric patients with neurofibromatosis-1 (NF-1) with 
large plexiform neurofibroma.13,19,20 In uveal melanoma, which is characterized by 
mutations in GNAQ and GNA11, G-binding protein alpha subunits that signal via the 
MAPK pathway, selumetinib (AZD6244) results in a higher response rate and prolonged 
progression free survival when compared with chemotherapy.21  
 
BVD-523FB (ulixertinib) represents a new targeted inhibitor of the MAPK pathway, 

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specifically targeting ERK1 and ERK2 protein kinases. Although BRAF- and/or MEK-
targeted therapy has demonstrated significant clinical benefit, we know from the adult 
experience that the majority of patients develop resistance and disease progression after 
approximately 12 months.22 Since reactivation of ERK signaling is a common driver of 
resistance in this setting, the clinical development of small-molecule ERK inhibitors is of 
considerable interest. Moreover, ERK signaling represents a key downstream effector of 
RAS mutations in many cancer types, suggesting that ERK inhibitors might eventually 
have multiple indications in oncology. 
 
 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
BVD-523FB (ulixertinib) is a novel, reversible, ATP-competitive ERK1/2 
inhibitor with high potency and ERK1/2 selectivity. BVD-523FB (ulixertinib) 
potently inhibits growth and survival in cultured cancer cell lines; melanoma, 
colorectal and pancreatic lines harboring BRAF or RAS mutations are among those 
most susceptible to the drug.23 In in vivo xenograft studies, BVD-523 showed 
dose-dependent growth inhibition and tumor regression. BVD-523 yielded 
synergistic anti-proliferative effects in a BRAFV600E mutant melanoma cell line 
xenograft model when used in combination with BRAF inhibition. Antitumor 
activity was also demonstrated in in vitro and in vivo models of acquired resistance 
to single-agent and combination BRAF/MEK targeted therapy.23 Based on these 
promising results, these studies demonstrate BVD-523FB (ulixertinib) holds 
promise as a treatment for ERK-dependent cancers, including those whose tumors 
have acquired resistance to other treatments targeting upstream nodes of the 
MAPK pathway.  
 
 
2.2.2 
Animal Toxicology 
When BVD-523 was characterized using in vitro screens against 66 receptors and 
ion channels no toxicologically significant interactions were identified. 
Additionally, BVD-523 was negative in bacterial mutation and in vivo 
micronucleus screening assays, so BVD-523 is not considered to have a significant 
genetic toxicology risk.24 
 
While BVD-523 modestly inhibits the hERG current (IC50 3.4 μM), no significant 
effects were seen in action potentials recorded from dog Purkinje fibers exposed 
to up to 10 μg/mL, and no significant cardiovascular findings were observed upon 
acute oral dosing of the compound at dose levels up to 50 mg/kg in dogs (Cmax = 
17.3 μM). Thus BVD-523 is considered to have a low potential to cause QT 
prolongation in patients, but the study will monitor for signs of cardiovascular 
effects of BVD-523 in humans.24 
 
No significant cytochrome P450 (CYP) inhibition has been observed with the 
compound. In vitro studies suggest that the compound is metabolized primarily via 
oxidation by multiple CYPs, including 3A4, 2D6, and 1A2. Furthermore, no 
significant CYP induction was observed after up to 14 days drug treatment in rats, 
nor during in vitro studies with human hepatocytes. These data suggest a limited 
potential for drug-drug interactions.24 
 

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BVD-523 HCl salt is orally available in multiple species (absolute bioavailability 
%F = 23% in dog to 100% in monkey) when formulated as a simple suspension in 
1% carboxymethylcellulose (CMC) and has a half-life of 2−4 hours across all 
species.24  
 
BVD-523 was administered to male and female Sprague-Dawley rats in several 
toxicology studies: a GLP study for up to 28 days at dose levels up to 50 mg/kg/day 
twice daily; for up to 14 days at dose levels up to 100 mg/kg twice daily; and for 
up to 5 days at dose levels up to 150 mg/kg/dose once daily. The incidence and 
severity of mineralization seen in these studies was dose-dependent and effects 
were observed in 1 or more tissues at toxic doses. In animals in which 
mineralization occurred after treatment with BVD-523, significantly increased 
serum phosphorus and modestly decreased serum calcium were seen; these effects 
were not observed in animals in which there was no mineralization. Therefore, the 
risk of tissue mineralization can be assessed by serum phosphorus and calcium 
monitoring. A clinical monitoring strategy similar to this was previously employed 
for related drugs that target the MAPK pathway because those compounds likewise 
elicited mineralization in rodents.24 
 
When BVD-523 was administered to male and female Sprague-Dawley rats for up 
to 28 days at a dose level of 25 or 50 mg/kg twice daily, it was poorly tolerated. 
Although most clinical signs and clinical pathology findings reversed following 4 
weeks of recovery, skin lesions and histopathology findings persisted in many 
tissues at both dose levels after the recovery phase. Based on these findings, 25 
and 50 mg/kg twice daily dose levels were considered severely toxic. 
Administration of 12.5 mg/kg twice daily for 28 days was generally well-tolerated 
by rats of both sexes; however, this dose level was associated with test article-
related findings that included: swelling in the neck; decreased forelimb strength; 
multiple clinical pathology findings; enlarged lymph nodes, spleen, and mammary 
gland. Based on these findings, the severely toxic dose in 10% of the animals 
(STD10) for BVD-523 when administered for up to 28 days in Sprague-Dawley 
rats is 12.5 mg/kg given twice daily (25 mg/kg/day). On Day 28 of the dosing 
phase, this dose level corresponded with a Cmax of 28700 and 15323 ng/mL and 
AUC0-12 of 264868 and 124341 hr.ng/mL for males and females, respectively.24 
 
BVD-523 was administered to male and female beagle dogs for up to 28 days at 
dose levels of 15, 5, or 2 mg/kg twice daily. Initial analysis of the toxicity profile 
observed shows that BVD-523 was well tolerated in dogs. The rat was designated 
the most sensitive species and rat data were used to calculate the starting dose in 
humans.24 
 
BVD-523 has a measured UV absorbance at 320 nm, which means that it can 
absorb both UV-A and UV-B. BVD-523 may therefore act as a photosensitizing 
agent in humans.24 
 
Based on the data accumulated to date, BVD-523 possesses a toxicology profile 
which presents no impediment to its development as an anti-cancer agent. 
 
 
 
 

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Adult Studies 
 
2.3.1 
Phase 1 Studies 
The final results of the first in human, phase 1 study of BVD-523FB (ulixertinib), 
NCT01781429) were recently presented at the American Society of Clinical 
Oncology (ASCO) annual conference, with a more detailed follow up publication. 
25,26 A total of 135 patients were enrolled in the dose escalation and dose expansion 
phases of the study. Twenty-seven patients were enrolled in the dose escalation 
phase (10-900 mg BID). The maximum tolerated dose (MTD) and recommended 
phase 2 dose (RP2D) was determined to be 600 mg twice daily given continuously. 
Dose-limiting toxicities (DLT) included rash, diarrhea, elevated AST, and elevated 
creatinine. Drug exposure was dose proportional up to the RP2D, which provided 
near-complete inhibition of ERK activity in whole blood. In expansion cohort (108 
patients), there were no drug related deaths; however, 65% of patients in cohort 
expansion had dose interruptions for adverse events regardless of attribution, with 
a median dose intensity of 89% at the RP2D. The most common adverse events 
were rash (76%), diarrhea (48%), fatigue (42%), and nausea (42%). In addition to 
3 patients with partial responses during escalation (12%), an additional 11 of 81 
(14%) evaluable patients at expansion had a partial response: 1 BRAF V600E 
mutant melanoma patient refractory to prior BRAF/MEK inhibitor treatment, 
3 NRAS mutant melanoma patients, 2 patients with BRAF V600E mutant lung 
cancers including response in brain metastases, 1 patient with BRAF L597Q 
mutant lung cancer, 1 with BRAF V600E mutant glioblastoma multiforme, 1 
with BRAF G469A head & neck cancer, 1 with BRAF G469A small bowel cancer, 
and 1 with BRAF L485W gallbladder cancer. The duration of response ranged 
from 2 to 24+ months.   
 
Based on these data it was concluded that BVD-523FB (ulixertinib) at 600 mg 
twice a day has an acceptable safety profile and has produced durable responses in 
patients with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid 
tumors including melanoma, glioblastoma multiforme, gallbladder, head and neck 
cancers, and lung cancers with clear CNS activity. BVD-523FB (ulixertinib) also 
resulted in durable responses in patients who progressed on prior BRAF +/- MEK 
inhibitor treatment or who were treatment naïve. A cohort-expansion phase (Part 
2 of Study BVD-523-01) to assess response in particular tumor types and/or 
cancers harboring specific activating mutations in the MAPK pathway is ongoing. 
 
Phase 1 studies of BVD-523FB (ulixertinib) in combination with chemotherapy 
are ongoing: BVD-523FB (ulixertinib) combined with palbociclib patients in 
advanced pancreatic and other solid tumors (NCT03454035); and BVD-523FB 
(ulixertinib) with nab-paclitaxel and gemcitabine in patients with metastatic 
pancreatic cancer (NCT02608229). 
 
 
2.3.2 
Phase 2 Studies 
No phase 2 studies of BVD-523FB (ulixertinib) have been completed to date. A 
phase 2 trial of BVD-523FB (ulixertinib) will be studied in uveal melanoma 
(NCT03417739). 
 

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While the preclinical toxicology studies of BVD-523 have not revealed any 
exposure-dependent ophthalmological toxicities, based on clinical studies of 
MEK1/2 inhibitors which highlighted ocular toxicities that may reflect 
mechanistically attributable risks observable in a proportion of patients, clinical 
studies of BVD-523 have included close monitoring for ocular toxicities. In the 
ongoing clinical trials to date, the following treatment-emergent adverse events 
(TEAEs) have been rarely reported: visual impairment (5 patients), vision blurred 
(3 patients), vitreous floaters (2 patients), and, in single patients, abnormal 
sensation in eye, chorioretinopathy, vision blurred, halo vision, retinal detachment, 
retinopathy. While it is not definitively understood whether ocular toxicities reflect 
primary pharmacology associated with global inhibition of the MAPK pathway, 
specific management and exclusion criteria will be defined in this study protocol 
as the toxicities could potentially severely and irreversibly impact patient well-
being. 
 
2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Absorption: 
Orally administered BVD-523 at doses ranging from 10 to 900 mg BID was 
generally slowly absorbed in patients with advanced malignancies, with individual 
tmax values of 2 to 8 hours at dose levels of 10 to 150 mg BID, and median tmax 
values of 3 to 4 hours at dose levels of 300 to 900 mg BID. After reaching Cmax, 
plasma BVD-523 concentrations remained somewhat sustained for approximately 
2-4 hours.24,25 
 
Exposure (Cmax and AUC0-12) to BVD-523, as well as selected metabolites, 
generally increased in a dose-related fashion from dose levels of 10 to 600 mg 
BVD-523 BID. At Day 1, a further increase in exposure was seen at 750 mg BVD-
523 BID, but exposure was similar between 750 and 900 mg BID. At Day 15, no 
further increase in exposure was observed as the dose increased from the 600 to 
900 mg BVD-523 BID, though this may in part be due to a limited number of 
patients treated at these higher dose levels. 24,25 
 
At Day 15, minimal accumulation of BVD-523 and metabolites were observed at 
the 10, 20, and 300 mg dose levels, whereas accumulation compared to Day 1 
ranged from approximately 1.3 to 4.0-fold for the other dose levels. Pre-dose 
concentrations on Day 22 were generally similar to those on Day 15, indicating 
that steady state had been attained by Day 15.24 
 
The combined AUC values of the three BVD-523 metabolites measured 
represented a maximum of 42% of that of BVD-523, indicating that the plasma 
exposure to drug-derived material was mainly to the parent drug. Moderate 
between-subject variability was seen in plasma exposure to the metabolites.24 
 
Metabolism: 
The majority of identified drug derived material in plasma was due to parent drug, 
with the plasma concentrations of metabolites relatively low at all dose levels. 
Metabolite-to-parent AUC0-12 ratios for three selected metabolites ranged from 
0.0313 to 0.292. For individual subjects, the sum of the AUC0-12 values for the 
three metabolites represented 9.57 to 41.6% of the AUC0-12 values for BVD-523.24 
 
 

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Elimination: 
After reaching Cmax, plasma concentrations of BVD-523 declined slowly. Since 
plasma drug concentrations were measured only up to 12 hours after the morning 
dose, it was not possible to calculate an effective or terminal phase. Based on 
limited data, the estimated T1/2 values ranged from 3.60 to 5.91 hours on Days 1 
and 15. However, these values should be interpreted with caution, because the true 
elimination phase at the higher doses may not have been captured.24 
 
The urinary excretion of unchanged BVD-523 was negligible (<0.2% of the dose) 
at all dose levels within 12 hours post-dose, and was not dose-related within the 
very low percentage range observed.24 
 
Renal clearance of BVD-523 appeared to be dose-independent. Individual renal 
clearance values ranged from 0.128 to 0.0895 L/hr (where n=1 per dose level) 
and mean values ranged from 0.0149 to 0.0300 L/hr (where n>3).24 
 
 
 
 
Clinical Pharmacology: 
In preliminary studies, measurements of phorbol ester-dependent RSK 
phosphorylation of whole blood samples collected from patients dosed orally with 
BVD-523 have demonstrated dose- and concentration-dependent bioactivity of 
BVD-523 (Figure 1). These ERK inhibitory effects are manifest following a single 
dose of BVD-523 and after repeated dosing, showing biological activity consistent 
with the mechanism of action of BVD-523.24 25 
 
Figure 1:  Patient Blood Samples Show Dose- and Concentration-Dependent Activity of BVD-523 
 
 
Detailed analysis of the effects of BVD-523FB (ulixertinib) on 24 patients in dose 
escalation and 81 patients from cohort expansion has been published. 27. Twelve 
hours of ECG data were collected through the use of continuous Holter monitors 

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on days 1 and 15 for these patients, along with 12-lead ECGs in triplicate at PK 
timepoints for a subset of patients.  Exposure-response modeling (ERM) provided 
a robust linear model between QTc and BVD-523FB (ulixertinib) Cmax, showing 
positive but not statistically significant correlation of 0.53 ms per µg/mL.  At 
expected exposures, upper 90% confidence intervals would predict a change to the 
QTc of < 10 ms.  No changes on PR or QRS intervals was seen. In summary, the 
risk of QT/QTc prolongation with BVD-523FB (ulixertinib) is low.24 
 
 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children  
There have been no prior studies of BVD-523FB (ulixertinib) in children.  
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
There have been no pediatric Pharmacology/Pharmacokinetics/Correlative 
Biological Studies of BVD-523FB (ulixertinib).  
 
 
Overview of Proposed Pediatric Study 
This is a phase 2 trial of BVD-523FB (ulixertinib) in children with recurrent or refractory 
solid tumors, CNS tumors, non-Hodgkin lymphomas and histiocytic disorders harboring 
specific activating mutations that result in pathologic activation of the MAPK pathway.  
 
Because the pediatric dose of BVD-523FB (ulixertinib) has not been established, there will 
be a limited dose finding phase consisting of the first 12 evaluable patients enrolled on 
study. BVD-523FB (ulixertinib) will be administered for 28-day cycles twice daily per 
nomogram by mouth on an empty stomach. The first 6 evaluable patients will be enrolled 
at a dose of 260 mg/m2/dose BID (450 mg BID Max Dose), equivalent to 75% of the 
maximum tolerated dose (MTD) in adults. There will be a single dose escalation to 350 
mg/m2/dose BID (100% of the adult MTD [600 mg BID Max Dose]) or de-escalation to 
175 mg/m2/dose BID (50% of the adult MTD [300 mg BID Max Dose]) for the next six 
subjects.  Following the first 12 evaluable patients, all subsequent patients will be enrolled 
at the highest dose level not exceeding the pediatric MTD. Patients enrolled in the dose 
escalation component will be included in the analysis of efficacy. 
 
The primary aim of this trial will be to establish the objective response rate to BVD-523FB 
(ulixertinib). While there will not be multiple pre-determined mutation-based cohorts, 
responses will be analyzed retrospectively with respect to specific MAPK pathway 
activating mutations.  
 
Key secondary objectives include further evaluation of the tolerability of BVD-523FB 
(ulixertinib) in pediatric patients. Toxicity will be assessed using CTCAE V5.0. Imaging 
for disease evaluation will occur every other cycle x 3, then every three cycles. Disease 
response will be assessed according to RECIST v1.1 for solid tumors and 2-dimensional 
measurement for CNS tumors. 
  
 

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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment Network 
(OPEN), a web-based registration system available on a 24/7 basis. It is integrated with the NCI 
Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient position in the RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.nih.gov/iam/ >). This is the same account (user id and password) used for 
credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user must 
have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://open.ctsu.org . Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU Enterprise 
System for regulatory and roster data and, upon enrollment, initializes the patient position in the 
Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in OPEN, the 
IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on the site’s IRB 
approval.  Please see Appendix IX for detailed CTEP and CTSU Registration Procedures including: 
registration in Registration and Credential Repository (RCR), requirements for site registration, 
submission of regulatory documents and how to check your site’s registration status. 
 
 
Genetic Screening Procedures for Eligibility  
Patient enrollment onto the APEC1621SC screening protocol is required. Tumor and blood 
samples will be obtained and the results of the evaluation of the tumor specimens will 
determine if the patient's tumor has an actionable Mutation of Interest (aMOI) for which a 
MATCH treatment subprotocol is available. 
 
The treatment assignment to MATCH to a subprotocol (if a relevant aMOI is detected)  
will be communicated to the enrolling institution via the COG or MATCHBox treatment 
assignment mechanism at the time the results of MATCH are returned, upon which a 
reservation to APEC1621J will be secured by COG. Reservations should be withdrawn by 
the institution if at any point the patient indicates they do NOT intend to consent to 
participation or the site investigator indicates the patient will never be eligible for 
APEC1621J. 
 
 
IRB Approval 
In order to participate in Pediatric MATCH, an institution must participate in the NCI 
Pediatric CIRB. NCI Pediatric CIRB approval of this study must be obtained by a site prior 
to enrolling patients  
 
Submitting Regulatory Documents:  Submit required forms and documents to the CTSU 
Regulatory Office, where they will be entered and tracked in the CTSU RSS.   
 
Online: http://www.ctsu.org (members’ section)  Regulatory Submission Portal 
 
Regulatory Help Desk: 866-651-2878 
                             
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 

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are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing, or amendment review.  However, sites must submit a Study 
Specific Worksheet for Local Context (SSW) to the CIRB (via IRBManager) to indicate 
their intention to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office for compliance in the RSS.  The Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study so that the study approval can be applied 
to those institutions.  Other site registration requirements (e.g., laboratory certifications, 
protocol-specific training certifications, or modality credentialing) must be submitted to 
the CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
 
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, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through the study-specific protocol.  Documentation of the informed consent for screening 
will be maintained in the patient’s research chart. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility) may be used for 
baseline values even if the studies were done before informed consent was obtained. 
 
 
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. 
 
 
Study Enrollment 
Following a MATCH treatment assignment to a protocol, patients may be enrolled on the 
study once all eligibility requirements for the study have been met. Before enrolling a 
patient on study, the Study Chair or Vice Chair should be notified. Patients who give 
informed consent for the protocol in order to undergo screening for eligibility are not 
considered enrolled and should not be enrolled until the screening is completed and they 
are determined to meet all eligibility criteria. Study enrollment is accomplished by going 
to the CTSU OPEN (Oncology Patient Enrollment Network) https://open.ctsu.org/open/. 
For questions, please contact the COG Study Research Coordinator, or the CTSU OPEN 
helpdesk at https://www.ctsu.org/CTSUContact.aspx.  Patients must be enrolled before 
treatment begins.  Patients must not receive any protocol therapy prior to enrollment. 
 
Patients must be enrolled within 12 weeks (84 days) of treatment assignment. Protocol 
therapy must start no later than 7 calendar days after the date of enrollment. Patients 
enrolling onto APEC1621J will have a COG ID obtained through their prior enrollment 
onto the screening protocol or from a prior COG study. 
 
Note:  No starter supplies will be provided. Drug orders of BVD-523FB (ulixertinib) 
should be placed with CTEP after enrollment and treatment assignment to 

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APEC1621J with consideration for timing of processing and shipping to ensure 
receipt of drug supply prior to start of protocol therapy 
 
 
Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621 
master screening protocol.  
 
 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and 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) 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. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) must be obtained within 14 days 
prior to start of protocol therapy (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.   
 
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. 
 
Inclusion Criteria 
 
4.1.1 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621J based on the presence of 
an actionable mutation as outlined in Appendix VIII. 
  
4.1.2 
Age:  Patients must be ≥ than 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
4.1.3 
BSA: Patients must have a body surface area ≥ 0.54 m2 at the time of study 
enrollment.  
 
4.1.4 
Disease Status: Patients must have radiographically measurable disease (See 
Section 12) at the time of study enrollment. Patients with neuroblastoma who do 
not have measurable disease but have MIBG+ evaluable disease are eligible. 
Measurable disease in patients with CNS involvement is defined as tumor that is 
measurable in two perpendicular diameters on MRI and visible on more than one 
slice. 

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Note:  The following do not qualify as measurable disease:  
- 
malignant fluid collections (e.g., ascites, pleural effusions) 
- 
bone marrow infiltration except that detected by MIBG scan for 
neuroblastoma 
- 
lesions only detected by nuclear medicine studies (e.g., bone, gallium or 
PET scans) except as noted for neuroblastoma 
- 
elevated tumor markers in plasma or CSF  
- 
previously radiated lesions that have not demonstrated clear progression 
post radiation  
- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1. 
 
4.1.5 
Performance Level:  Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age (See Appendix I).  Note:  Neurologic deficits in 
patients with CNS tumors must have been relatively 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. 
 
4.1.6 
Prior Therapy 
 
4.1.6.1 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. See https://www.cogmembers.org/site/disc/devthe
rapeutics/default.aspx  for commercial and Phase 1 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. 
i. 
 ≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent. See https://www.cogmembers.org/site/disc/devthe
rapeutics/default.aspx for commercial and Phase 1 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. 

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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 growth factors 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.  The duration of this interval must be discussed with the study 
chair and the study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than hematopoetic 
growth factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than hematopoetic 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 DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
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. 
 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): 
≥ 
42 
days 
after 
systemically 
administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to BVD-523FB 
(ulixertinib) or other ERK inhibitors. 
 
4.1.7 
Organ Function Requirements 
 
 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in Section 

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4.1.7.1.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.  
 
 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
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 GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
 
 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 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.)  
- 
Serum albumin ≥ 2 g/dL. 
 
 Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  ≥ 27% by echocardiogram, or 
- 
Ejection fraction of ≥ 50% by gated radionuclide study. 
-  
QTc interval ≤ 480 milliseconds 
 
4.1.8 
Patients must be able to swallow intact capsules.  
 
4.1.9 
Informed Consent: 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.  
 
 
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. 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 an 
effective contraceptive method for the duration of study treatment and for 3 months 
after last dose of BVD-523FB (ulixertinib).  
 
 
 

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4.2.2 
Concomitant Medications 
 
 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 4.1.6.1.d). 
 
 Investigational Drugs:  
Patients who are currently receiving another investigational drug are not 
eligible. 
 
 Anti-cancer Agents:   
Patients who are currently receiving other anti-cancer agents are not 
eligible. 
 
 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. 
 
 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. See Appendix II for a list of agents.  Note: CYP3A4 inducing 
anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on 
a stable dose, are allowed. 
 
 CYP2D6 and CYP1A2: Patients who are currently receiving drugs that 
are strong inducers or inhibitors of CYP1A2 and CYP2D6 are not eligible. 
Strong inhibitors of CYP1A2 (eg., ciprofloxacin, enoxacin, fluvoxamine, 
zafirlukast) should be avoided from 14 days prior to enrollment to the end 
of the study. Strong inhibitors of CYP2D6 (e.g., bupropion, paroxetine, 
fluoxetine, quinidine, terbinafine) should also be avoided from 14 days 
prior to enrollment to the end of the study. 
 
 Patients with known significant ophthalmologic conditions (uncontrolled 
glaucoma, history of retinal vein occlusion or retinal detachment, 
excluding patients with longstanding findings secondary to existing 
conditions) are not eligible. 
 
4.2.3 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
4.2.4 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.5 
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 PROGRAM 
 
 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Days 1-28 
BVD-523FB (ulixertinib) orally 
twice daily 
Day 28 
Evaluation 
 
Patients will receive BVD-523FB (ulixertinib) twice daily, continuously for 28-day cycles 
(please see dosing nomogram in Appendix V).  Evaluations will occur at the end of every 
other cycle x 3, then every 3 cycles. A cycle may be repeated up to a total duration of 
therapy of 2 years (maximum 26 cycles). 
 
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. Take by mouth on an empty 
stomach either 1 hour before a meal or 2 hours after a meal. Capsules should not be opened, 
crushed or chewed. If a patient misses or vomits a dose of BVD-523FB (ulixertinib), an 
additional dose should not be taken. Patients should resume dosing at the next scheduled 
time. 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years provided the patient meets the criteria for starting 
subsequent cycles (Section 5.2) and does not meet any of the criteria for removal from 
protocol therapy criteria (Section 10.0). 
 
5.1.1 
Determination of Recommended Phase 2 Dose (RP2D)/Tolerable Dose 
 
Dose Level 
BVD-523FB (ulixertinib)Dose (mg/m2) 
-1 
175 mg/m2/dose  PO BID* (300 mg BID Max Dose) 
1* 
260 mg/m2/dose  PO BID* (450 mg BID Max Dose) 
2 
350 mg/m2//dose  PO BID* (600 mg BID Max Dose) 
*Refer to the dosing nomogram in Appendix V for more information.  
 
The starting BVD-523FB (ulixertinib) dose will be 260 mg/m2/dose (Dose Level 
1), which is approximately 25% below the adult MTD. Accrual will be temporarily 
suspended after enrollment to the first 6 toxicity-evaluable subjects to assess for 
toxicity as outlined in Section 11.  
 
If there are fewer than 2 DLTs in the first 6 toxicity-evaluable subjects enrolled at 
the starting dose, the dose will be escalated to Dose Level 2. If ≥ 2 of the first 6 
toxicity-evaluable subjects enrolled at Dose Level 2 have DLTs, all subsequent 
subjects will be enrolled at the original starting dose. Otherwise, remaining 
subjects will continue to enroll at Dose Level 2. 
 
If there are 2 or more DLTs during cycle 1 among the first 6 toxicity-evaluable 
subjects enrolled at Dose Level 1, the next cohort will enroll at Dose Level -1.  If 
≥ 2 of the first 6 toxicity-evaluable subjects enrolled at the reduced dose have 

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DLTs, the study will be closed for toxicity.  Otherwise, remaining subjects will 
continue to enroll at Dose Level -1. 
 
5.1.2 
Therapy Delivery Map 
See Appendix VI for therapy delivery map for Cycle 1 and subsequent cycles. 
5.1.3 
Intra-Patient Escalation 
Intrapatient dose escalation is not allowed. 
 
 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0 and 
eligible to continue agent administration per the requirements in Section 6.0 
   
 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the current version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment 
areas should have access to a copy of the current version of the CTCAEv5.0.  A copy of 
the CTCAEv5.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
 
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. Dose limiting hematological and non-hematological 
toxicities are defined differently. The DLT evaluation period for the purpose of dose 
escalation will be Cycle 1 of therapy. 
 
5.4.1 
Non-Hematological Dose-Limiting Toxicity 
 Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days. See 
Appendix XI for values that represent thresholds between CTCAE grades.   
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L 
regardless of baseline. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation. 
 
• 
Any Grade 2 visual disturbance that persists for ≥ 1 week. 
• 
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. 
 
 
 

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5.4.2 
Hematological dose limiting toxicity  
 Hematological dose limiting toxicity is defined as: 
 
a) In patients evaluable for hematological toxicity (see Section 4.1.7.1),   
• 
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration 
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days within a 7-day period 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles (e.g. platelets <100K or ANC <1000). 
 
 Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
If a patient experiences hematological toxicity as defined in Section 5.4.2.1, the 
treatment will be held.  Counts should be checked every 3-4 days for 
thrombocytopenia and every other day for neutropenia during this time. If the 
toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose (see Appendix 
V for capsule formulation dosing nomogram). Doses reduced for toxicity will not 
be re-escalated, even if there is minimal or no toxicity with the reduced dose.  
 
6.1.2 
If toxicity does not resolve to meet eligibility parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
6.1.3 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol therapy. 
 
 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.4.1, the treatment will be held. When the toxicity resolves to meet 
eligibility parameters or baseline within 14 days of drug discontinuation, the 
patient may resume treatment at a reduced dose (see Appendix V for capsule 
formulation dosing nomogram). Doses reduced for toxicity will not be re-
escalated, even if there is minimal or no toxicity with the reduced dose. 
 
6.2.2 
If toxicity does not resolve to meet eligibility or baseline parameters within 14 
days of drug discontinuation, the patient must be removed from protocol therapy. 
 
6.2.3 
If dose-limiting toxicity recurs in a patient who has resumed treatment at the 

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reduced dose, the patient must be removed from protocol therapy. 
 
 
Dose Modifications for Visual Disturbances  
 
Grade  
Action 
Grade 1 
• 
Maintain Dose  
Grade 2 
 
• 
Hold BVD-523FB (ulixertinib) until eye exam is completed; If the 
ophthalmology exam is normal and the toxicity resolves to < Grade 1 within 
1 week or an alternate cause for the vision problem is identified – restart 
BVD-523FB (ulixertinib) at the same dose level. Otherwise Grade 2 visual 
disturbance that persists for ≥ 1 week will be considered a DLT and require 
a dose reduction as per Section 6.2. 
Grade 3 or 4 
 
• 
Hold BVD-523FB (ulixertinib) until eye exam is completed; if alternate 
etiology for vision change is identified, contact Study Chair to discuss 
restarting of BVD-523FB (ulixertinib). Otherwise ≥ Grade 3 visual 
disturbance will be considered a DLT and require a dose reduction as per 
Section 6.2. 
 
 
Dose Modifications for GI Toxicities (Nausea, Vomiting, Dehydration) 
 
Heightened attention should be paid to hydration during treatment for all patients on study. 
 
Management and Dose Modification Guidelines for Diarrhea 
Diarrhea 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
Loperamide:  Please see weight-
based dosing of loperamide in 
Appendix 
XIII. 
Please 
use 
loperamide at first onset of 
diarrhea. 
• 
If diarrhea >24 hours: Continue 
loperamide and add second line 
anti-diarrhea drug if needed.  
• 
Oral hydration 
• 
IV hydration if indicated  
• 
Continue 
BVD-523FB 
(ulixertinib).  
• 
Start loperamide and continue 
anti-diarrhea medications until 
diarrhea resolves to Grade ≤1. 
Grade 2 
• 
Hold 
BVD-523FB 
(ulixertinib). 
• 
Start loperamide and continue 
anti-diarrhea medications until 
diarrhea resolves to Grade ≤1. 
• 
If Grade 2 diarrhea resolves in 
< 7 days, may resume BVD-
523FB 
(ulixertinib) 
once 
diarrhea resolves to Grade ≤1. 
• 
If Grade 2 diarrhea persists for 
≥ 7 days, this will be considered 
a DLT. Hold BVD-523FB 
(ulixertinib) 
until 
diarrhea 
resolves to baseline and restart 
with one dose level reduction 
per Section 6.2. 
Grade 3 
 
• 
Hold 
BVD-523FB 
(ulixertinib). 
• 
Start loperamide and continue 
anti-diarrhea medications until 

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Management and Dose Modification Guidelines for Diarrhea 
Diarrhea 
Adverse Event Management 
Action and Dose Modification 
diarrhea resolves to baseline. 
• 
This will be considered a DLT 
and restart with one dose level 
reduction per Section 6.2 once 
diarrhea resolves to baseline. 
Grade 4 
 
Complicated diarrhea: 
• 
Discontinue 
BVD-523FB 
(ulixertinib) 
If treatment is delayed by > 14 days or a DLT recurs after dose reduction, permanently discontinue BVD-
523FB (ulixertinib). 
 
 
Management and Dose Modification Guidelines for Nausea 
Nausea 
Adverse Event Management 
Dose modifications 
Grade 1 
5-HT3 antagonist and additional
anti-emetics as needed 
IV hydration as needed 
Drugs that are strong inhibitors or 
inducers of CYP1A2, CYP2D6,
and CYP3A4 must be avoided (see 
Sections 
4.2.2.5 
and 
4.2.2.6; 
Appendix II). 
• 
Medical management. 
• 
Continue BVD-523FB (ulixertinib). 
Grade 2 
• 
Medical management 
• 
Continue BVD-523FB (ulixertinib). 
• 
If Grade 2 nausea persists for ≥ 7 days 
and 
is 
considered 
sufficiently 
medically significant or sufficiently 
intolerable by patients that it requires 
treatment interruption per Section 
5.4.1.1 will be considered a DLT. Hold 
BVD-523FB (ulixertinib) until nausea 
resolves to baseline and restart with 
one dose level reduction per Section 
6.2. 
Grade 3 
• 
Medical management. 
• 
Hold BVD-523FB (ulixertinib).  
• 
If Grade 3 nausea persists for > 3 days, 
this will be considered a DLT. Hold 
BVD-523FB (ulixertinib) until nausea 
resolves to baseline and restart with 
one dose level reduction per Section 
6.2. 
If treatment is delayed by > 14 days or a DLT recurs after dose reduction, permanently discontinue BVD-
523FB (ulixertinib). 
 
 
 
Management and Dose Modification Guidelines for Vomiting  
Vomiting 
Adverse Event Management  
Dose modification 
Grade 1 
5-HT3 antagonist and additional
anti-emetics as needed 
• 
Medical management. 
• 
Continue BVD-523FB (ulixertinib). 

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Grade 2 
IV hydration as needed 
Drugs that are strong inhibitors or
inducers of CYP1A2, CYP2D6, and
CYP3A4 must be avoided (see
Sections 
4.2.2.5 
and 
4.2.2.6;
Appendix II). 
• 
Medical management 
• 
Hold BVD-523FB (ulixertinib). 
• 
If Grade 2 vomiting resolves in < 7
days, may resume BVD-523FB
(ulixertinib) once vomiting resolves
to Grade ≤1. 
• 
If Grade 2 vomiting persists for ≥ 7
days, this will be considered a DLT.
Hold BVD-523FB (ulixertinib) until
vomiting resolves to baseline and
restart with one dose level reduction
per Section 6.2. 
Grade 3 
• 
Medical management. 
• 
Hold BVD-523FB (ulixertinib).  
• 
If Grade 3 vomiting persists for > 3
days, this will be considered a DLT.
Hold BVD-523FB (ulixertinib) until
vomiting resolves to baseline and
restart with one dose level reduction
per Section 6.2. 
Grade 4  
Off protocol therapy 
If treatment is delayed by > 14 days or a DLT recurs after dose reduction, permanently discontinue BVD-
523FB (ulixertinib). 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
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. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
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. See Section 
7.5 for drugs that should not be used concomitantly due to potential interactions with BVD-
523FB (ulixertinib). See below for recommendations on management of specific toxicities 
associated with BVD-523FB (ulixertinib). 
 
7.3.1 
Recommendations for Visual Disturbance: 
Patients who experience visual disturbance should undergo complete 
ophthalmologic examination including visual acuity, visual fields (if feasible) and 
fundoscopic exam. Optical coherence tomography (OCT) is particularly helpful in 
identifying retinal pathology that can be seen with MAPK inhibitors, and so is 
strongly encouraged as an adjunct to the above assessment. 

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7.3.2 
Advise patients to minimize sun exposure, use broad-spectrum sunscreens, and 
wear sunglasses. Patients should be informed that relevant sun exposure may occur 
even through glass, such as while driving. 
 
 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
 
Concomitant Medications 
 
7.5.1 
CYP3A4/5 inhibitors or inducers:  
Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to 
enrollment to the end of the study. See Appendix II for a list of agents.  Note: 
CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or 
metastases, on a stable dose, are allowed. 
 
7.5.2 
CYPA1A2 and CYP2D6: 
Patients must not be receiving drugs that are strong inducers or inhibitors of 
CYP1A2 and CYP2D6. Strong inhibitors of CYP1A2 (eg., ciprofloxacin, 
enoxacin, fluvoxamine, zafirlukast) should be avoided from 14 days prior to 
enrollment to the end of the study. Strong inhibitors of CY2D6 (eg., bupropion, 
paroxetine, fluoxetine, quinidine, terbinafine) should also be avoided from 14 days 
prior to enrollment to the end of the study.    
 
7.5.3 
BVD-523FB (ulixertinib) is a P-glycoprotein (P-gp) transporter substrate, and is 
highly protein bound (99-100% protein binding). Use caution in patients who are 
also receiving strong P-gp inhibitors (eg., amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and 
ritonavir, verapamil) or highly protein-bound drugs with narrow therapeutic 
ranges. 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) 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) 
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. Imaging studies, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 

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STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam  with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)2,3 
Weekly2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
ECHO or gated radionuclide study 
X 
 
Every 3 cycles  
EKG 
X 
End of Cycle 1 
 
 
Ophthalmologic Exam10 
X 
 
 
Tumor Disease Evaluation4-A, 4-B, 4-C 
X 
 
Every other Cycle x 3 then q 
3 Cycles 4 
Plain radiograph tibial growth plate 
(bone x-ray tests)11 
X 
 
Prior to Cycles 2 and 5, then 
every 6 months 
Bone Marrow Aspirate and/or biopsy5,6 
X6 
 
 
Medication Diary7 
 
Weekly 
X 
Pharmacokinetics (optional)8 
 
X 
 
Circulating Tumor DNA (ctDNA-
optional)9 
 
 
Cycle 5, Day 1 and (for 
patients receiving ≥ 5 cycles 
only)  at end of Protocol 
Therapy OR disease 
progression  
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
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 method of 
birth control. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
3 
If patients develop Grade 3 or higher thrombocytopenia then CBCs should be checked every 3-4 days 
until recovery per Section 6.1 
4 
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. 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-A  Neurological exam also required for CNS patients  
4-B  Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8    
4-C   Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if 
 
the patient was enrolled with or has a history of having MIBG avid tumor. Otherwise the patient 
 
must have both CT/MRI and bone scan prior to enrollment. For patients with neuroblastoma and 
 
measurable disease by CT or MRI, lesions should be measured and followed using the same 
 
modality (CT or MRI) in addition to MIBG or bone scan. For patients with neuroblastoma and 
 
evaluable disease by MIBG scintigraphy or bone scan, use the same modality (MIBG scintigraphy 
 
or bone scan) to image and follow patients; CT/MRI are not required but may be performed as 

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clinically indicated. Refer to Section 12.5.4 and  Section 12.9 
5 
Bone marrow aspirate and/or biopsy only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data. Should only 
be performed on patients with known bone marrow involvement at baseline.   
6 
Bone marrow aspirate and/or biopsy should be performed only when complete response or partial 
response is identified in target disease or when progression in bone marrow is suspected. 
7.  Medication diary (see Appendix III) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. The medication diary should be collected and reviewed weekly during cycle 1. 
8. See Section 8.4 for details of PK studies. 
9. With consent two samples will be collected on this protocol (Cycle 5 Day 1; and for patients receiving 
≥  5 cycles,  at progression or end of protocol therapy) see Section 8.5 and Appendix IV for details 
of the ctDNA studies. Note that a ctDNA sample is scheduled to be obtained on the APEC162SC 
screening protocol prior to the initiation of treatment on this subprotocol  
10.  Ophthalmological examinations will be performed by an ophthalmologist at screening and if clinically 
indicated during treatment. 
11. Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to first dose 
of protocol therapy. In patients with open growth plates, follow-up plain radiographs of the same 
growth plate(s) should be obtained according to Section 8.2.1. 
 
 
Monitoring for Specific Toxicities 
8.2.1 
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 prior to Cycles 2, 
5 and every 6 months. 
• 
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 undergo more frequent x-ray follow up at least every 3 
cycles or 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 BVD-523FB (ulixertinib) 
should be made after discussion with the Study Chair or Study Vice-Chair 
and MATCH Leadership, taking into account the presence of any 
symptoms referable to the knee as well as the patient’s response to BVD-
523FB (ulixertinib). 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 BVD-523FB 
(ulixertinib)  or not. 
 
 
Radiology Studies 
 
8.3.1 
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.  The Operations center will notify the site when a 
patient has met the criteria for review. The tumor disease evaluations to be 

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submitted for review include baseline (prestudy) evaluations as well as all end of 
cycle tumor disease evaluations which occurred while the patient was on the 
subprotocol therapy study 
 
8.3.2 
Technical Details of Submission:  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
and Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
Submission of Diagnostic Imaging data in DICOM format is required.  
Submission of the digital files and reports via TRIAD is preferred.  Instructions for 
TRIAD set up are below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. 
 
Corresponding Radiology reports may be submitted along with the electronic 
submission via TRIAD or sFTP or may be emailed to DataSubmission@QARC.o
rg.  The COG operations center and IROC are available to assist with any queries 
regarding the corresponding radiology reports which should be included when the 
scans are submitted 
 
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM and DICOM RT files and other digital objects, such as reports. 
TRIAD de-identifies and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account.  Please refer to 
CTEP Registration Procedures of the protocol for instructions on how to request a 
CTEP-IAM account. 
 
To submit images, the site TRIAD user must be on the site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.   
 
TRIAD Installations: 
 

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When a user applies for a CTEP-IAM account with the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be able 
to submit images. TRIAD installation documentation can be found by following 
this link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low- 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created. 
 
Sites not able to submit imaging electronically may submit imaging via CD.   CD’s 
may be sent by courier to:  
 
Address for submission: IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway  
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:     (401) 753-7601 
Web:    http://irocri.qarc.org 
 
 
Pharmacology (optional) 
 
8.4.1 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of BVD-523FB 
(ulixertinib) in children. Pharmacokinetic analysis will be conducted at a 
centralized laboratory using validated assays. 
 
8.4.2 
Sampling Schedule  
 
Blood samples will be obtained at the following time points:  
 
Blood 
Sample No. 
Time Point 
 
Scheduled Collection Time 
1 
Cycle 1, Day 1 
Pre-dose 

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Cycle 1 Day 1 AM Dose 
The PM dose of BVD-523FB (ulixertinib) on Day 1, Cycle 1 will not 
be given for patients undergoing these PK studies. 
2 
Cycle 1, Day 1 
1 hr after AM dose 
3 
Cycle 1, Day 1  
2 hrs after AM dose 
4 
Cycle 1, Day 1 
4 hrs after AM dose 
5 
Cycle 1, Day 1 
6-8 hrs after AM dose 
6 
Cycle 1, Day 2 
Pre-dose 
7 
Cycle 1, Day 15 
Pre-dose 
 Cycle 1 Day 15 AM Dose 
8 
Cycle 1, Day 15 
1 hr after AM dose 
9 
Cycle 1, Day 15 
2 hrs after AM dose 
10 
Cycle 1, Day 15 
4 hrs after AM dose 
11 
Cycle 1, Day 15 
6-8 hrs after AM dose 
12 
Cycle 1, Day 22 
Pre-dose 
  * Please contact study chair or pharmacologist to adjust PK schedule if there are 
missed doses during Days 1-21. 
 
8.4.3 
Sample Collection and Handling Instructions 
Blood samples (2 ml for each time point) will be collected in K2-EDTA (lavender 
top) tubes for pharmacokinetic evaluation. Record the exact time that the sample 
is drawn along with the exact time that the drug is administered. 
 
Sites are expected to use their own standard materials for PK sample collection as 
kits will not be provided for the PK studies for this study. 
 
8.4.4 
Sample Processing and Storage 
Following collection, the sample will be immediately gently mixed by inversion 
8-10 times.  The sample will be stored on wet ice until centrifugation.   
• 
The sample will be centrifuged at 1500 x g for 15 minutes at 4° C within 60 
minutes after the sample is drawn.  
• 
The resultant plasma should be withdrawn in two aliquots: 
- 
0.5 mL in Aliquot 1 (label as “PK Primary”) and the remainder in 
Aliquot 2 (label as “PK Back-up”) into two clearly labeled 2mL 
polypropylene screw cap cryovials. 
• 
Secure the cryovial caps and within 60-120 min after collection, place the 
samples into storage at (-20°C to -70°C) until shipment. 
• 
Backup samples (Aliquot 2) will be held at the study site at (-20°C to -70°C), 
until the end of the study or as requested by the sponsor. 
 
 

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8.4.5 
Sample Labeling 
Please label Aliquot 1 as “PK Primary” and Aliquot 2 as “PK Back-up”.Each tube 
must be labeled with the patient’s study registration number, the study I.D 
(APEC1621J), and the date and time the sample was drawn.  Data should be 
recorded on the appropriate transmittal form found in RAVE. 
 
8.4.6 
Sample Shipping Instructions 
Ship the aliquots overnight frozen on dry ice. The samples must be securely packed 
in boxes to avoid breakage during transit, double-bagged to contain leaks, 
 
Attn:  Anita Wyeth, Covance Laboratories Inc.  
3301 Kinsman Blvd  
Attn: Andrea Varese, Sample Management—Bioanalytical (Rm 1S 160) 
Madison WI 53704    
Email:   anita.wyeth@covance.com 
 
Biomed Valley Discoveries FedEx account number is #438681043 
 
 
Circulating Tumor DNA Study (optional)   
 
8.5.1 
Sampling Schedule   
An initial sample was previously required at time of enrollment onto the 
APEC1621SC screening protocol. Two additional samples (optional) will be 
collected into Streck Cell-Free DNA BCT tubes at the timepoints: 
 
 (1) Cycle 5 Day 1 
 (2) At disease progression or end of protocol therapy (for patients receiving ≥ 5 
cycles of therapy only) 
  
 
Peripheral blood samples for circulating tumor DNA should be obtained as 
follows:  
• 
For patients ≥ 10 kg collect 20 mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg collect 10 mL (one tube)  
• 
For patients < 5 kg research samples will not be collected  
 
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 

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venipuncture. To guard against backflow, observe the following precautions: 
• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results. 
 
8.5.2 
Sample Processing 
Samples do not need to be processed at the collection site. 
 
8.5.3 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621J), and the date and time the sample was drawn. Data should be 
recorded on the appropriate transmittal form found in RAVE, which must 
accompany the sample(s). 
 
8.5.4 
Sample Shipping Instructions 
Specimen should be shipped at room temperature to the BPC (address below). 
Upon arrival separation, extraction, and storage of plasma and cellular DNA will 
be performed. Samples should be shipped from Monday through Friday for 
Tuesday through Saturday delivery. If blood is collected in the Streck tube on 
Friday, over the weekend or on the day before a holiday, the sample should be 
stored in a refrigerator until shipped on the next business day. Ship by FedEx 
Priority Overnight using the COG FedEx account. Blood samples should be 
shipped the same day as collection, ship blood for Saturday delivery if shipped on 
Friday. 
 
Ship specimens to the following address: 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol APEC1621J-Peds MATCH* 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
*Be sure to include the room number. Packages received without the room 
number may be returned to the sender. Packages must be labeled “Peds MATCH” 
in order to expedite processing at the BPC. 
 
9.0 
 AGENT INFORMATION 
 

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BVD-523FB (ulixertinib) 
NSC# 799018 IND# 134661  
  
9.1.1 
Structure and molecular weight  
 
Chemical Name: (S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(1-(3- 
chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide hydrochloride 
 
Molecular Formula: C21H22Cl2N4O2·HCl 
Molecular Weight:  469.79 g/mol for HCl salt 
 
 
9.1.2 
Supplied by:  
BVD-523FB (ulixertinib) is supplied by BioMed Valley and distributed by a 
Division of Cancer Treatment and Diagnosis the Pharmaceutical Management 
Branch (DCTD), NCI. 
 
9.1.3 
Formulation 
BVD-523FB (ulixertinib) is supplied as mono-chloride salt in hard gelatin capsule. 
Each yellow size 0 capsule contains 150 mg of drug substance (FB or free base 
equivalent) and is packaged in a 30-count white HDPE bottle with induction seal 
and child-resistant polypropylene cap. 
 
9.1.4 
Storage 
Store at 15°C to 25°C (59°F to 77°F). 
 
If a storage temperature excursion is identified, promptly return BVD-523FB 
(ulixertinib) to controlled room temperature 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.   
 
9.1.5 
Stability 
Shelf life studies are ongoing. Dispense BVD-523FB (ulixertinib) in the original 

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manufacturer’s container. Do not repackage capsules. 
 
9.1.6 
Administration 
See treatment (Section 5.0) and Dose Modification (Section 6.0) sections of the 
protocol. Take by mouth on an empty stomach either 1 hour before a meal or 2 hours 
after a meal. Capsules should not be opened, crushed or chewed. If a patient misses 
or vomits a dose, an additional dose should not be taken. Patients should resume 
dosing at the next scheduled time. 
 
 
 
9.1.7 
Potential Drug Interactions 
In vitro studies suggest that BVD-523FB (ulixertinib) is metabolized primarily by 
CYP450-mediated oxidation, involving CYP isozymes 3A4, 2D6 and 1A2. 
Concomitant use of strong inducers or inhibitors of CYP 1A2, 2D6 or 3A4 is 
prohibited during the study.  
 
In vitro and ex vivo results indicate that BVD-523FB (ulixertinib) has minimal 
potential to inhibit CYP 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 isozymes. The 
potential for BVD-523FB (ulixertinib) to affect CYP450 as an inducer is 
considered low even though some increases in CYP450 activity were observed in 
human hepatocyte and animal liver microsome systems. 
 
BVD-523FB (ulixertinib) is a highly cell permeable, putative P-glycoprotein (P-
gp) transporter substrate, and is highly protein bound in multiple species, including 
humans at 99-100% protein binding. Use caution in patients who are also receiving 
strong P-gp inhibitors or highly protein-bound drugs with narrow therapeutic 
ranges. 
 
9.1.8 
Patient Care Implications:  
Advise patients to minimize sun exposure, use broad-spectrum sunscreens, and 
wear sunglasses. Patients should be informed that relevant sun exposure may occur 
even through glass, such as while driving. 
 
Advise study participants to use contraception while receiving study treatment and 
for 3 months after the last dose of BVD-523FB (ulixertinib). 
 
Inhalation of powder or contact with skin and mucous membranes, especially those 
of the eyes, must be avoided. Should accidental exposure of the eye or skin occur, 
copious irrigation with water should be instituted immediately. 
 
9.1.9 
BVD-523FB (ulixertinib) Toxicities 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer to 
the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.ca
ncer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 

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further clarification. Frequency is provided based on 208 patients. Below is the 
CAEPR for BVD-523FB (ulixertinib). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER. If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 
 
 
Version 2.1, October 31, 20181 
 
 Adverse Events with Possible  
 Relationship to BVD-523FB (ulixertinib) 
 (CTCAE 5.0 Term) 
[n= 208] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Thrombotic 
thrombocytopenic 
purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
EYE DISORDERS 
  
 
Blurred vision 
 
 Blurred vision (Gr 2) 
 
Eye disorders – Other2 (eye 
symptoms)  
 
 Eye 
disorders 
– 
Other2 
(eye 
symptoms) (Gr 2) 
 
 
Eye disorders - Other (retinal vein 
occlusion) 
  
 
Photophobia 
 
 Photophobia (Gr 2) 
 
 
Retinal detachment 
  
 
Vision decreased 
 
 Vision decreased (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Bloating 
 
 Bloating (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastritis 
 
 Gastritis (Gr 2) 
 
Gastroesophageal reflux disease 
 
 Gastroesophageal reflux disease 
(Gr 2) 
 
 
Gastrointestinal disorders - Other 
(gastrointestinal hemorrhage)3  
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 

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 Adverse Events with Possible  
 Relationship to BVD-523FB (ulixertinib) 
 (CTCAE 5.0 Term) 
[n= 208] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Edema face 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
 
Pain 
 
 Pain (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased 
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
 
Electrocardiogram QT corrected 
interval prolonged 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased  
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hyperphosphatemia 
 
 Hyperphosphatemia (Gr 2) 
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 2) 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Generalized muscle weakness 
 
 Generalized muscle weakness (Gr 2) 
 
Musculoskeletal and connective 
tissue disorder – Other (muscle 
twitch) 
 
 Musculoskeletal and connective 
tissue disorders – Other (muscle 
twitch) (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - 
Other (squamous cell carcinoma, 
keratoacanthoma-type, mid 
forehead) 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 

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 Adverse Events with Possible  
 Relationship to BVD-523FB (ulixertinib) 
 (CTCAE 5.0 Term) 
[n= 208] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Paresthesia 
 
 Paresthesia (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
 Anxiety (Gr 2) 
 
Delirium 
 
 Delirium (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
 Acute kidney injury (Gr 2) 
 
Hematuria 
 
 Hematuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Sore throat 
 
 Sore throat (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
 
 
Erythroderma 
  
 
Nail changes 
 
 Nail changes (Gr 1) 
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
  
 
Photosensitivity 
 
 Photosensitivity (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash acneiform 
 
 
 Rash acneiform (Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (skin fissures) 
 
 Skin and subcutaneous tissue 
disorders - Other (skin fissures) 
(Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
Hot flashes 
 
 Hot flashes (Gr 2) 
 
Hypotension 
 
 Hypotension (Gr 2) 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2 Eye symptoms may include floaters, night blindness, and watering eyes, and halo vision. 
 
3 Gastrointestinal hemorrhage may include gastric hemorrhage, colonic hemorrhage, rectal hemorrhage, or other 
gastrointestinal tract hemorrhage. 
 
4 Infection may include infections around the rectum, eyes, mucosa, and other sites. 
 
Adverse events reported on BVD-523FB (ulixertinib) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that BVD-523FB (ulixertinib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Myocardial infarction; Pericardial effusion; Sinus bradycardia; Sinus 
tachycardia 

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GASTROINTESTINAL DISORDERS - Anal pain; Colonic ulcer; Flatulence; Gastrointestinal disorders - Other 
(diverticulum); Hemorrhoids; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait disturbance  
INVESTIGATIONS - Blood lactate dehydrogenase increased; Platelet count decreased; Weight loss; White blood 
cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hypoglycemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Flank pain; Muscle 
cramp; Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness) 
NERVOUS SYSTEM DISORDERS - Headache; Ischemia cerebrovascular; Nervous system disorders - Other 
(neuropathy peripheral); Seizure 
PSYCHIATRIC DISORDERS - Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Oropharyngeal pain; Pleural effusion; Pneumothorax; Stridor 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hirsutism; Pain of skin; Scalp pain; Skin and 
subcutaneous tissue disorders - Other (skin lesion) 
VASCULAR DISORDERS - Flushing; Hematoma; Thromboembolic event 
 
Note: BVD-523 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. 
 
 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational agents 
for the study should be ordered under the name of one lead participating investigator at that 
institution. 
                           
Note: No starter supplies will be provided. Drug orders of BVD-523FB (ulixertinib) 
should be placed with CTEP after enrollment and treatment assignment to 
APEC1621J with consideration for timing of processing and shipping to ensure 
receipt of drug supply prior to start of protocol therapy. If expedited shipment is 
required, sites should provide an express courier account through the Online Agent Order 
Processing (OAOP) application. Provide the patient ID number in the comment box when 
submitting an order request. 
 
 
Clinical Drug Request and Investigator Brochure Availability 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. The current versions of the IBs for the agents will also 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,  “current” 
password, and active person registration status. 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. Questions about IB access 
may be directed to the PMB IB coordinator via email. 
 
 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 

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(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. 
 
9.4.1 
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.html    
• 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  
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/ 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
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 6). 
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 it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
j) 
Patient did not receive protocol treatment after study enrollment 
 
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 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
 

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Follow-Up Data Submission and APEC1621SC Off Study Criteria 
Patients who are off subprotocol therapy will continue to be followed on the APEC1621SC 
screening protocol. Follow-up data submission will occur until one of the APEC1621SC 
Off Study Criteria is met (See Section 10 of APEC1621SC for details). 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 until off study 
criteria are met unless consent is withdrawn or the patient dies or is lost to follow-up. 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
 
Sample Size and Study Duration 
APEC1621J will require a minimum of 4 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of  10-30 
biomarker positive patients per year, the primary cohort of this subprotocol is expected to 
be completed within  0.8-2.4 years. 
 
 
Dosing Considerations  
 
11.2.1 Pediatric MATCH Sub-arm Dosing in the Absence of Pediatric Phase 1 Data 
Please see Section 5.1 for a specific discussion of the dosing of BVD-523FB 
(ulixertinib) to be used in this study.  As there is no prior pediatric Phase 1 data, 
study investigators have reviewed relevant data with the pharmaceutical partner to 
identify a drug specific dosing plan for testing in children with relapsed or 
refractory cancer, and trial participants will be closely monitored to ensure 
tolerability of the selected dose. Limited pharmacokinetic sampling may be done 
for patients enrolled on these arms.   
 
11.2.2 Determination of Recommended Phase 2 Dose (RP2D)/Tolerable Dose 
Because the adult RP2D of the agent is the adult MTD, the pediatric subprotocol 
will evaluate an initial cohort of patients at a dose level approximately 30% below 
the adult MTD and then complete the study using the adult RP2D, assuming that 
both dose levels are tolerated..  The DLT evaluation period for the purpose of dose 
escalation will be Cycle 1 of therapy. Note that adverse events that begin during 
Cycle 1 and specify a duration of time in order to be considered a DLT must be 
followed to resolution or until the definition of DLT has been met, regardless of 
the schedule end of Cycle 1 (e.g.  grade 2 thrombocytopenia would be considered 
a DLT if it developed during Cycle 1 of therapy and caused, or would have caused, 
a delay of >14 days to begin Cycle 2). Patients enrolled during the determination 
of the recommended Phase 2 dose who are not evaluable for toxicity during Cycle 
1 at a given dose level will be replaced. 
 
The rolling six phase 1 trial design28 will be used for the conduct of this study. 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.  
 

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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* 
 
 
 
 
 
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 
dose escalation will be stopped. 
 
In addition to determination of the RP2D, a descriptive summary of all toxicities will be 
reported. 
 

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Study Design 
The primary cohort defined below will employ single stage A’Hern designs of N=20 and 
N=10 respectively. The agent will be deemed worthy of further study in the relevant subset 
of patients (i.e. biomarker positive in any histology, biomarker positive in a particular 
histology, etc) if the decision rule is met. Operating characteristics are shown below. 
 
Cohort 
N 
Decision Rule Alpha Power 
Primary biomarker positive 20 ≥ 3 responses 
10% 
90% 
 
Histology-specific biomarker positive expansion cohorts will, by definition, be deemed 
worthy of further study, since they will have at least 3 responses. The table below shows 
90% confidence intervals (Wilson method) for a range of observable response rates. 
 
Cohort Size Observed Response Rate 90% Confidence Interval 
10 
30% 
13% - 56% 
10 
40% 
19% - 65% 
10 
50% 
27% - 73% 
 
11.3.1 Primary Cohort:  
APEC1621J will evaluate a primary cohort of 20 mutation-matched (“biomarker 
positive”) evaluable patients of any histology for the primary study aim of 
determining the objective response rate (CR/PR according to the response criteria 
in Section 12.3) to the agent. Using an A’Hern design29 with alpha=10%, a sample 
of N=20 will provide 90% power to detect an improvement in response rate from 
5%, if the treatment is ineffective, to 25% if the targeted therapy is sufficiently 
effective to warrant further study. If there are at least 3 responses out of 20 in the 
primary cohort, the biomarker/therapy match will be deemed a success.  
 
11.3.2 Histology-Specific Biomarker Positive Expansion Cohorts:  
If ≥ 3 patients in the primary cohort with the same histology show signs of 
objective response (CR/PR according to the response criteria  in Section 12.3), a 
histology-specific biomarker positive expansion cohort will open after the primary 
cohort is completed to up to 7 evaluable patients for a total sample size of 10 
evaluable biomarker positive patients with that histology. This will allow us to 
estimate more precisely the activity in biomarker positive patients of that 
histology. See Appendix VII for a list of target tumor histologies.  
We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 histologies have ≥ 3 responses, we will open a total of 3 expansion cohorts as 
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts. 
 
 
 
Methods of Analysis 
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.30 Decision making for A’Hern design 
cohorts will follow rules described above. 
 

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Any responses or lack thereof in patients enrolled during the determination of the 
Recommended Phase 2 Dose (dose finding phase) will count toward the objective response 
rate in their respective cohort. 
 
Toxicity tables will be constructed to summarize the observed incidence by type of toxicity 
and grade. A patient will be counted only once for a given toxicity for the worst grade of 
that toxicity reported for that patient. Toxicity information recorded will include the type, 
severity, time of onset, time of resolution, and the probable association with the study 
regimen.   
 
 
Evaluability for Response 
Any eligible patient who is enrolled and receives at least one dose of protocol therapy will 
be considered evaluable for response. Any patient who receives non-protocol anti-cancer 
therapy during the response evaluation period will be considered a non-responder for the 
purposes of the statistical rule, unless they show an objective response prior to receiving 
the non-protocol anti-cancer therapy (in which case they will be considered a responder). 
Patients who demonstrate a complete or partial response confirmed by central review will 
be considered to have experienced a response. When opening expansion cohorts, the 
evaluation period for determination of best response will be 6 treatment cycles. All other 
patients will be considered non-responders. Patients who are not evaluable for response 
evaluation may be replaced for the purposes of the statistical rule. All patients considered 
to have a response (CR or PR) must have imaging studies reviewed centrally at the COG. 
Centers will be notified by the COG about requests for scans of patients with stable disease. 
Preliminary assessment of activity using institutionally provided tumor measurements will 
be entered into CDUS quarterly. The central review by COG will be provided as the final 
reviewed assessment of response when such becomes available. 
 
Evaluability for Toxicity   
All eligible patients who receive at least one dose of protocol therapy will be considered in 
the evaluation of toxicity. In addition, for the dose-escalation portion during Cycle 1, 
patients without DLT must receive at least 85% of the prescribed dose per protocol 
guidelines and must have the appropriate toxicity monitoring studies performed to be 
considered evaluable for toxicity for the purpose of determining dose escalation and 
defining the recommended phase 2 dose. Patients under Section 4.1.7 are not evaluable for 
DLT if they do not experience a non-hematologic DLT. 
 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of protocol treatment 
to the occurrence of any of the following events: disease progression or disease recurrence 
or death from any cause. All patients surviving at the time of analyses without events will 
be censored at their last follow-up date. 
 
PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. 
Patients with local calls of disease progression (i.e. calls made by the treating institution), 
will be counted as having had an event, even if the central review does not declare 
progression. We will also report PFS based on central radiology review as a secondary 
analysis, if adequate number of disagreements in progressions exist between the treating 
institutions and the central radiology review to make such an analysis meaningful.     
 
 
Correlative Studies 
A descriptive analysis of pharmacokinetic (PK) parameters will be performed to define 
systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK 

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parameters will be summarized with simple summary statistics, including means, medians, 
ranges, and standard deviations (if numbers and distribution permit).   
 
A descriptive analysis of the exploratory aims described in Section 1.3 will be performed 
and will be summarized with simple summary statistics. All of these analyses will be 
descriptive in nature. 
 
 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 
Racial category 
Ethnicity 
Total 
Not Hispanic 
or Latino 
Hispanic or 
Latino 
Female Male Female Male 
American Indian/Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native 
Hawaiian 
or 
Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
5 
0 
0 
8 
White 
12 
20 
4 
2 
38 
More than one race 
1 
0 
0 
0 
1 
Total 
17 
26 
4 
2 
49 
 
This distribution was derived from the demographic data for patients enrolled on recent COG 
Phase 2 trials. 
 
12.0 
EVALUATION CRITERIA 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in the current version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the current CTCAEv5.0.  A 
copy 
of 
the 
CTCAEv5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov). 
 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
 
 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle 

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following initial documentation of objective response. 
 
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor (non-CNS) and measurable disease (Section 12.4); b) 
neuroblastoma with MIBG positive lesions (Section 12.5); c) CNS tumor (Section 12.7); 
and d) Non-Hodgkin lymphoma/hystiocytosis (Section 12.8). Note: Neuroblastoma 
patients who do not have MIBG positive lesions should be assessed for response as solid 
tumor patients with measurable disease. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-
247, 2009].  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. 
 
12.3.1 Definitions 
 
12.3.1.1 Evaluable for objective response:  
Eligible patients who receive at least one dose of protocol therapy will 
be considered 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-
responders 
 
12.3.1.2 Evaluable Non-Target Disease Response: 
  
Eligible patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease and have received 
at least one dose of protocol therapy will be considered evaluable for 
non-target disease response. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
 
12.3.2 Disease Parameters 
 
12.3.2.1 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. 
 
12.3.2.2 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. 

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12.3.2.3 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. 
 
12.3.2.4 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. 
 
12.3.2.5 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.  
 
12.3.3 Methods for Evaluation of 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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12.3.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
12.3.3.2 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.  
 
12.3.3.3 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 (e.g. 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.  
 
12.3.3.4 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.   
 
12.3.3.5 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.  
 
12.3.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., 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. 
 
12.3.3.7 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:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 

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b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If 
the positive FDG-PET at follow-up corresponds to a new site of 
disease 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. 
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.31  
Response Criteria for Patients with Solid Tumor and Measurable 
Disease 
 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease  
12.4.1 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 

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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 
 
12.4.2 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.     
 
12.4.3 Overall Response Assessment 
 
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 
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 

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*      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. 
 
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Table 3: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
12.4.4 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 
12.9  from a sequence of overall response assessments. 
 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.5.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.5.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 

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persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.5.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  
1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 

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to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
12.5.4 Overall Response Assessment 
 
Table 4: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
12.5.5 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 from the sequence of the 
overall response assessments as described in Section 12.9. 
 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
12.6.1 Bone Marrow Involvement  
Note: patients with bone marrow as the ONLY site of disease are not eligible for 
this study. Response criteria in this section are intended to be used when 
assessing marrow involvement as a component of overall response.  
 
Histologic analysis at the local institution of marrow tumor cell involvement is 
required for patients with a history of marrow involvement. Marrow aspirate and 
biopsy should be evaluated at baseline and every 2 cycles thereafter. Note: If 
progressive disease is documented by RECIST criteria using tumor measurements 
or by MIBG scan, then a repeat BM is not needed to confirm PD.  
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 

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morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 
 
Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
12.6.2 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 from the sequence of the 
overall response assessments as described in Section 12.9. 
 
 
 
 
 
 
Response Criteria for Patients with CNS Tumors 
 
12.7.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.7.2 Evaluable Disease  
Evaluable disease is defined as 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, 
CSF cytology, or other reliable measures. 
 
12.7.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.7.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 

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established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. Off all steroids 
with stable or improving neurologic examination. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements; on a stable or decreasing dose of steroids with 
a stable or improving neurologic examination. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD; on a stable or 
decreasing dose of steroids with a stable or improving neurologic examination. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
 
Increasing doses of corticosteroids required to maintain stable neurological status 
should be strongly considered as a sign of clinical progression unless in the context 
of recent wean or transient neurologic change due e.g. to radiation effects. 
 
12.7.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.7.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.7.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 

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Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
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 
12.9 from a sequence of overall response assessments. 
 
 
 
Response Criteria for Patients with non- Hodgkin Lymphoma/Histiocytosis 
 
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 Criteria31, with modification from the Lugano classification.32 
 
 
 
12.8.1 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 (e.g., 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. 
 
12.8.2 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. 
 

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Complete Response 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. 
 
No Response (Stable Disease) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
Progressive disease 
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  
 
Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)32 
 
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. 
 
12.8.3 Evaluation of organ enlargement32  
 
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 
 
 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 

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determinations, separated by at least a 3 week time period, are required to determine the 
patient’s overall best response. Two objective status determinations of CR before 
progression are required for best response of CR. Two determinations of PR or better 
before progression, but not qualifying for a CR, are required for a best response of PR. 
Two determinations of stable/no response or better before progression, but not qualifying 
as CR or PR, are required for a best response of stable/no response; if the first objective 
status is unknown, only one such determination is required. Patients with an objective 
status of progression on or before the second evaluations (the first evaluation is the first 
radiographic evaluation after treatment has been administered) will have a best response of 
progressive disease. Best response is unknown if the patient does not qualify for a best 
response of progressive disease and if all objective statuses after the first determination and 
before progression are unknown. 
 
12.9.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
Table 5.  Sequences of overall response assessments with corresponding best 
response. 
 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
12.9.2 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, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 

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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 grade (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. 
 
 
 
 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
13.1.1 Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair 
have the primary responsibility for AE identification, documentation, grading, and 
assignment of attribution to the investigational agent/intervention. It is the 
responsibility of the treating physician to supply the medical documentation 
needed to support the expedited AE reports in a timely manner.  
 

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Note: All expedited AEs (reported via CTEP-AERS) must also be reported via 
routine reporting. Routine reporting is accomplished via the Adverse Event (AE) 
Case Report Form (CRF) within the study database.   
 
13.1.2 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page  
https://ctepcore.nci.nih.gov/ctepaers/pages/task. 
 
Send supporting documentation to the NCI by fax (fax# 301-897-7404) and by 
email to both COGCAdEERS@childrensoncologygroup.org 
 and to the APEC1621J COG Study Assigned Research Coordinator.  ALWAYS 
include the ticket number on all faxed and emailed documents. 
 
 
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 current version of the NCI CTCAEv5.0.  
The descriptions and grading scales found in the current version of the CTCAEv5.0 
will be used for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAEv5.0.  A copy of the CTCAEv5.0 can be downloaded from 
the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAEv5.0. 
 
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.  
 
• 
Any medical event equivalent to CTCAEv5.0 grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless 
of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
• 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that 
resolves and then recurs during a subsequent cycle does not require CTEP-AERS 
reporting unless (1) the Grade increases; or (2) hospitalization is associated with the 
recurring AE. 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable). Once internet connectivity is restored, a 24-hour notification 
phoned in must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 

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Table A: Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
7 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements: 
 
• Myelosuppression, (Grade 1 through Grade 4 adverse events as defined in the table below), 
does not require expedited reporting, unless it is associated with hospitalization. 

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Category 
Adverse Events 
INVESTIGATIONS 
Platelet count decreased 
INVESTIGATIONS 
White blood cell decreased 
INVESTIGATIONS 
Neutrophil count decreased 
INVESTIGATIONS 
Lymphocyte count decreased 
BLOOD/LYMPHATICS DISORDERS 
Anemia 
 
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.9 
of the protocol.   
 
 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 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. 
 
13.4.2 If an adverse event progresses through several grades during one course of therapy, 
only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects.  
 
13.4.4 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."   
 
13.4.5 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.  
 
 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 
13.5.2 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. 
 
 
Specific Examples for Expedited Reporting 
 
13.6.1 Reportable Categories of Death 
• Death attributable to a CTCAEv5.0 term.  

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• Death Neonatal: A disorder characterized by “Newborn deaths 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 v5.0 term associated with Grade 5.  
• Death NOS: A cessation of life that cannot be attributed to a CTCAE v5.0 term 
associated with Grade 5.  
• Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” under the system organ class (SOC) of “General Disorders and 
Administration Site Conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
• Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
• Any death that occurs more than 30 days after the last dose of treatment with 
an investigational agent which can be attributed (possibly, probably, or 
definitely) to the agent and is not clearly due to progressive disease must be 
reported via CTEP-AERS per the timelines outlined in the table above. 
 
13.6.2 Reporting Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, 
radiation 
or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 

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13.6.3 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal 
loss”, 
the 
Pregnancy 
Information 
Form, 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 897-7404. 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. 
 
Pregnancy 
Pregnancy needs to be followed until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow-ups. This form is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf. If the baby is born with a birth defect or anomaly, then a 
second CTEP-AERS report is required. 
 
Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE v5.0 as “Death in utero.” 
 
Any pregnancy loss, needs to 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. 
 
Death Neonatal 
Neonatal death, defined in CTCAEv5.0 as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least possibly 
due to the investigational agent/intervention, should be reported expeditiously, as 
Grade 4 “Death Neonatal” under the system organ class (SOC) of “General 
disorders and administration site conditions.” 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.  
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, 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 COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 

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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. 
 
 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 
31 and October 31.  This is not a responsibility of institutions participating in this trial.  
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.   
 
 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
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.go
v/industryCollaborations2/intellectual_property.htm) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing 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 
NIH, 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. 
 

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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/industr
yCollaborations2/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 rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 
 

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Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG 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 developmental therapy 
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 COG Developmental Therapeutics 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 Web 
site. 
 
14.4.2 Monitoring by the Study Chair and MATCH Leadership  
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 
MATCH Chair, Vice Chair and Statistician on a weekly conference call. 

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REFERENCES 
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See WL, Tan IL, Mukherjee J, et al: Sensitivity of glioblastomas to clinically available MEK 
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Chakraborty R, Hampton OA, Shen X, et al: Mutually exclusive recurrent somatic mutations in 
MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 
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Goetz EM, Ghandi M, Treacy DJ, et al: ERK mutations confer resistance to mitogen-activated 
protein kinase pathway inhibitors. Cancer Res 74:7079-89, 2014 
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Nissan MH, Pratilas CA, Jones AM, et al: Loss of NF1 in cutaneous melanoma is associated with 
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Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF 
inhibition alone in melanoma. N Engl J Med 371:1877-88, 2014 
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Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAF-mutated 
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Robert C, Karaszewska B, Schachter J, et al: Improved overall survival in melanoma with 
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Ascierto PA, Schadendorf D, Berking C, et al: MEK162 for patients with advanced melanoma 
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Janne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced non-
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Jessen WJ, Miller SJ, Jousma E, et al: MEK inhibition exhibits efficacy in human and mouse 
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Dombi E, Baldwin A, Marcus LJ, et al: Activity of Selumetinib in Neurofibromatosis Type 1-
Related Plexiform Neurofibromas. N Engl J Med 375:2550-2560, 2016 
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Carvajal RD, Sosman JA, Quevedo JF, et al: Effect of selumetinib vs chemotherapy on progression-
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Germann UA, Furey BF, Markland W, et al: Targeting the MAPK Signaling Pathway in Cancer: 
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Biomed Valley Discoveries Inc: BVD-523 Investigator's Brochure  Version 3, 2016.  
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Sullivan RJ, Infante JR, Janku F, et al: First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in 
Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and 
Expansion Study. Cancer Discov 8:184-195, 2018 
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Li B, Janku F, Patel M, et al: First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients 
with advanced solid tumors: Final results of a phase I dose escalation and expansion study. J Clin 
Oncol 35, :(suppl; abstr 2508), 2017 
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Mendzelevski B, Ferber G, Janku F, et al: Effect of ulixertinib, a novel ERK1/2 inhibitor, on the 
QT/QTc interval in patients with advanced solid tumor malignancies. Cancer Chemother 
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28. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the Timeline of Pediatric Phase I Trials: 
The Rolling Six Design. Journal of Clinical Oncology 26:190-195, 2008 
29. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
30. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
31. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
32. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 

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APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
 
This is not an 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 
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 

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Page 76 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
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 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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Version Date: 12/09/2020 
 
Page 77 
APPENDIX III:  MEDICATION DIARY FOR BVD-523FB (ULIXERTINIB) 
 
COG Patient ID:___________ Acc#_________________ Institution :________________________________  
Please do not write patient names on this form. 
 
Complete each day with the time and dose given for BVD-523FB (ulixertinib). If a dose is not due or is accidentally skipped 
leave that day blank. Make note of other drugs and supplements taken under the Comments section below. BVD-523FB 
(ulixertinib) capsules should not be opened, chewed, or crushed but should be swallowed whole. If capsule is broken and the 
powder of the capsules gets on skin, wash the exposed area with as much water as necessary. Inform your study doctor or nurse 
if that occurs. BVD-523FB (ulixertinib) should be taken by mouth on an empty stomach either 1 hour before a meal or 2 hours 
after a meal. If you miss or vomit a dose, an additional dose should not be taken. Resume dosing at the next scheduled time. Add 
the dates to the calendar below and return the completed diary to the study clinic after each treatment cycle (weekly during 
cycle 1, and then after each treatment cycle).  
 
*Please Note: If you are taking part in the optional pharmacokinetic studies. For Day 1 of cycle 1, only take the AM dose, do 
not take the PM dose.  
 
EXAMPLE 
 
 
Number of BVD-523FB 
(ulixertinib) capsules 
Comments 
 
 
Date 
Time 
150 mg 
 
Day 1 
1/15/14 
8:30 AM 
1 
He felt nauseated an hour after taking 
the drug but did not vomit. 
   
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|     
                              End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2/dose                                                             
    
WEEK 1 
Date 
Time 
# of BVD-523FB (ulixertinib) 150 mg 
capsules prescribed to take 
 
       AM#___                       PM#___ 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
# of BVD-523FB (ulixertinib) 150 mg 
capsules taken  
 
Day 1* 
 
 
AM 
 
 
 
PM* 
 
 
Day 2 
 
 
AM 
 
 
 
PM 
 
 
Day 3 
 
 
AM 
 
 
 
PM 
 
 
Day 4 
 
 
AM 
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 

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Page 78 
WEEK 2 
Date 
Time 
# of BVD-523FB (ulixertinib) 150 mg 
 capsules prescribed to take 
 
AM#___                       PM#___ 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
# of BVD-523FB (ulixertinib) 150 mg 
capsules taken 
Day 8 
 
 
AM 
 
 
 
PM 
 
 
Day 9 
 
 
AM 
 
 
 
PM 
 
 
Day 10 
 
 
AM 
 
 
 
PM 
 
 
Day 11 
 
 
AM 
 
 
 
PM 
 
 
Day 12 
 
 
AM 
 
 
 
PM 
 
 
Day 13 
 
 
AM 
 
 
 
PM 
 
 
Day 14 
 
 
AM 
 
 
 
PM 
 
 
WEEK 3 
Date 
Time 
# of BVD-523FB (ulixertinib) 150 mg 
 capsules prescribed to take 
 
AM#___                      PM#___ 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
# of BVD-523FB (ulixertinib) 150mg 
capsules taken 
 
Day 15 
 
 
AM 
 
 
 
PM 
 
 
Day 16 
 
 
AM 
 
 
 
PM 
 
 
Day 17 
 
 
AM 
 
 
 
PM 
 
 
Day 18 
 
 
AM 
 
 
 
PM 
 
 
Day 19 
 
 
AM 
 
 
 
PM 
 
 
Day 20 
 
 
AM 
 
 
 
PM 
 
 
Day 21 
 
 
AM 
 
 
 
PM 
 
 
 
 

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Page 79 
WEEK 4 
Date 
Time 
# of BVD-523FB (ulixertinib) 150 mg 
capsules prescribed to take 
AM#___                            PM#___ 
Comments 
(Describe any missed or extra 
doses, vomiting and/or bothersome 
effects.) 
# of  BVD-523FB (ulixertinib) 150mg 
capsules taken  
Day 22 
 
 
AM 
 
 
 
PM 
 
 
Day 23 
 
 
AM 
 
 
 
PM 
 
 
Day 24 
 
 
AM 
 
 
 
PM 
 
 
Day 25 
 
 
AM 
 
 
 
PM 
 
 
Day 26 
 
 
AM 
 
 
 
PM 
 
 
Day 27 
 
 
AM 
 
 
 
PM 
 
 
Day 28 
 
 
AM 
 
 
 
PM 
 
 
 
If this form will be used as a source document, the site personnel who administered the drug must sign and date this 
form below: 
 
Signature: ______________________________________________                    Date: __________________________ 
 
 
(site personnel who administered the drug) 

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APEC1621J 
                                                                                                                                                         
 
Version Date: 12/09/2020 
 
Page 80 
; 
APPENDIX IV CORRELATIVE STUDIES 
 
Correlative 
Study 
 
Section. 
Blood Volume 
Tube Type 
Volume per Sample 
Total Cycle 1 
Pharmacokinetics 
8.4 
2 mL 
24 mL 
K2 EDTA lavender top 
Total Blood Volume in 
Cycle 1 
 
 24 mL 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total 
Cycle 5 
Day 1 
Circulating 
tumor DNA 
(optional)  
8.5 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥  5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 
mL 
Streck Cell-Free DNA BCT 
tubes 
Total Blood Volume in 
Cycle 5 Day 1 
 
10-20 
mL 
 
 
Correlative 
Study 
 
Section 
Blood Volume 
Tube Type 
Volume per Sample 
Total  ‘Time of 
progression’ or ‘End 
of protocol therapy’* 
Circulating 
tumor DNA 
(optional) 
8.5 
• 
For patients ≥ 10 kg collect 20 
mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥  5 kg but < 10 kg 
collect 10 mL (one tube)  
• 
For patients < 5 kg research 
samples will not be collected  
 
10-20 mL 
Streck Cell-Free 
DNA BCT tubes 
Total Blood Volume in 
‘Time of progression or 
End of protocol therapy’ 
 
10-20 mL 
 
*Only for patients receiving ≥ 5 cycles of therapy only 
 
 
 
 
 
 

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Version Date: 12/09/2020 
 
Page 81 
APPENDIX V: BVD-523FB (ULIXERTINIB) DOSING NOMOGRAM 
BVD-523FB (ulixertinib) Dose Assignment: 175 mg/m2/dose PO BID  
 (Dose Level -1) 
 
 
 
 
 
 
 
 
 
 
 
 
BVD-523FB (ulixertinib) Dose Assignment: 260 mg/m2/dose PO BID 
 (Dose Level 1) 
BSA (m2) 
BVD-523FB 
(ulixertinib) dosing  
Total Daily 
dose (mg/day) 
Total Daily  
pill count 
Dose Reduction for 
Toxicity 
0.54-0.72 
150 mg PO BID 
300 
2 
off study 
0.73-1.07 
300 mg PO AM, 
150 mg PO PM 
450 
3 
150 mg PO BID 
1.08-1.29 
300 mg PO BID 
600 
4 
300 mg PO AM, 
150 mg PO PM 
1.3-1.58 
450 mg PO AM, 
300 mg PO PM 
750 
5 
300 mg PO AM, 
150 mg PO PM 
≥1.59 
450 mg PO BID 
900 
6 
300 mg PO BID 
 
 
BVD-523FB (ulixertinib) Dose Assignment: 350 mg/m2/dose PO BID 
 (Dose Level 2) 
 
 
BSA (m2) 
BVD-523FB 
(ulixertinib) dosing 
Total Daily 
dose (mg/day) 
Total Daily 
pill count 
Dose Reduction for 
Toxicity 
0.54-0.72 
Off-Study 
Off-Study 
Off-study 
Off-study 
0.73-1.07 
150 mg PO BID 
300 
2 
Off-Study 
1.08-1.58 
300 mg PO AM, 
150 mg PO PM 
450 
3 
150 mg PO BID 
≥1.59 
300 mg PO BID 
600 
4 
300 mg PO AM, 
150 mg PO PM 
BSA (m2) 
BVD-523FB 
(ulixertinib) dosing 
Total Daily 
dose (mg/day) 
Total Daily 
pill count 
Dose Reduction for 
Toxicity 
0.54-0.72 
300 mg PO AM, 
150 mg PO PM 
450 
3 
150 mg PO BID 
0.73-1.07 
300 mg PO BID 
600 
4 
300 mg PO AM, 
150 mg PO PM 
1.08-1.29 
450 mg PO BID 
900 
6 
300 mg PO BID 
1.3-1.58 
600 mg PO AM, 
450 mg PO PM 
1050 
7 
450 mg PO AM, 
300 mg PO PM 
≥1.59 
600 mg PO BID 
1200 
8 
450 mg PO BID 

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                                                                                                                                                        Page 1 of 2 
 
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Page 82 
Cycle 1  
 
APPENDIX VI: APEC1621J THERAPY DELIVERY MAP 
Therapy Delivery Map – Cycle 1 
This Therapy Delivery Map (TDM) relates to Cycle 1. Each cycle lasts 28 days.  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number 
 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1.  
 
DRUG 
ROUTE 
DOSAGE 
DA
YS 
IMPORTANT NOTES 
 BVD-
523FB 
(ulixertinib) 
IND # 
134661 
PO 
Dose Level -1: 175 mg/m2/dose 
BID (max 300 mg BID) 
 
Dose Level 1: 260 mg/m2/dose 
BID (max 450 mg BID) 
 
Dose Level 2: 350 mg/m2/dose 
BID (max 600 mg BID) 
1-28 
Refer to dosing nomogram (Appendix V) 
 
Take by mouth on an empty stomach either 1 hour 
before a meal or 2 hours after a meal. Capsules 
should not be opened, crushed or chewed. If a 
patient misses or vomits a dose, an additional dose 
should not be taken. Patients should resume dosing 
at the next scheduled time. If capsule is broken and 
the powder of the capsules gets on skin, wash the 
exposed area with as much water as necessary. 
 
 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
BVD-523FB (ulixertinib) 
________mg AM            ______mg PM 
Studies 
 
 
 
Enter calculated dose above as per dosing 
nomogram and actual dose administered 
below 
 
 
 
1 
________mg AM            ______mg PM 
g* 
 
 
2 
________mg AM            ______mg PM 
g 
 
 
3 
________mg AM            ______mg PM 
c 
 
 
4 
________mg AM            ______mg PM 
 
 
 
5 
________mg AM            ______mg PM 
 
 
 
6 
________mg AM            ______mg PM 
 
 
 
7 
________mg AM            ______mg PM 
 
 
 
8 
________mg AM            ______mg PM 
a, c, d, e, f 
 
 
9 
________mg AM            ______mg PM 
 
 
 
10 
________mg AM            ______mg PM 
 
 
 
11 
________mg AM            ______mg PM 
 
 
 
12 
________mg AM            ______mg PM 
c 
 
 
13 
________mg AM            ______mg PM 
 
 
 
14 
________mg AM            ______mg PM 
 
 
 
15 
________mg AM            ______mg PM 
a, c, d, e, f, g 
 
 
16 
________mg AM            ______mg PM 
 
 
 
17 
________mg AM            ______mg PM 
 
 
 
18 
________mg AM            ______mg PM 
c 
 
 
19 
________mg AM            ______mg PM 
 
 
 
20 
________mg AM            ______mg PM 
 
 
 
21 
________mg AM            ______mg PM 
 
 
 
22 
________mg AM            ______mg PM 
a, c, d, e, f, g 
 
 
23 
________mg AM            ______mg PM 
 
 
 
24 
________mg AM            ______mg PM 
 
 
 
25 
________mg AM            ______mg PM 
c 

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                                                                                                                                                        Page 2 of 2 
 
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Page 83 
Cycle 1  
 
 
 
26 
________mg AM            ______mg PM 
 
 
 
27 
________mg AM            ______mg PM 
 
 
 
28/1 
________mg AM            ______mg PM 
a, b, c, d, e, f, h, i, j 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are met 
(whichever occurs later).  
 
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
* The PM dose of BVD-523FB (ulixertinib) on Day 1, Cycle 1 will not be given for patients undergoing these PK studies.
 
 
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. For information related to prestudy observations please refer to section 8.1. Studies on Day 
28/1 may be obtained within 72 hours prior to the start of the subsequent cycle. 
 
 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
a. 
History/Physical Exam (including VS).  
b. 
Ht/Wt/BSA 
c. 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should be checked at least 
every other day until recovery to Grade 3 or until meeting the criteria for dose limiting toxicity.  If 
patients develop Grade 3 or greater thrombocytopenia then CBCs should be checked every 3 to 4 days 
until recovery per Section 6.1.  
d. 
Electrolytes including Ca++, PO4, Mg++   
e. 
Creatinine, ALT, bilirubin   
f. 
Medication Diary- (see Appendix III) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. The medication diary should be collected weekly.   
g. 
Pharmacokinetics- see Section 8.4 for details of PK studies.  
h. 
  EKG For information related to prestudy observations please refer to section 8.1 
i. 
Plain radiograph tibial growth plate (bone x-ray tests) - Plain radiographs of at least one tibial growth 
plate should be obtained in all patients prior to first dose of protocol therapy and prior to cycle 2.  
j. 
 Albumin 

 
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                                                                               Page 1 of 3 
 
Version Date: 12/09/2020 
 
Page 84 
Subsequent Cycles 
All Subsequent Cycles 
Therapy Delivery Map – All Subsequent Cycles 
This Therapy Delivery Map (TDM) relates to all subsequent cycles. Each cycle lasts 
28 days. Treatment may continue in the absence of disease progression or unacceptable 
toxicity. Use a copy of this page once for each cycle (please note cycle number below).  
____________________________ 
Patient COG ID number 
_______________________ 
Accession number 
 
Criteria to start each cycle are listed in Section 5.2. Extensive treatment details are in Section 5.1. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
BVD-523FB 
(ulixertinib) 
IND # 134661 
PO 
 
Dose Level -1: 175 
mg/m2/dose BID (max 
300 mg BID) 
 
Dose Level 1: 260 
mg/m2/dose BID (max 
450 mg BID) 
 
Dose Level 2: 350 
mg/m2/dose BID (max 
600 mg BID) 
1-28 
Refer to dosing nomogram (Appendix V) 
 
Take by mouth on an empty stomach either 1 
hour before a meal or 2 hours after a meal. 
Capsules should not be opened, crushed or 
chewed. If a patient misses or vomits a dose, an 
additional dose should not be taken. Patients 
should resume dosing at the next scheduled 
time. If capsule is broken and the powder of the 
capsules gets on skin, wash the exposed area 
with as much water as necessary. 
 
 
Enter Cycle #: _____  
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
BVD-523FB (ulixertinib) 
________mg AM            ______mg PM 
Studies 
 
 
 
Enter calculated dose above as per dosing 
nomogram and actual dose administered below 
 
 
 
1 
________mg AM            ______mg PM 
a-f, j  
 
 
2 
________mg AM            ______mg PM 
 
 
 
3 
________mg AM            ______mg PM 
 
 
 
4 
________mg AM            ______mg PM 
 
 
 
5 
________mg AM            ______mg PM 
 
 
 
6 
________mg AM            ______mg PM 
 
 
 
7 
________mg AM            ______mg PM 
 
 
 
8 
________mg AM            ______mg PM 
c 
 
 
9 
________mg AM            ______mg PM 
 
 
 
10 
________mg AM            ______mg PM 
 
 
 
11 
________mg AM            ______mg PM 
 
 
 
12 
________mg AM            ______mg PM 
 
 
 
13 
________mg AM            ______mg PM 
 
 
 
14 
________mg AM            ______mg PM 
 
 
 
15 
________mg AM            ______mg PM 
c 
 
 
16 
________mg AM            ______mg PM 
 
 
 
17 
________mg AM            ______mg PM 
 
 
 
18 
________mg AM            ______mg PM 
 
 
 
19 
________mg AM            ______mg PM 
 
 
 
20 
________mg AM            ______mg PM 
 
 
 
21 
________mg AM            ______mg PM 
 
 
 
22 
________mg AM            ______mg PM 
c 
 
 
23 
________mg AM            ______mg PM 
 
 
 
24 
________mg AM            ______mg PM 
 

 
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                                                                               Page 2 of 3 
 
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Page 85 
Subsequent Cycles 
 
 
25 
________mg AM            ______mg PM 
 
 
 
26 
________mg AM            ______mg PM 
 
 
 
27 
________mg AM            ______mg PM 
 
 
 
28/1 
________mg AM            ______mg PM 
a-f, g*,i. j*, k* l*, m* 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are met 
(whichever occurs later).  
 
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines 
* Please refer to section 8.1 for the specific timing of these observations. Studies on Day 28/1 may 
be obtained within 72 hours prior to the start of the subsequent cycle. 
 
 
Required Observations in All Subsequent Cycles 
 
a. 
History/Physical Exam (including VS) 
b. 
Ht/Wt/BSA 
c. 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should be checked 
at least every other day until recovery to Grade 3 or until meeting the criteria for dose limiting 
toxicity.  If patients develop Grade 3 or greater thrombocytopenia then CBCs should be 
checked every 3 to 4 days until recovery per section 6.1. 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. 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. 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 
h. 
Bone Marrow Aspirate and/or biopsy- Only required in patients suspected of having bone 
marrow metastasis on the basis of history, symptoms, laboratory evaluation or other clinical 
data.  Should only be performed on patients with known bone marrow involvement at baseline. 
Bone marrow aspirate and/or biopsy should be performed only when complete response or 
partial response is identified in target disease or when progression in bone marrow is suspected. 
i. 
Medication Diary- (see Appendix III) should be reviewed after completion of each treatment 
cycle and uploaded into RAVE. The medication diary should be collected weekly.  
j. 
Circulating Tumor DNA (ctDNA-optional)- With consent,  two samples will be collected on 
this protocol (Cycle 5 Day 1; and for patients receiving ≥ 5 cycles,  at progression or end of 
protocol therapy) see Section 8.5 for details of the ctDNA studies.  
k.    Plain radiograph tibial growth plate (bone x-ray tests) - Plain radiographs of at least one tibial 
growth plate should be obtained in all patients prior to first dose of protocol therapy. In patients 
with open growth plates, follow-up plain radiographs of the same growth plate(s) should be 
obtained prior to Cycles 2 and 5, then every 6 cycles. 
l. 
   Ophthalmological examinations will be performed by an ophthalmologist at prestudy and if 
clinically indicated during treatment. 
m. 
ECHO or gated radionuclide study- Every 3 Cycles. 
 
 
 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 

 
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                                                                               Page 3 of 3 
 
Version Date: 12/09/2020 
 
Page 86 
Subsequent Cycles 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621J EXPANSION COHORTS 
 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
 
 
 
 
Tumor type 
1. Ependymoma 
2. Ewing Sarcoma/Peripheral PNET 
3. Hepatoblastoma 
4. Glioma, high grade 
5. Glioma, low grade 
6. Langerhans Cell Histiocytosis 
7. Malignant Germ Cell Tumor 
8. Medulloblastoma  
9. Neuroblastoma 
10. Non-Hodgkin Lymphoma 
11. Non-RMS Soft Tissue Sarcoma 
12. Osteosarcoma 
13. Rhabdoid Malignancy 
14. Rhabdomyosarcoma 
15. Wilms Tumor 
16. Other Histology (based on COG/NCI-CTEP approval) 

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Version Date: 12/09/2020 
 
Page 87 
APPENDIX VIII: APEC1621J ACTIONABLE MUTATIONS OF INTEREST 
 
NON-HOTSPOT 
RULES 
  
  
  
Gene Name 
Description 
Variant Type 
Region 
LOE 
NF1  
Include 
Deleterious 
  
3.2 
MAPK1 
Include 
missense 
aa 321-321 
2 
BRAF 
Include 
missense 
aa 485-485 
2 
INCLUSION 
VARIANTS 
  
  
  
Hotspots 
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
NRAS 
COSM586 
SNV 
p.Q61H 
3.2 
NRAS 
COSM585 
SNV 
p.Q61H 
3.2 
NRAS 
COSM583 
SNV 
p.Q61L 
3.2 
NRAS 
COSM582 
SNV 
p.Q61P 
3.2 
NRAS 
COSM584 
SNV 
p.Q61R 
2.2 
NRAS 
COSM30646 
MNV 
p.Q61L 
3.2 
NRAS 
COSM33693 
MNV 
p.Q61R 
2.2 
NRAS 
COSM580 
SNV 
p.Q61K 
2.2 
NRAS 
COSM581 
SNV 
p.Q61E 
3.2 
NRAS 
COSM53223 
MNV 
p.Q61K 
2.2 
NRAS 
COSM12725 
MNV 
p.Q61L 
3.2 
NRAS 
COSM579 
MNV 
p.Q61R 
2.2 
NRAS 
COSM12730 
MNV 
p.Q61K 
2.2 
NRAS 
COSM574 
SNV 
p.G13V 
2.2 
NRAS 
COSM573 
SNV 
p.G13D 
3.2 
NRAS 
COSM575 
SNV 
p.G13A 
3.2 
NRAS 
COSM572 
MNV 
p.G13V 
2.2 
NRAS 
COSM569 
SNV 
p.G13R 
3.2 
NRAS 
COSM570 
SNV 
p.G13C 
3.2 
NRAS 
COSM571 
SNV 
p.G13S 
3.2 
NRAS 
COSM564 
SNV 
p.G12D 
3.2 
NRAS 
COSM565 
SNV 
p.G12A 
3.2 
NRAS 
COSM566 
SNV 
p.G12V 
3.2 
NRAS 
COSM561 
SNV 
p.G12R 
3.2 
NRAS 
COSM563 
SNV 
p.G12S 
3.2 
NRAS 
COSM562 
SNV 
p.G12C 
3.2 
HRAS 
COSM503 
SNV 
p.Q61H 
3.2 
HRAS 
COSM502 
SNV 
p.Q61H 
3.2 
HRAS 
COSM499 
SNV 
p.Q61R 
3.2 
HRAS 
COSM500 
SNV 
p.Q61P 
3.2 
HRAS 
COSM498 
SNV 
p.Q61L 
3.2 
HRAS 
COSM33695 
MNV 
p.Q61R 
3.2 
HRAS 
COSM501 
MNV 
p.Q61R 
3.2 
HRAS 
COSM497 
SNV 
p.Q61E 
3.2 
HRAS 
COSM496 
SNV 
p.Q61K 
3.2 
HRAS 
COSM52978 
MNV 
p.Q61L 
3.2 
HRAS 
COSM490 
SNV 
p.G13D 
3.2 
HRAS 
COSM489 
SNV 
p.G13V 
3.2 

                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621J 
 
 
 
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Page 88 
HRAS 
COSM488 
SNV 
p.G13C 
3.2 
HRAS 
COSM487 
SNV 
p.G13S 
3.2 
HRAS 
COSM486 
SNV 
p.G13R 
3.2 
HRAS 
COSM483 
SNV 
p.G12V 
3.2 
HRAS 
COSM484 
SNV 
p.G12D 
3.2 
HRAS 
COSM485 
SNV 
p.G12A 
3.2 
HRAS 
COSM482 
SNV 
p.G12R 
3.2 
HRAS 
COSM481 
SNV 
p.G12C 
3.2 
HRAS 
COSM480 
SNV 
p.G12S 
3.2 
KRAS 
COSM19900 
SNV 
p.A146V 
3.2 
KRAS 
COSM19404 
SNV 
p. A146T 
3.2 
KRAS 
COSM19940 
SNV 
p.K117N 
3.2 
KRAS 
COSM28519 
SNV 
p.K117N 
3.2 
KRAS 
COSM554 
SNV 
p.Q61H 
3.2 
KRAS 
COSM555 
SNV 
p.Q61H 
3.2 
KRAS 
COSM553 
SNV 
p.Q61L 
3.2 
KRAS 
COSM552 
SNV 
p.Q61R 
3.2 
KRAS 
COSM551 
SNV 
p.Q61P 
3.2 
KRAS 
COSM1168052 
MNV 
p.Q61R 
3.2 
KRAS 
COSM550 
SNV 
p.Q61E 
3.2 
KRAS 
COSM549 
SNV 
p.Q61K 
3.2 
KRAS 
COSM87298 
MNV 
p.Q61K 
3.2 
KRAS 
COSM539 
SNV 
p.G15D 
3.2 
KRAS 
COSM538 
SNV 
p.G15S 
3.2 
KRAS 
COSM87280 
MNV 
p.G13E 
3.2 
KRAS 
COSM30567 
MNV 
p.G13E 
3.2 
KRAS 
COSM533 
SNV 
p.G13A 
3.2 
KRAS 
COSM534 
SNV 
p.G13V 
3.2 
KRAS 
COSM532 
SNV 
p.G13D 
3.2 
KRAS 
COSM531 
MNV 
p.G13D 
3.2 
KRAS 
COSM530 
MNV 
p.G13V 
3.2 
KRAS 
COSM12721 
MNV 
p.G13V 
3.2 
KRAS 
COSM528 
SNV 
p.G13S 
3.2 
KRAS 
COSM527 
SNV 
p.G13C 
3.2 
KRAS 
COSM529 
SNV 
p.G13R 
3.2 
KRAS 
COSM13643 
MNV 
p.G12N 
3.2 
KRAS 
COSM512 
MNV 
p.G12F 
3.2 
KRAS 
COSM514 
MNV 
p.G12L 
3.2 
KRAS 
COSM87281 
MNV 
p.G13C 
3.2 
KRAS 
COSM520 
SNV 
p.G12V 
3.2 
KRAS 
COSM521 
SNV 
p.G12D 
3.2 
KRAS 
COSM522 
SNV 
p.G12A 
3.2 
KRAS 
COSM14209 
MNV 
p.G12D 
3.2 
KRAS 
COSM515 
MNV 
p.G12V 
3.2 
KRAS 
COSM518 
SNV 
p.G12R 
3.2 
KRAS 
COSM517 
SNV 
p.G12S 
3.2 
KRAS 
COSM516 
SNV 
p.G12C 
3.2 
KRAS 
COSM513 
MNV 
p.G12C 
3.2 

                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621J 
 
 
 
Version Date: 12/09/2020 
 
Page 89 
KRAS 
PM_COSM5413585 
MNV 
p.G12A 
3.2 
KRAS 
PM_COSM1716372 
MNV 
p.G12L 
3.2 
KRAS 
PM_COSM249888 
MNV 
p.G12R 
3.2 
KRAS 
PM_COSM4387522 
MNV 
p.G12V 
3.2 
KRAS 
PM_COSM4745557 
MNV 
p.G13R 
3.2 
ARAF 
COSM5044705 
SNV 
p.S214C 
3.2 
ARAF 
COSM1742787 
SNV 
p.S214A 
3.2 
ARAF 
COSM612884 
SNV 
p.S214F 
3.2 
BRAF 
COSM308550 
MNV 
p.V600D 
3.2 
BRAF 
COSM477 
MNV 
p.V600D 
3.2 
BRAF 
COSM475 
MNV 
p.V600E 
2.2 
BRAF 
COSM1127 
MNV 
p.V600R 
3.2 
BRAF 
COSM1583011 
MNV 
p.V600R 
3.2 
BRAF 
COSM473 
MNV 
p.V600K 
3.2 
BRAF 
COSM474 
MNV 
p.V600R 
3.2 
BRAF 
COSM6137 
SNV 
p.V600G 
3.2 
BRAF 
COSM18443 
SNV 
p.V600A 
3.2 
BRAF 
COSM249889 
MNV 
p.V600Q 
3.2 
BRAF 
COSM476 
SNV 
p.V600E 
2.2 
BRAF 
COSM1130 
SNV 
p.V600M 
3.2 
BRAF 
COSM219798 
SNV 
p.V600L 
3.2 
BRAF 
COSM33808 
SNV 
p.V600L 
3.2 
BRAF 
COSM1132 
SNV 
p.K601N 
3.2 
BRAF 
COSM6265 
SNV 
p.K601N 
3.2 
BRAF 
COSM1133 
DEL 
p.V600_K601>E 
3.2 
BRAF 
PM_COSM30730 
INS 
p.T599_V600insT 
3.2 
BRAF 
PM_COSM26625 
INS 
p.A598_T599insV 
3.2 
BRAF 
COSM457 
SNV 
p.G469R 
3.2 
BRAF 
COSM455 
SNV 
p.G469R 
3.2 
BRAF 
COSM1112 
SNV 
p.G466R 
3.2 
BRAF 
COSM478 
SNV 
p.K601E 
3.2 
BRAF 
COSM472 
SNV 
p.T599I 
3.2 
BRAF 
COSM21549  
SNV 
p.A598V 
3.2 
BRAF 
COSM1126 
MNV 
p.L597S 
3.2 
BRAF 
COSM1125 
SNV 
p.L597Q 
2.2 
BRAF 
COSM471 
SNV 
p.L597R 
3.2 
BRAF 
COSM470  
SNV 
p.L597V 
3.2 
BRAF 
COSM469  
SNV 
p.G596R 
3.2 
BRAF 
COSM53198 
SNV 
p.F595L 
3.2 
BRAF 
COSM468 
SNV 
p.F595L 
3.2 
BRAF 
COSM21612 
SNV 
p.F595L 
3.2 
BRAF 
COSM466 
SNV 
p.D594V 
3.2 
BRAF 
COSM467 
SNV 
p.D594G 
3.2 
BRAF 
COSM211600 
MNV 
p.D594N 
3.2 
BRAF 
COSM1583010 
SNV 
p.D594A 
3.2 
BRAF 
COSM27639 
SNV 
p.D594N 
3.2 
BRAF 
COSM463 
SNV 
p.E586K 
3.2 
BRAF 
COSM462 
SNV 
p.N581S 
3.2 

                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621J 
 
 
 
Version Date: 12/09/2020 
 
Page 90 
BRAF 
COSM1133046  
SNV 
p.Y472C 
3.2 
BRAF 
COSM459 
SNV 
p.G469V 
3.2 
BRAF 
COSM460 
SNV 
p.G469A 
2.2 
BRAF 
COSM461 
SNV 
p.G469E 
3.2 
BRAF 
COSM451 
SNV 
p.G466V 
3.2 
BRAF 
 COSM453 
SNV 
p.G466E 
3.2 
BRAF 
COSM452 
SNV 
p.G466A 
3.2 
BRAF 
COSM253328  
SNV 
p.G466R 
3.2 
BRAF 
COSM449 
SNV 
p.G464E 
3.2 
BRAF 
COSM450 
SNV 
p.G464V 
3.2 
BRAF 
COSM1448615 
SNV 
p.G464R 
3.2 
BRAF 
COSM1111  
SNV 
p.G464R 
3.2 
BRAF 
COSM448 
SNV 
p.I463S 
3.2 
BRAF 
COSM447  
SNV 
p.R462I 
3.2 
MAP2K1 
PM_E1 
DEL 
p.F53_Q58delFLTQKQaddL 
3.2 
MAP2K1 
PM_E2 
DEL 
p.Q56_V60delQKQKV 
3.2 
MAP2K1 
COSM1235481 
SNV 
p.Q56P 
3.2 
MAP2K1 
COSM4756761 
SNV 
p.K57T 
3.2 
MAP2K1 
COSM1235478 
SNV 
p.K57N 
3.2 
MAP2K1 
COSM5520914 
SNV 
p.K57N 
3.2 
MAP2K1 
PM_COSM4166150 
DEL 
p.K57_G61del 
3.2 
MAP2K1 
PM_COSM5031101 
DEL 
p.Q58_E62delQKVGE 
3.2 
MAP2K1 
PM_COSM5031100 
DEL 
p.Q58_E62delQKVGE 
3.2 
MAP2K1 
PM_COSM1235479 
SNV 
p.D67N 
3.2 
MAP2K1 
COSM1678546 
SNV 
p.D67N 
3.2 
MAP2K1 
PM_COSM404998 
DEL 
p.E102_I103delEI 
3.2 
MAP2K1 
PM_COSM4166152 
DEL 
p.E102_I103del 
3.2 
MAP2K1 
PM_COSM4166153 
DEL 
p.E102_I103del 
3.2 
MAP2K1 
PM_COSM5730253 
DEL 
p.I103_K104delIK 
3.2 
MAP2K1 
PM_COSM5702512 
DEL 
p.I103_K104del 
3.2 
MAP2K1 
PM_E3 
SNV 
p.E120Q 
3.2 
MAP2K1 
PM_COSM555601 
SNV 
p.C121S 
3.2 
MAP2K1 
COSM1315829 
SNV 
p.C121S 
3.2 
MAP2K1 
PM_E4 
SNV 
p.S123T 
3.2 
MAP2K1 
COSM1374186 
SNV 
p.G128D 
3.2 
MAP2K1 
COSM232755 
SNV 
p.E203K 
3.2 
GNA11 
COSM52969 
SNV 
p.Q209L 
3.2 
GNA11 
COSM52970 
SNV 
p.Q209P 
3.2 
GNAQ 
COSM28757 
SNV 
p.Q209L 
3.2 
GNAQ 
COSM28758 
SNV 
p.Q209P 
3.2 
GNAQ 
COSM28760 
SNV 
p.Q209R 
3.2 
GNAQ 
COSM52975 
SNV 
p.R183Q 
3.2 
MAPK1 
COSM461148 
SNV 
p.E322K 
2 
MAPK1 
COSM1616272 
SNV 
p.E322V 
3 
FUSIONS: 
  
  
  
  
BRAF 
AGAP3-BRAF.A10B11 
Fusion 
AGAP3-BRAF.A10B11 
3.2 
BRAF 
AGAP3-BRAF.A9B9 
Fusion 
AGAP3-BRAF.A9B9 
3.2 

                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621J 
 
 
 
Version Date: 12/09/2020 
 
Page 91 
BRAF 
AGK-BRAF.A2B8 
Fusion 
AGK-BRAF.A2B8 
3.2 
BRAF 
AGTRAP-BRAF.A5B8.COSF828.1 
Fusion 
AGTRAP-BRAF.A5B8.COSF828.1 
3.2 
BRAF 
AKAP9-BRAF.A21B10 
Fusion 
AKAP9-BRAF.A21B10 
3.2 
BRAF 
AKAP9-BRAF.A22B9 
Fusion 
AKAP9-BRAF.A22B9 
3.2 
BRAF 
AKAP9-BRAF.A28B9 
Fusion 
AKAP9-BRAF.A28B9 
3.2 
BRAF 
AKAP9-BRAF.A7B11 
Fusion 
AKAP9-BRAF.A7B11 
3.2 
BRAF 
AKAP9-BRAF.A8B9.COSF1013.1 
Fusion 
AKAP9-BRAF.A8B9.COSF1013.1 
3.2 
BRAF 
AP3B1-BRAF.A22B9 
Fusion 
AP3B1-BRAF.A22B9 
3.2 
BRAF 
ARMC10-BRAF.A4B11 
Fusion 
ARMC10-BRAF.A4B11 
3.2 
BRAF 
ATG7-BRAF.A18B9 
Fusion 
ATG7-BRAF.A18B9 
3.2 
BRAF 
BAIAP2L1-BRAF.B12B9 
Fusion 
BAIAP2L1-BRAF.B12B9 
3.2 
BRAF 
BBS9-BRAF.B19B4 
Fusion 
BBS9-BRAF.B19B4 
3.2 
BRAF 
BCL2L11-BRAF.B3B10 
Fusion 
BCL2L11-BRAF.B3B10 
3.2 
BRAF 
BRAF-AP3B1.B8A23 
Fusion 
BRAF-AP3B1.B8A23 
3.2 
BRAF 
BRAF-BRAF.B1B11 
Fusion 
BRAF-BRAF.B1B11 
3.2 
BRAF 
BRAF-BRAF.B1B9 
Fusion 
BRAF-BRAF.B1B9 
3.2 
BRAF 
BRAF-BRAF.B3B11 
Fusion 
BRAF-BRAF.B3B11 
3.2 
BRAF 
BRAF-BRAF.B3B9 
Fusion 
BRAF-BRAF.B3B9 
3.2 
BRAF 
BRAF-CIITA.B9C6 
Fusion 
BRAF-CIITA.B9C6 
3.2 
BRAF 
BRAF-MACF1.B8M15 
Fusion 
BRAF-MACF1.B8M15 
3.2 
BRAF 
BRAF-MRPS33.B1M2 
Fusion 
BRAF-MRPS33.B1M2 
3.2 
BRAF 
BRAF-SLC26A4.B3S7 
Fusion 
BRAF-SLC26A4.B3S7 
3.2 
BRAF 
BRAF-SUGCT.B1S13 
Fusion 
BRAF-SUGCT.B1S13 
3.2 
BRAF 
BTF3L4-BRAF.B3B11 
Fusion 
BTF3L4-BRAF.B3B11 
3.2 
BRAF 
C7orf73-BRAF.C2B9 
Fusion 
C7orf73-BRAF.C2B9 
3.2 
BRAF 
CCDC6-BRAF.C1B9 
Fusion 
CCDC6-BRAF.C1B9 
3.2 
BRAF 
CCDC91-BRAF.C11B9 
Fusion 
CCDC91-BRAF.C11B9 
3.2 
BRAF 
CCNY-BRAF.C1B10 
Fusion 
CCNY-BRAF.C1B10 
3.2 
BRAF 
CDC27-BRAF.C16B9.1 
Fusion 
CDC27-BRAF.C16B9.1 
3.2 
BRAF 
CEP89-BRAF.C16B9 
Fusion 
CEP89-BRAF.C16B9 
3.2 
BRAF 
CLCN6-BRAF.C2B11.COSF1440 
Fusion 
CLCN6-BRAF.C2B11.COSF1440 
3.2 
BRAF 
CLIP2-BRAF.C6B11 
Fusion 
CLIP2-BRAF.C6B11 
3.2 
BRAF 
CUL1-BRAF.C7B9 
Fusion 
CUL1-BRAF.C7B9 
3.2 
BRAF 
CUX1-BRAF.C10B9 
Fusion 
CUX1-BRAF.C10B9 
3.2 
BRAF 
DYNC1I2-BRAF.D7B10 
Fusion 
DYNC1I2-BRAF.D7B10 
3.2 
BRAF 
EML4-BRAF.E6B10 
Fusion 
EML4-BRAF.E6B10 
3.2 
BRAF 
EPS15-BRAF.E22B10 
Fusion 
EPS15-BRAF.E22B10 
3.2 
BRAF 
ERC1-BRAF.E12B10 
Fusion 
ERC1-BRAF.E12B10 
3.2 
BRAF 
ERC1-BRAF.E17B8 
Fusion 
ERC1-BRAF.E17B8 
3.2 
BRAF 
FAM114A2-BRAF.F9B11 
Fusion 
FAM114A2-BRAF.F9B11 
3.2 
BRAF 
FAM131B-BRAF.F1B10.COSF1191 
Fusion 
FAM131B-BRAF.F1B10.COSF1191 
3.2 
BRAF 
FAM131B-BRAF.F2B9.COSF1189.1 
Fusion 
FAM131B-BRAF.F2B9.COSF1189.1 
3.2 
BRAF 
FAM131B-BRAF.F3B9.COSF1193 
Fusion 
FAM131B-BRAF.F3B9.COSF1193 
3.2 
BRAF 
FCHSD1-BRAF.F13B9.COSF403 
Fusion 
FCHSD1-BRAF.F13B9.COSF403 
3.2 
BRAF 
FXR1-BRAF.F13B10 
Fusion 
FXR1-BRAF.F13B10 
3.2 
BRAF 
GATM-BRAF.G2B11 
Fusion 
GATM-BRAF.G2B11 
3.2 
BRAF 
GHR-BRAF.G1B10 
Fusion 
GHR-BRAF.G1B10 
3.2 
BRAF 
GNAI1-BRAF.G1B10.COSF1442 
Fusion 
GNAI1-BRAF.G1B10.COSF1442 
3.2 

                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621J 
 
 
 
Version Date: 12/09/2020 
 
Page 92 
BRAF 
GTF2I-BRAF.G4B10 
Fusion 
GTF2I-BRAF.G4B10 
3.2 
BRAF 
HERPUD1-BRAF.H4B7 
Fusion 
HERPUD1-BRAF.H4B7 
3.2 
BRAF 
KCTD7-BRAF.K3B8 
Fusion 
KCTD7-BRAF.K3B8 
3.2 
BRAF 
KCTD7-BRAF.K4B8 
Fusion 
KCTD7-BRAF.K4B8 
3.2 
BRAF 
KDM7A-BRAF.K11B11 
Fusion 
KDM7A-BRAF.K11B11 
3.2 
BRAF 
KIAA1549-BRAF.K12B11 
Fusion 
KIAA1549-BRAF.K12B11 
3.2 
BRAF 
KIAA1549-BRAF.K12B9.COSF1474 
Fusion 
KIAA1549-BRAF.K12B9.COSF1474 
3.2 
BRAF 
KIAA1549-BRAF.K13B9 
Fusion 
KIAA1549-BRAF.K13B9 
3.2 
BRAF 
KIAA1549-BRAF.K14B11.COSF1226 
Fusion 
KIAA1549-BRAF.K14B11.COSF1226 
3.2 
BRAF 
KIAA1549-BRAF.K14B9.COSF483 
Fusion 
KIAA1549-BRAF.K14B9.COSF483 
3.2 
BRAF 
KIAA1549-BRAF.K15B10.COSF1283.1 
Fusion 
KIAA1549-BRAF.K15B10.COSF1283.1 
3.2 
BRAF 
KIAA1549-BRAF.K15B11.COSF485.1 
Fusion 
KIAA1549-BRAF.K15B11.COSF485.1 
3.2 
BRAF 
KIAA1549-BRAF.K15B9.COSF481.1 
Fusion 
KIAA1549-BRAF.K15B9.COSF481.1 
3.2 
BRAF 
KIAA1549-BRAF.K16B10 
Fusion 
KIAA1549-BRAF.K16B10 
3.2 
BRAF 
KIAA1549-BRAF.K17B10.COSF509 
Fusion 
KIAA1549-BRAF.K17B10.COSF509 
3.2 
BRAF 
KIAA1549-BRAF.K18B9.COSF511 
Fusion 
KIAA1549-BRAF.K18B9.COSF511 
3.2 
BRAF 
KIAA1549-BRAF.K9B9 
Fusion 
KIAA1549-BRAF.K9B9 
3.2 
BRAF 
KLHL7-BRAF.K5B9 
Fusion 
KLHL7-BRAF.K5B9 
3.2 
BRAF 
LSM12-BRAF.L3B9 
Fusion 
LSM12-BRAF.L3B9 
3.2 
BRAF 
LSM14A-BRAF.L9B9 
Fusion 
LSM14A-BRAF.L9B9 
3.2 
BRAF 
MACF1-BRAF.M60B9 
Fusion 
MACF1-BRAF.M60B9 
3.2 
BRAF 
MAD1L1-BRAF.M16B9 
Fusion 
MAD1L1-BRAF.M16B9 
3.2 
BRAF 
MAD1L1-BRAF.M17B10 
Fusion 
MAD1L1-BRAF.M17B10 
3.2 
BRAF 
MKRN1-BRAF.M4B11.COSF1444 
Fusion 
MKRN1-BRAF.M4B11.COSF1444 
3.2 
BRAF 
MKRN1-BRAF.M4B9 
Fusion 
MKRN1-BRAF.M4B9 
3.2 
BRAF 
MYRIP-BRAF.M16B9 
Fusion 
MYRIP-BRAF.M16B9 
3.2 
BRAF 
MZT1-BRAF.M2B11 
Fusion 
MZT1-BRAF.M2B11 
3.2 
BRAF 
NUB1-BRAF.N3B9 
Fusion 
NUB1-BRAF.N3B9 
3.2 
BRAF 
NUDCD3-BRAF.N4B9 
Fusion 
NUDCD3-BRAF.N4B9 
3.2 
BRAF 
NUP214-BRAF.N21B10 
Fusion 
NUP214-BRAF.N21B10 
3.2 
BRAF 
PAPSS1-BRAF.P5B9.1 
Fusion 
PAPSS1-BRAF.P5B9.1 
3.2 
BRAF 
PLIN3-BRAF.P1B9 
Fusion 
PLIN3-BRAF.P1B9 
3.2 
BRAF 
RAD18-BRAF.R7B10 
Fusion 
RAD18-BRAF.R7B10 
3.2 
BRAF 
RBMS3-BRAF.R11B11 
Fusion 
RBMS3-BRAF.R11B11 
3.2 
BRAF 
RNF11-BRAF.R1B11 
Fusion 
RNF11-BRAF.R1B11 
3.2 
BRAF 
RNF130-BRAF.R3B9.COSF1483 
Fusion 
RNF130-BRAF.R3B9.COSF1483 
3.2 
BRAF 
RP2-BRAF.R3B10 
Fusion 
RP2-BRAF.R3B10 
3.2 
BRAF 
SLC12A7-BRAF.S17B11 
Fusion 
SLC12A7-BRAF.S17B11 
3.2 
BRAF 
SLC45A3-BRAF.S1B8.COSF871 
Fusion 
SLC45A3-BRAF.S1B8.COSF871 
3.2 
BRAF 
SND1-BRAF.S10B11 
Fusion 
SND1-BRAF.S10B11 
3.2 
BRAF 
SND1-BRAF.S10B9 
Fusion 
SND1-BRAF.S10B9 
3.2 
BRAF 
SND1-BRAF.S11B11 
Fusion 
SND1-BRAF.S11B11 
3.2 
BRAF 
SND1-BRAF.S14B11 
Fusion 
SND1-BRAF.S14B11 
3.2 
BRAF 
SND1-BRAF.S14B9 
Fusion 
SND1-BRAF.S14B9 
3.2 
BRAF 
SND1-BRAF.S16B9.1 
Fusion 
SND1-BRAF.S16B9.1 
3.2 
BRAF 
SND1-BRAF.S18B10 
Fusion 
SND1-BRAF.S18B10 
3.2 
BRAF 
SND1-BRAF.S9B2 
Fusion 
SND1-BRAF.S9B2 
3.2 
BRAF 
SND1-BRAF.S9B9 
Fusion 
SND1-BRAF.S9B9 
3.2 

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BRAF 
SOX6-BRAF.S5B9 
Fusion 
SOX6-BRAF.S5B9 
3.2 
BRAF 
SOX6-BRAF.S6B9 
Fusion 
SOX6-BRAF.S6B9 
3.2 
BRAF 
STRN3-BRAF.S3B10 
Fusion 
STRN3-BRAF.S3B10 
3.2 
BRAF 
TANK-BRAF.T4B9 
Fusion 
TANK-BRAF.T4B9 
3.2 
BRAF 
TAX1BP1-BRAF.T8B11.1 
Fusion 
TAX1BP1-BRAF.T8B11.1 
3.2 
BRAF 
TMEM178B-BRAF.T2B9 
Fusion 
TMEM178B-BRAF.T2B9 
3.2 
BRAF 
TMPRSS2-BRAF.T3B11 
Fusion 
TMPRSS2-BRAF.T3B11 
3.2 
BRAF 
TRIM24-BRAF.T10B9 
Fusion 
TRIM24-BRAF.T10B9 
3.2 
BRAF 
TRIM24-BRAF.T11B2 
Fusion 
TRIM24-BRAF.T11B2 
3.2 
BRAF 
TRIM24-BRAF.T3B10 
Fusion 
TRIM24-BRAF.T3B10 
3.2 
BRAF 
TRIM24-BRAF.T3B11 
Fusion 
TRIM24-BRAF.T3B11 
3.2 
BRAF 
TRIM24-BRAF.T5B8 
Fusion 
TRIM24-BRAF.T5B8 
3.2 
BRAF 
TRIM24-BRAF.T9B9.1 
Fusion 
TRIM24-BRAF.T9B9.1 
3.2 
BRAF 
TRIM4-BRAF.T6B10 
Fusion 
TRIM4-BRAF.T6B10 
3.2 
BRAF 
UBN2-BRAF.U3B11 
Fusion 
UBN2-BRAF.U3B11 
3.2 
BRAF 
ZC3HAV1-BRAF.Z3B10 
Fusion 
ZC3HAV1-BRAF.Z3B10 
3.2 
BRAF 
ZC3HAV1-BRAF.Z7B11 
Fusion 
ZC3HAV1-BRAF.Z7B11 
3.2 
BRAF 
ZKSCAN5-BRAF.Z2B9 
Fusion 
ZKSCAN5-BRAF.Z2B9 
3.2 
BRAF 
ZSCAN30-BRAF.Z3B10 
Fusion 
ZSCAN30-BRAF.Z3B10 
3.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IX: 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), 

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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.  
 
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; 
• 
Rostered at the site on the IRB/REB approval 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 
Registration and Credential Repository (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; 

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• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization (PO) 
on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 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 ForAPEC1621J 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. 

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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: 
• 
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. 
.   
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. 
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 

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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/ae
guidelines.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 and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   
 
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 

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data from patients’ charts (i.e., source data verification).  
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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APPENDIX X: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, BVD-523FB (ulixertinib). This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
BVD-523FB (ulixertinib) interacts with certain enzymes in your liver and a transport protein that 
helps move drugs in and out of cells.  
 
• The enzymes in question are CYP 3A4, 2D6 and 1A2, which are responsible for breaking 
down BVD-523FB (ulixertinib) in the body. BVD-523FB (ulixertinib) may be affected 
by strong inhibitors or inducers of these enzymes. 
  
• The protein in question is P-glycoprotein (P-gp) which moves BVD-523FB (ulixertinib) in 
and out of cells/organs in the body. BVD-523FB (ulixertinib) may be affected by strong 
inhibitors of P-gp. 
 
• BVD-523FB (ulixertinib) is highly protein-bound and may interfere with binding of other 
drugs that are also highly protein-bound. Use caution with these drugs that have narrow 
therapeutic ranges. 
 To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
BVD-523FB (ulixertinib) may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
 

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These are the things that you and they need to know:  
 
BVD-523FB (ulixertinib) must be used very carefully with other medicines that are strong 
inhibitors of CYP 3A4, 2D6 or 1A2, strong inducers of CYP3A4 or strong inhibitors of the P-gp 
transport protein that is responsible for moving BVD-523FB (ulixertinib) in and out of cells in 
your body. Also, BVD-523FB (ulixertinib) is highly protein-bound and might affect how well 
other highly protein-bound drugs work in your body. 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 of CYP 3A4, 2D6, 1A2 or P-
glycoprotein or strong inducers of CYP 3A4.” 
 
• 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.  
• Avoid ingesting grapefruit, grapefruit juice or Seville oranges while taking BVD-523FB 
(ulixertinib). 
• 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. 
Your study doctor’s name is _____________________________________ and he or she can be 
contacted at _____________________________________.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
BVD-523FB (ulixertinib).  This clinical trial is sponsored by the NCI.  
BVD-523FB (ulixertinib) may interact with drugs that affect certain 
liver enzymes, the P-gp transport protein in your body or affect the 
protein-binding of other drugs in your body.  Because of this, it is very 
important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 Avoid ingesting grapefruit, grapefruit juice or Seville oranges while 
taking BVD-523FB (ulixertinib). 
 Avoid prolonged exposure to the sun and wear protective clothing 
and sunscreen when out in the sun 
BVD-523FB (ulixertinib) interacts with CYP 3A4, 2D6, 1A2 and P-gp 
transport protein and is highly-protein bound and must be used very 
carefully with other medicines that interact with these CYP enzymes, 
P-gp or are highly protein-bound.  
 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 of CYP 3A4, 2D6, 1A2, strong inducers of CYP3A4, strong 
inhibitors of P-gp transporter or are highly-protein bound.” 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  
 

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APPENDIX XI: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3 x ULN 
Grade 3: 
> 3 x ULN -10 x ULN 
Grade 4: 
> 10 x ULN 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
≤ 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 AST is 50 U/L regardless of baseline. 
 
Grade 1: 
≤ 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 x ULN 
Grade 3: 
> 5 x ULN-20 x ULN 
Grade 4: 
> 20 x ULN 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX XII: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621J 
(for children from 7 through 12 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
1. We have been talking with you about your cancer. You have had treatment for the cancer already 
but it 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.  
 
3. You agreed to be part of a study to see if your cancer has any specific changes that could help us 
decide what medicine might “match” best to your cancer. 
 
4. We have found a medicine called BVD-523FB (ulixertinib) that could “match” your tumor. The 
doctors want to see if BVD-523FB (ulixertinib) will help children with your type of cancer get 
better. We don’t know if BVD-523FB (ulixertinib) will work well to get rid of your cancer. That is 
why we are doing the study. 
 
5. 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 BVD-523FB 
(ulixertinib) 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. 
 
6. 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 problems, or side effects 
from BVD-523FB (ulixertinib). There may be risks that we don’t know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your cancer that your 
doctor can tell you about.  
 
8. If you decide to be treated with BVD-523FB (ulixertinib) you might have some tests and check-
ups done more often than you might if you weren’t part of the study. 
 
9. As part of the study we are also trying to learn more about children’s cancers and how BVD-
523FB (ulixertinib) works in them. We will draw some extra blood samples for this if your family 
agrees. 
 
 
 
 
 
 

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INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621J 
(for teens from 13 through 17 years of age) 
A study of Molecular Analysis for Therapy Choice (MATCH) in children 
with a cancer that has come back after treatment or is difficult to treat 
 
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. 
 
3. The main purpose of this study is to learn how well cancers that have specific changes (mutations) 
respond to medicines that are aimed at those changes. This combination of a tumor with a mutation and 
a medicine that aims at that mutation is called a “match”. 
 
4.  Your tumor has a mutation that matches BVD-523FB (ulixertinib), and so you have been assigned to 
BVD-523FB (ulixertinib). The doctors want to see if BVD-523FB (ulixertinib) will make children with 
your type of cancer get better. We don’t know if BVD-523FB (ulixertinib) will work well to get rid of 
your cancer. That is why we are doing the study. 
 
5.  You will get BVD-523FB (ulixertinib) by mouth twice daily for a 28-day period. This entire 28-day 
period is called a cycle. BVD-523FB (ulixertinib) should be swallowed whole, not chewed or opened. 
You may continue to receive BVD-523FB (ulixertinib) for up to about 24 months (approximately 26 
cycles) as long as you do not have bad effects from it and your cancer does not get any worse. If you 
decide to be treated with BVD-523FB (ulixertinib), you will also have exams and tests done that are 
part of normal cancer care. Some of these may be done more often while you are being treated with 
BVD-523FB (ulixertinib). The doctors want to see if BVD-523FB (ulixertinib) will help children or 
adolescents with your type of cancer get better. We don’t know if BVD-523FB (ulixertinib) is better 
than other medicines. That is why we are doing this study.  
 
6. 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 BVD-523FB 
(ulixertinib) 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. 
 
7. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The primary risk to you from this study is that you may have side effects, from BVD-
523FB (ulixertinib). Your doctor will talk to you about the risks we know about from BVD-523FB 
(ulixertinib). There may be other risks from BVD-523FB (ulixertinib) that we don’t know about yet.  
 
8. Your family can choose to be part of this study or not. Your family can also decide to stop being in this 
study at any time once you start. 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.  
 
9. As part of the study we are also trying to learn more about the mutations that occur in cancers that happen 
in children and teens, as well as how BVD-523FB (ulixertinib) works. If your family agrees we will 
draw some extra blood samples to do these tests. 
 
 
 
 
 

                                 THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621J 
 
 
 
Version Date: 12/09/2020 
 
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APPENDIX XIII:  PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to begin treatment at 
the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent 
than normally expected for the patient. Patients will also be instructed to contact their physician if any 
diarrhea occurs. Patients will be given loperamide based on body weight.  
 
LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours.  During the night, the 
patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral 
solution) every 4 hours.  Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [1 teaspoonful] of the 1 mg/5 mL oral solution or one-half  
tablet) after the first loose bowel movement, followed by 1 mg (5 mL [one 
teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. 
During the night, the patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 
mL oral solution or one-half tablet) every 4 hours.  Do not exceed 6 mg (30 mL or 
6 teaspoonfuls) per day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 3 hours.  During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 8 mg (40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1  tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] 
of the 1 mg/5 mL oral solution or one-half tablet) every 2 hours.  During the night, 
the patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution 
or 1 tablet) every 4 hours. Do not exceed 12 mg (60 mL or 12 teaspoonfuls) per 
day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 mL oral solution or 2 capsules 
or tablets) after the first loose bowel movement, followed by 2 mg (10 mL 
[2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 
2 hours.  During the night, the patient may take 4 mg (20 mL [4 teaspoonfuls] of 
the 1 mg/5 mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 
16 mg (80 mL or 16 teaspoonfuls) per day.