NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of Erdafitinib in Patients With Tumors Harboring FGFR1/2/3/4 Alterations
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Recurrent Childhood Ependymoma, Recurrent Childhood Malignant Germ Cell Tumor, Recurrent Childhood Medulloblastoma, Recurrent Childhood Non-Hodgkin Lymphoma, Recurrent Childhood Osteosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Neuroblastoma, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Refractory Childhood Malignant Germ Cell Tumor, Refractory Childhood Osteosarcoma, Refractory Childhood Rhabdomyosarcoma, Refractory Childhood Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Wilms Tumor
Sponsor: National Cancer Institute (NCI)

  
 
 
 
i 
 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children's Research  
Institute 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
Children's Hospital Colorado 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Executive Director of Clinical  
Research Operations 
Mary Beth Sullivan, MPH 
msullivan@childrensoncology 
group.org  
 
Executive Director of 
Data Operations 
Thalia Beeles, MPH 
tbeeles@childrensoncology 
group.org 
 
Executive Director of 
Administration and Finance 
Lee Ann DeRita, MBA, CMA,  
CFE 
lderita@childrensoncology 
group.org 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
1333 S. Mayflower Avenue 
Suite 260 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
 
 
October 28, 2022 
 
 
Martha Kruhm, M.S., RAC 
Protocol and Information Office (PIO) Head 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
RE: Request for Amendments with FDA requested language for Pediatric MATCH 
consents 
 
Dear Ms. Kruhm, 
 
The study committee thanks CTEP for forwarding the Amendment Request dated 
October 17, 2022. In response to the request, please see attached Amendment #4 to 
APEC1621B. The complete list of changes can be found below.  
 
Please contact us if you have any further questions. 
 
Sincerely, 
 
Lee Baker, MPH, Protocol Coordinator (for) 
Alice Lee, M.D., APEC1621B Study Chair, and 
Douglas S. Hawkins, M.D., Group Chair, Children’s Oncology Group 
 
 
 
 
  
 

  
ii 
I. 
Changes made to the protocol by the Principal Investigator: 
# 
Section 
Comments 
1. 
General 
The version date has been updated throughout the protocol. 
 
 
II. Changes made to the informed consent document by the Principal Investigator: 
# 
Section 
Comments 
2. 
General 
The version date has been updated throughout the informed consent document. 
3.  
Why is this 
study being 
done? 
The following phrase has been added: 
• 
Please know that your eligibility for this trial may have been determined in 
part on the basis of a laboratory-developed test that has not been reviewed or 
approved by the FDA. 
4. 
Specimens 
for 
additional 
optional 
research 
tests 
The descriptions of the correlative studies have been updated to match their associated title. 
 

 
 
APEC1621B 
 
                                                                                            
 
 
 
Page 1 
Version Date: 10/28/2022 
 
Activated:  10/5/17 
Version Date:   10/28/2022 
Closed: 
 
Amendment # 4 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
APEC1621B 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF ERDAFITINIB IN PATIENTS WITH TUMORS HARBORING 
FGFR1/2/3/4 ALTERATIONS 
 
 
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 
Alice Lee, M.D. 
Montefiore Medical Center – Moses Campus 
111 East 210th Street 
Bronx, NY 10467 
Phone: (718) 741-2342 
Email: alee5@montefiore.org 
 

 
 
APEC1621B 
 
 
 
Version Date: 10/28/2022 
 
Page 2 
 
 
 
Contact Information 
For Regulatory Requirements 
For Patient Enrollments 
For Data Submission 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
 (Sign in at https://www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-CTSU (2878) 
for regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol must be downloaded from the protocol-specific page located on the 
CTSU members’ website (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 log in with a 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 Regulatory 
Support System (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. 
 
 
 

 
 
APEC1621B 
 
 
 
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Page 3 
 
TABLE OF CONTENTS 
SECTION 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
6 
STUDY COMMITTEE, CONT. 
7 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aims 
9 
1.3 
Exploratory Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Effect of erdafitinib in human subjects 
10 
2.3 
Pediatric Studies 
16 
2.4 
Overview of Proposed Pediatric Study 
16 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
16 
3.1 
Study Enrollment 
16 
3.2 
Informed Consent/Assent 
19 
3.3 
Screening Procedures 
19 
3.4 
Eligibility Checklist 
19 
3.5 
Study Enrollment 
20 
3.6 
Institutional Pathology Report 
20 
3.7 
Dose Assignment 
20 
4.0 
PATIENT ELIGIBILITY 
20 
4.1 
Inclusion Criteria 
21 
4.2 
Exclusion Criteria 
24 
5.0 
TREATMENT PROGRAM 
25 
5.1 
Overview of Treatment Plan 
25 
5.2 
Criteria for Starting Subsequent Cycles 
26 
5.3 
Grading of Adverse Events 
26 
5.4 
Definition of Dose-Limiting Toxicity (DLT) 
26 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
27 
6.1 
Dose Modifications for Hematological Toxicity 
27 
6.2 
Dose Modifications for Non-Hematological Toxicity 
28 
6.3 
Dose Modifications for Hepatic Adverse Events 
28 
6.4 
Guidelines for the Management of Elevated Phosphate Levels 
28 
6.5 
Guidelines for the Management of Dry Skin and Skin Toxicity 
30 
6.6 
Dose Modifications for Dermatology/Skin Disorders 
31 
6.7 
Guidelines for Management of Nail Toxicity (Onycholysis, Onychodystrophy, and 
Paronychia) 
31 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
34 
7.1 
Concurrent Anticancer Therapy 
34 
7.2 
Investigational Agents 
34 
7.3 
Supportive Care 
34 

 
 
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7.4 
Growth Factors 
35 
7.5 
Concomitant Medications 
35 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
36 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
36 
8.2 
Monitoring for Specific Toxicities 
37 
8.3 
Radiology Studies 
38 
8.4 
Pharmacology and Plasma Protein Binding (Optional) 
39 
8.5 
Circulating Tumor DNA Study (Optional) 
42 
9.0 
AGENT INFORMATION 
43 
9.1 
Erdafitinib        (01-30-2022) 
43 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
50 
10.1 
Criteria for Removal from Protocol Therapy 
50 
10.2 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
51 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
51 
11.1 
Sample Size and Study Duration 
51 
11.2 
Dosing Considerations 
51 
11.3 
Study Design 
52 
11.4 
Methods of Analysis 
53 
11.5 
Evaluability for Response 
53 
11.6 
Evaluability for Toxicity 
53 
11.7 
Progression free survival (PFS) 
53 
11.8 
Correlative Studies 
54 
11.9 
Gender and Minority Accrual Estimates 
54 
12.0 
EVALUATION CRITERIA 
54 
12.1 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
54 
12.2 
Progression-Free Survival 
54 
12.3 
Response Criteria for Patients with Solid Tumors 
55 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
58 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
60 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
62 
12.7 
Response Criteria for Patients with CNS Tumors 
63 
12.8 
Response Criteria for Patients with non- Hodgkin Lymphoma/Histiocytosis 
65 
12.9 
Best Response 
67 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
68 
13.1 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
68 
13.2 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
69 
13.3 
Additional Instructions and Exceptions to CTEP-AERS Expedited Reporting 
Requirements: 
72 
13.4 
Definition of Onset and Resolution of Adverse Events 
72 
13.5 
Other Recipients of Adverse Event Reports 
73 
13.6 
Specific Examples for Expedited Reporting 
73 
13.7 
Special Reporting Situations 
75 
13.8 
Product Quality Compliant (PQC) 
75 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
76 
14.1 
Categories of Research Records 
76 
14.2 
CDUS 
76 

 
 
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14.3 
CRADA/CTA/CSA 
76 
14.4 
Data and Safety Monitoring Plan 
78 
REFERENCES 
79 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
80 
APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
81 
APPENDIX III-A:  MEDICATION DIARY FOR ERDAFITINIB 
84 
APPENDIX III-B:  PATIENT WALLET CARD 
87 
APPENDIX IV: ERDAFITINIB DOSING NOMOGRAM 
88 
APPENDIX V: APEC1621B THERAPY DELIVERY MAP 
89 
APPENDIX VI:  CORRELATIVE STUDIES 
93 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621B EXPANSION COHORTS 
94 
APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS FOR SUBPROTOCOL FOR 
APEC1621B 
95 
APPENDIX IX: YOUTH INFORMATION SHEETS 
99 
APPENDIX X CTEP AND CTSU REGISTRATION PROCEDURES 
101 
APPENDIX XI TOXICITY-SPECIFIC GRADING 
105 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Page 6 
 
STUDY COMMITTEE 
STUDY CHAIR                                                                VICE CHAIR 
Alice Lee, M.D.                                                                 Alexander Chou, MD 
Montefiore Medical Center – Moses Campus                   Weill Cornell Medicine 
111 East 210th Street                                                          Pediatric Hematology/Oncology  
Bronx, NY 10467                                                              525 East 68th Street, Payson 695 
Phone: (718) 741-2342                                                      New York, NY 10065 
Email: alee5@montefiore.org                                          Phone: (212) 746-3494 
                          Email: alc9001@med.cornell.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 
 
E-mail: seibelnl@mail.nih.gov  
Yoon-Jae Cho MD 
 
Oregon Health and Science University 
Douglas S. Hawkins, MD 
3181 SouthWest Sam Jackson Park Road 
Seattle Children’s Hospital 
Portland, OR 97239 
Mailstop: JMB, 1900 9th Avenue 
Phone: (503) 494- 3322 
Seattle, WA 98101 
Email: chyo@ohsu.edu 
Phone:  (206) 884-1107 
 
Todd Alonzo, PhD 
Email: doug.hawkins@seattlechildrens.org 
Study Statistician  
 
COG Statistics and Data Center- Monrovia 
Stacey Berg, MD 
Phone: (626) 241-1522 
Study Design and Logistics 
Fax: (626) 445-4334 
Baylor College of Medicine 
Email: talonzo@childrensoncologygroup.org 
Pediatric Oncology  
 
6621 Fannin Street 
 
MC3-3320 
 
Houston, TX 77030 
Joel Reid, PhD. 
Phone: (832) 824-4588 
Study Pharmacologist 
Fax:  (832) 825-4039 
Mayo Clinic 
Email: sberg@txch.org 
Guggenheim 17-37 
 
200 First St SW 
Elizabeth Fox, MD 
Rochester, MN 55905 
Study Design and Logistics 
Phone: (507) 284-0822 
Saint Jude Children’s Research Hospital 
Fax: (507) 284-3906 
262 Danny Thomas Place 
E-mail: reid.joel@mayo.edu  
Memphis, TN 38105 
  
Phone: (901) 595-3300 
 
Fax:  (901) 595-7031 
 
Email: elizabeth.fox@stjude.org 
 
 
 
 

 
 
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Version Date: 10/28/2022 
 
Page 7 
 
STUDY COMMITTEE, CONT. 
Jin Piao, PhD 
Study Statistician 
Olga Militano, PharmD  
COG Pharmacist 
COG Statistics and Data Center- Monrovia 
Children’s Oncology Group – Operations Center 
Phone: (626) 241-1572 
Phone: (626) 241-1557 
Fax: (626) 445-4334 
E-mail: omilitano@childrensoncologygroup.org 
Email: jpiao@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
Ha-Mill McLearan, PharmD 
 
Study Pharmacist 
 
UC Davis Comprehensive Cancer Center 
 
2315 Stockton Blvd. 
 
Sacramento, CA 95817 
 
Phone: (916) 703-7223 
 
Fax: (916) 703-4079 
 
Email: hhmclearan@ucdavis.edu 
 
COG Operations Staff 
 
 
 
Lauren Saguilig-Doyle, MS 
Vanessa Fierro, BS 
Master Statistician  
Research Coordinator 
Children’s Oncology Group – Operations Center 
Children’s Oncology Group – Operations Center 
Phone: (626) 241-1547 
Phone: (626) 241-1615 
Fax (626) 445-4334 
Email: vafierro@childrensoncologygroup.org 
 
 
 
 
 
Lee Baker, MPH 
 
Protocol Coordinator 
 
Children’s Oncology Group-Operations Center 
 
Phone: (626) 241-1614                                                          
Email: lebaker@childrensoncologygroup.org  
 
 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
https://members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents: 
Erdafitinib  
 
(NSC# 781558 , 
) 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
 
 

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APEC1621B 
 
 
 
  
 
 
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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 NCI-COG Pediatric MATCH trial APEC1621. The APEC1621SC 
screening protocol details the process used to identify actionable mutations in patient tumor samples which 
will determine eligibility for this subprotocol. This is a phase 2 trial of erdafitinib in children and 
adolescents with recurrent or refractory solid tumors (including non-Hodgkin lymphomas, histiocytoses 
and CNS tumors) harboring specified activating mutations of the  FGFR1/2/3/4 pathway. 
 
Erdafitinib is an orally bioavailable, highly potent inhibitor of FGFR-1, 2, 3 and 4 with nanomolar affinity. 
Erdafitinib has demonstrated a broad spectrum of antitumor activity in cell line, xenograft and patient-
derived explant models harboring abnormalities in the FGFR signaling pathway such as FGFR gene 
amplification, activating mutation and translocation. In addition, early clinical trials with erdafitinib have 
resulted in an objective response rate of 42% in advanced urothelial cancer, in which FGFR mutations are 
highly prevalent, and an unconfirmed partial response in a patient whose tumor carried an FGFR2:OFD1 
translocation, suggesting its broad utility against cancers with FGFR mutation, amplification and 
translocation.  
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-28 
4.7 mg/m2 erdafitinib once daily, with 
maximum of 8 mg per day 
Day 28 
Evaluation 
 
Erdafitinib will be administered orally once a day on a continuous basis; a cycle will be 28 days. 
Evaluations will occur at the end 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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Page 9 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with erdafitinib) with advanced solid tumors 
(including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that 
harbor genetic alterations in the FGFR1/2/3/4 pathway. 
1.2 
Secondary Aims 
 
 
To estimate the progression free survival in pediatric patients treated with 
erdafitinib with advanced solid tumors (including CNS tumors), non-Hodgkin 
lymphomas or histiocytic disorders that harbor genetic alterations in the 
FGFR1/2/3/4. 
 
 
To obtain information about the tolerability of erdafitinib in children with relapsed 
or refractory cancer. 
 
 
To provide preliminary estimates of the pharmacokinetics of erdafitinib in children 
with relapsed or refractory cancer. 
 
1.3 
Exploratory Aims 
 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
 
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases regulates 
several aspects of growth and development and when inappropriately activated, results in 
abnormal development and disease. Four different FGFRs have been identified (FGFR1, 
FGFR2, FGFR3, FGFR4) and bind to an array of fibroblast growth factors (FGFs), 
inducing their dimerization then auto- and cross-phosphorylation.  This, in turn, leads to 
subsequent downstream phosphorylation events, which activate a number of molecules and 
signaling pathways such as the mitogen-activated protein kinase pathway and the 
phosphoinositide 3-kinase pathway, which contribute to FGFR-mediated cell proliferation, 
survival and migration.1 
 
Deregulated, constitutive FGFR signaling secondary to amplifications, translocations, and 
point mutations in FGFR genes has been shown to mediate oncogenic downstream 
signaling1 and these genetic lesions represent biomarkers that may predict response to 
FGFR inhibitors.2-4 For example, in pediatric malignancies, translocations involving 
FGFR1 or FGFR3 are present in 2.9% of glioblastomas5, 6; activating mutations of FGFR1 
are seen in 3% of rhabdomyosarcoma7; activating mutations of FGFR4 are seen in 8% of 
rhabdomyosarcoma7 and infrequently in other pediatric types.  
 
Given these recurrent genetic alterations in FGFR genes and the key role of FGFR 
signaling in the pathogenesis of multiple pediatric tumor types, targeting FGFRs represents 

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an attractive anti-cancer strategy. 
Erdafitinib is a potent, oral pan-FGFR tyrosine kinase inhibitor with IC50 values in the low 
nanomolar range for all members of the FGFR family (FGFR1-4).  When evaluated against 
a panel of 387 kinases (KinomeScan) using a competition binding assay which shows 
thermodynamic interaction affinities independent of the adenosine triphosphate (ATP) 
concentration, erdafitinib showed high selectivity with binding affinity (Kd) of less than 
10 nM to only 10 of the 387 kinases tested and Kd values as low as 1 nM for all 4 members 
of the FGFR family [ref JNJ Study Number: EDMS-ERI-37672174]. 
 
Erdafitinib has demonstrated potent inhibition of cell proliferation with IC50 values 
ranging from <1 to <1000 nM in FGFR pathway-activated cancer cell lines including 
squamous non-small cell lung cancer (NSCLC), gastric, breast, hepatocellular cancer 
(HCC), endometrial, bladder, multiple myeloma, and acute myeloid leukemia. Non-FGFR 
driven cell lines require significantly higher drug concentration for inhibition of cell 
proliferation to be observed, supporting on-target efficacy of erdafitinib.  
 
Target inhibition and pathway modulation have been demonstrated in cellular models at 
the active cellular concentrations. Brief exposure (1 hour) to erdafitinib has been 
demonstrated to result in long term (>8 hours) target inhibition and erdafitinib inhibits the 
growth of pre-established subcutaneously (s.c.) and orthotopically injected xenograft 
tumors in both immunodeficient mice and rats. Tumor regression was observed in the 
human SNU-16 (over-expressing the FGFR2 receptor) gastric xenograft implanted s.c. 
after oral administration at 20 and 50 mg/kg daily doses of erdafitinib in the rat model. 
Similar findings were observed when using the SNU-16 tumors in the mouse model and 
mouse xenografts using tumor cells from patients with gastric, breast, hepatocellular, and 
NSCLC cancers.8, 9 
 
2.2 
Effect of erdafitinib in human subjects 
 
Overview 
As of June 3, 2016, eight clinical trials studying erdafitinib in humans have been opened 
(ongoing and completed) with a total of 305 subjects treated with erdafitinib. 
Pharmacokinetic data are based on Studies EDI1001, EDI1002, EDI1003, and EDI1004 
below, while efficacy data are based on Studies EDI1001 and BLC2001 and in part, 
GAC100110.  
 
Summary of clinical studies 
Study EDI1001: Study EDI1001 is a Phase 1, first-in-human, open label, multicenter, 4-
part, dose escalation study to explore the safety, pharmacokinetics, and pharmacodynamics 
of erdafitinib administered orally to subjects ≥ 18 years of age with advanced or refractory 
solid malignancies or lymphoma who are not candidates for approved or available 
therapies.  
 
Part 1 of Study EDI1001 was the Dose Escalation Phase, guided by pharmacokinetics and 
safety. Two recommended Phase 2 doses (9 mg once daily and 10 mg intermittent [7 days 
on, 7 days off]) were selected based upon results from Part 1 of this study.  
 
Part 2 of Study EDI1001 was the Target Inhibition Confirmation Cohort, to confirm the 
safety and pharmacodynamic activity of erdafitinib at doses of 6 mg once daily and 9 mg 
once daily. 
 

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Part 3 of Study EDI1001 explored potential clinical activity at the first recommended Phase 
2 dose of 6 mg once daily in tumor subtypes likely driven by FGFR pathway activation. 
Up to 30 subjects for each tumor subtype (squamous non-small cell lung cancer [NSCLC], 
small cell lung cancer, breast cancer, and other solid tumor subtypes with FGFR pathway 
activation and KRAS wild-type) were treated. 
 
Part 4 of Study EDI1001, which as of the writing of this protocol is ongoing, explores 
potential clinical activity at the second recommended Phase 2 dose of 10 mg intermittent 
(7 days on, 7 days off; with option to up-titrate to 12 mg based on phosphate level) in tumor 
subtypes likely driven by FGFR pathway activation, with the intention to treat up to 30 
subjects with NSCLC (squamous and non-squamous), along with up to 120 subjects with 
other solid tumor subtypes based on evolving information regarding FGFR molecular 
aberrations. 
 
As of June 3, 2016, Parts 1, 2, and 3 were completed and part 4 was on-going with a total 
of 185 subjects having received treatment with erdafitinib in 8 dose schedules ranging from 
0.5 mg daily to 12 mg daily. The subject population is 57% women and 43% men, 
predominantly white (91%), with a median age of 60.0 years (range 21 to 84). One hundred 
thirty-eight subjects (74.6%) have discontinued treatment due to disease progression. 
Twenty subjects (10.8%) are continuing treatment; all of these subjects are in Part 4 (10 
mg intermittent dose regimen). 
 
The median extent of drug exposure as of the data cut-off for the total population was 7.0 
weeks (range: 0 to 102 weeks). There does not appear to be any dose-related trends in mean 
or median drug exposure, suggestive of tolerability to the drug. 
 
Study EDI1002 
Study EDI1002 was a PK study conducted in 8 healthy volunteers to evaluate the relative 
bioavailability of an oral solution to an oral tablet. The pharmacokinetic results indicated 
that the erdafitinib oral tablets and oral solution exhibit comparable bioavailability. 
 
Study EDI1003 
Study EDI1003 was a PK study conducted in 12 healthy volunteers to evaluate the relative 
bioavailability of an oral capsule to an oral tablet. The pharmacokinetic results indicated 
that the erdafitinib oral tablets and oral capsules exhibit comparable bioavailability. 
 
Study EDI1004 
Study EDI1004 was a PK study conducted in 12 healthy volunteers to evaluate the relative 
bioavailability of 2 prototype tablet formulations with larger particle sizes (77 microns and 
122 microns) and clinical tablet formulation (particle size of 19 microns). The 
pharmacokinetic results indicated that the 2 prototype tablet formulations and the reference 
clinical tablet formulation were bioequivalent in both AUC and Cmax. 
 
Study EDI1005 
Study EDI1005 is a PK study conducted in 8 healthy men to evaluate the absorption, 
metabolism, and excretion of erdafitinib after administration of a single oral dose of 12 mg 
of unlabeled erdafitinib admixed with 14C-labeled erdafitinib (14C JNJ42756493). This 
study was ongoing at the time of writing of this protocol. 
 
Study BLC2001 
Study BLC2001 was a Phase 2 study to evaluate the objective response rate following 

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treatment with 1 of 2 dose regimens (Regimen 1: 10 mg dose, 7 days on/7 days off [with 
option to up-titrate to 12 mg 7 days on/7 days off] in 28 day cycles; Regimen 2: 6 mg dose, 
once daily [with option to up-titrate to 8 mg 7 days on/7 days off] in 28 day cycles) in 
subjects with metastatic or surgically unresectable urothelial cancers that harbor specific 
FGFR genomic alterations. These 2 dose regimens were initially selected to test whether 
high exposure levels with intermittent dosing could maximize antitumor effects while 
minimizing drug-related toxicities as compared with moderate exposures sustained over a 
longer period. The 6 mg daily was the lowest sustained dose that was predicted to generate 
continuously efficacious drug concentrations for the majority of patients, and the 10 mg 
dose was the lowest intermittent dose given for a 1 week on/1 week off schedule that 
generates drug exposures continuously in the efficacious range for most patients. 
 
As recommended by the Data Review Committee (DRC) following their review of Interim 
Analysis 1 (IA1) data for Study BLC2001, an analysis was conducted of safety and efficacy 
data in urothelial cancer of the 2 dosing schedules. No new safety signals were identified. 
Also, it was observed that, for subjects attaining a phosphate level of at least 5.5 mg/dL, 
the objective response rate (ORR) was higher (57%, 4/7 subjects) as compared to those 
who did not attain this same level (21%, 3/14 subjects). From Study EDI1001, it was 
known that 6 mg once daily continuous was a well-tolerated schedule without significant 
unplanned treatment interruptions, while 9 mg once daily continuous in non-selected 
patients frequently led to treatment interruptions or dose reductions. Based on observed 
data and PK/PD modeling, it seemed possible to increase the highest continuous dose to 9 
mg once daily in subjects who did not attain the target phosphate level of 5.5 mg/dL or 
higher. Furthermore, approximately half of the subjects starting at 6 mg once daily were 
up-titrated to 8 mg once daily, and most tolerated this higher dose without the need for 
interruptions for hyperphosphatemia or other drug-related, mainly skin and nail, toxicity. 
Modeling was performed to assess different scenarios for dosing. Based on this modeling, 
the starting dose of the study was increased to 8 mg once daily, with a provision for up-
titration to 9 mg once daily for subjects whose serum phosphate levels on Day 14 did not 
reach a target of at least 5.5 mg/dL, in the absence of drug-related toxicity. It was 
determined that 8 mg daily continuous dosing was the recommended Phase 2 dose, as the 
study drug was found to be tolerable in the range of doses studied (10% of patients 
discontinued treatment due to adverse events) and that the mean relative dose intensity was 
over 90% for both dosing regimens.  
 
Of the 99 patients in the 8 mg/day group, the confirmed response rate was 40% (95% CI, 
31 to 50). The response rate among the 74 patients with FGFR mutations in the 8 mg/day 
group was 49%; an additional 26 patients with FGFR mutations had stable disease for a 
median of 3.7 months (range, 0 to 13.6). Responses were not affected by the presence of a 
specific mutation. Among the 25 patients with FGFR fusions, the response rate was 16%. 
In terms of safety and toxicity, all 99 patients in the 8 mg/day group reported an adverse 
event due to any cause during treatment. Of all adverse events, 67% were considered grade 
3 or 4 with 46% of the patients having a > grade 3 adverse event considered related to 
treatment. The most commonly reported > grade 3 adverse events were hyponatremia 
(11%), stomatitis (10%), and asthenia (7%). Serious adverse events were reported in 39 
patients. Disease progression was the most common reason for treatment discontinuation, 
occurring in 62 patients. Thirteen patients discontinued treatment because of adverse 
events, including detachment of the retinal pigment epithelium, hand–foot syndrome, dry 
mouth, and skin or nail events. A dose reduction due to toxicity was required in 55 patients 
with the most common reasons being stomatitis (16 patients) and hyperphosphatemia (9 
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Study GAC1001 
This study was an open-label, multicenter, 2-part, Phase 1 dose escalation study followed 
by dose expansion to evaluate the safety, PK, and pharmacodynamics of erdafitinib in 
Japanese and Asian patients. Nineteen (19) subjects were treated at 5 different dose levels. 
The study was terminated, not pertaining to any safety observations, but because of the 
lack of an appropriate assay to detect molecular eligible patients in this population. The 
subject population was 58% men and 42% women, with a median age of 65.0 (range 32 to 
79). The median drug exposure was 6.4 weeks (range 1-18 weeks). All 19 subjects 
discontinued treatment, 16 subjects due to disease progression, 2 subjects due to 
withdrawal of consent, and 1 subject due to an investigator decision. 
 
The best response to treatment was stable disease, for 1 subjects in the 4 mg group 
continuous dosing cohort. Fifteen of the 18 response-evaluable subjects (83.3%) 
experienced progressive disease; 2 subjects were not evaluable. All subjects (100%) 
experienced a treatment-emergent adverse event (TEAE) and 18 subjects (94.7%) 
experienced a drug-related TEAE. No Grade 3 or Grade 4 TEAEs were reported. No deaths 
or serious AEs were reported. The most frequently reported AEs were hyperphosphatemia 
(73.7%), nausea (36.8%), dysguesia (26.3%), stomatitis (26.3%), and dry mouth (21.1%). 
A single subject, in the 12 mg intermittent dosing cohort, discontinued study treatment due 
to detachment of retinal pigment epithelium, which was considered a dose limiting toxicity 
[DLT]). 
 
Study HCC1001 
This study was an open-label, multicenter, 2-part, Phase 1/2a study to evaluate the safety, 
PK, PD, and clinical responses of erdafitinib administered orally to Asian subjects ≥18 
years of age and with advanced HCC. Eleven subjects have been treated in this study, 3 
subjects in the 8.0 mg group, and 8 subjects in the 10.0 mg group. The subject population 
was all male (91%) with 1 female (9%), with a median age of 49 years (range 31-67). 
Median duration of exposure is 5.9 weeks (range 2-33 weeks). Six subjects (54.5%) have 
discontinued treatment; 5 subjects due to progressive disease and 1 subject due to death. 
 
The best response to treatment was partial response (PR), for 1 subject in the 10 mg group. 
Five of the 7 response-evaluable subjects (71.4%) experienced progressive disease; 1 
subject was not evaluable. All subjects (100%) experienced a TEAE and 9 subjects (81.8%) 
experienced a drug-related TEAE. The most frequently reported AEs were 
hyperphosphatemia (72.7%), anemia (36.4%), ALT increased (27.3%) and AST increased 
(27.3%). Grade 3 or 4 AEs were reported for 4 subjects, and were hyponatremia, abdominal 
pain, bacterial infection, hypovolemic shock, nosocomial infection, fatigue, ALT 
increased, AST increased, bilirubin increased, urine output decreased, and 
hyperbilirubinemia. Four subjects experienced serious AEs, these were abdominal pain, 
gastrointestinal hemorrhage, esophageal varices hemorrhage, pyrexia, bacteremia, 
hemoptysis, and hypovolemic shock. Esophageal varices hemorrhage led to treatment 
discontinuation and death of 1 subject. None of the Grade 3 or 4 AEs, serious AEs, or AEs 
resulting in death or treatment discontinuation was considered by the investigator to be 
related to study drug. 
 
 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Preliminary pharmacokinetic characteristics of erdafitinib have been studied after 
single and repeat administration in healthy volunteers and in patients with cancer 
from Studies EDI1001, EDI1002, EDI1003, and EDI1004. 
 

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Single dose PK 
Erdafitinib exhibits a linear increase of Cmax and AUC24 with dose (ranged from 
0.5 mg to 12 mg following a single dose). Median tmax ranged from 2-3 hrs 
following oral administration of capsules, respectively. Mean total plasma terminal 
phase half-life of erdafitinib is long and is between 44 to 56 hrs.   
 
Total plasma pharmacokinetics of erdafitinib was lower in healthy volunteers 
when compared with those in patients with cancers. However, α1-AGP level in 
healthy volunteers is also lower when compared with patients with cancers, 
resulting in similar unbound plasma exposure of erdafitinib in both healthy 
volunteers and patients with cancers. 
 
Multiple dose PK 
Erdafitinib exhibits a linear increase of Cmax and AUC with dose (ranged from 
0.5 mg to 12 mg following multiple daily dosing) and time-independent PK. 
Median tmax ranged from 2 to 4 hrs following multiple daily dosing using the 
capsule formulation. Erdafitinib has low total plasma oral clearance (mean CL/F 
ranged from 0.3 to 0.5 L/h) following oral administration of capsules. 
 
Long plasma terminal phase half-life of erdafitinib resulted in approximately 3-
fold accumulation in Cmax and AUC following multiple daily dosing. In patients 
with cancers, average free fractions of erdafitinib in human plasma were small 
(~0.36%). 
 
Bioavailability 
Erdafitinib oral tablets and oral solution exhibit comparable bioavailability in 
humans. 
 
Distribution 
Plasma protein binding 
The plasma protein binding of erdafitinib was studied by equilibrium dialysis in 
human. Erdafitinib was highly bound to plasma proteins. Binding of 3H-erdafitinib 
to human purified α1-acid glycoprotein (α1-AGP) and human serum albumin 
(HSA) was shown to be dependent on the protein concentration. Depending on the 
level of α1-AGP in individuals, total plasma concentration of erdafitinib may vary 
between individuals. In patients and healthy volunteers, average free fractions of 
erdafitinib in human plasma were 0.36 and 0.50%, respectively. 
 
Transporters 
Based on Caco-2 data, erdafitinib showed an intermediate to high permeability. 
Studies using LLC-PK1 cells stably expressing ABCB1 (P-glycoprotein) showed 
that erdafitinib is a P-glycoprotein (P-gp) substrate with an efflux ratio of about 5. 
 
Volume of distribution 
Volume of distribution of total plasma erdafitinib in healthy subjects is small (31 
L), suggesting erdafitinib tends to stay in the blood binding to plasma protein 
(Study EDI1003). 
 
Metabolism 
The metabolism of 3H-erdafitinib in human liver microsomes was limited leading 
to relatively low metabolite levels. CYP3A4 and CYP2C9 are the dominant 

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CYP450 enzymes involved in the metabolism of 3H-erdafitinb in human liver 
microsomes and human hepatocytes based on inhibition of the formation of 
metabolites by diagnostic inhibitors. Other minor cytochromes involved in the 
microsomal metabolism of erdafitinib were CYP2C8 and CYP2D6 (based on 
inhibition data in human liver microsomes and heterologous expression systems). 
 
Inter- and intra-subject variability in PK 
The between- and within-subject variability in the PK of erdafitinib was studied in 
both healthy volunteers and patients with cancer. In Study EDI1003, the between-
subject variability for plasma clearance and central volume of distribution in 
healthy volunteers were 32% and 38%, respectively. Intra-subject variability of PK 
of total plasma erdafitinib in studies EDI1002 and EDI1003 was 11% or lower in 
healthy volunteers. Similarly, the between-subject variability of Cmax and AUC 
in patients with cancer ranged from 30% to 50% in Study EDI1001. 
 
Effect of Intrinsic Factors (Special Population) 
There is no specific study conducted to investigate the influence of intrinsic factors 
on the PK of erdafitinib. Based on limited and preliminary data from EDI1001 in 
cancer patients, population PK analysis suggested that no major influence by age, 
gender, race, BW, Height, BSI, BMI, renal function (creatinine clearance), and 
LFT (AST, total bilirubin) on the PK of erdafitinib. The influence of intrinsic 
factors on the PK of erdafitinib will be further investigated in future studies. 
 
PK-PD relationship 
QT or QTc Interval 
Pre-clinical studies have shown erdafitinib is an intrinsic hERG blocker with a 
proarrhythmic liability and QT prolongation associated with erdafitinib was seen 
across several species in nonclinical studies. However, intravenous administration 
of erdafitinib to female anesthetized guinea-pigs yielded no adverse effects up to 
a total plasma exposure of 771 ng/mL and a CV threshold of unbound fraction ~ 
81 ng/ml. At the highest clinical dose tested in Study EDI1001 (i.e., 12 mg once 
per day), mean unbound Cmax on Day 8 was 7.26 ng/mL, approximately 1/11th 
times (or 9%) of the CV threshold. Review of subjects for any AEs of QT 
prolongation concluded that the risk of QT prolongation due to treatment with 
erdafitinib in human subjects is low. 
 
Serum Phosphate 
There is an expected exposure-related increase in serum phosphate observed based 
on inhibition of renal FGF-23 mediated signaling by erdafitinib. This relationship 
was quantified using a non-linear mixed effects PK-PD approach. Using a 3-
compartment PK model, factoring in the effect of erdafitinib fraction unbound and 
AAG, the phosphate change from baseline was linearly related to erdafitinib 
unbound plasma concentration via an effect compartment. Simulations based on 
this model were performed to support the dose recommendation and modification 
recommended in the BLC2001 study. 
 
Efficacy 
In Study EDI1001, 153 subjects were evaluable for response. The best response 
was partial response, confirmed for 17 subjects and not confirmed for 2 subjects. 
The overall response rate, including unconfirmed responses, was 12.4%. 
Responses were observed at doses of 9 mg once daily and higher. Among subjects 

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with bladder cancer, the response rate was 35.7% (10/28 subjects. Furthermore, 
among subjects with bladder cancer that was FGFR mutation positive, the response 
rate was 40.0% (10/25 subjects). The best response in subjects with lung cancer 
was stable disease (5/17 subjects, 29.4%). Three subjects with breast cancer have 
responded with a best response of partial response (3/25 subjects, overall response 
rate of 12.0%).  
 
In Study BLC2001, 30 subjects were evaluable for response. Accounting for 
responses that were not confirmed (due to lost to follow-up or still awaiting 
confirmation), a best response of partial response was observed for 6 subjects in 
the 6 mg group and 6 subjects in 10 mg group. The overall response rate was 42.9% 
in the 6 mg group and 37.5% in the 10 mg dosing group. 
 
2.3 
Pediatric Studies 
 
 
Prior Experience in Children  
 
 
 
None. 
 
2.4 
Overview of Proposed Pediatric Study 
This Phase 2 study will assess the clinical effects of erdafitinib administered orally, once 
daily, in 28-day cycles to pediatric and adolescent patients.  
 
Since the adult RP2D (8 mg PO once daily) is below the MTD (at least 12 mg PO once 
daily) the starting dose as per standard Pediatric MATCH routine (described in additional 
detail in Section 11.2.1 of the screening protocol APEC1621SC) will be the adult RP2D 
adjusted for BSA, which is 4.7 mg/m2/day (8 mg/1.7 m2) up to a maximum daily dose of 8 
mg PO once daily. 
 
Disease status will be evaluated by CT or MRI after every other cycle x 3 then every 3 
cycles. Radiographic response will be assessed using RECIST criteria. Toxicity will be 
graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0.  
 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
3.1 
Study Enrollment 
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:  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data 
and with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 

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Requirements for OPEN access:  
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, 
ETCTN Corresponding roster, or PO roster with the role of Registrar. Registrars 
must hold a minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Please see Appendix X 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. 
 
 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. For 
CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must 
be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating 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 

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establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on 
the IRB/REB approval) must meet the following criteria in order for the processing 
of the IRB/REB approval record to be completed: 
 
• 
Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable 
CIRB Signatory Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; 
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); 
• 
An active roster affiliation with the NCI CIRB roster under at least one 
CIRB Signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix X. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. 
 

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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://www.ctsu.org. Registrars must hold a minimum of an AP 
registration type.   
 
 
Genetic Screening Procedures for Eligibility  
Patient enrollment onto the APEC1621SC screening protocol is required. In Stage 
2 of Pediatric MATCH (effective with Amendment #4 of APEC1621SC for 
patients enrolling on screening protocol) tumor genomic testing results from a 
CAP/CLIA-certified laboratory will be reviewed by the APEC1621SC Molecular 
Review Committee after APEC1621SC screening protocol enrollment to confirm 
the identification of an actionable Mutation of Interest (aMOI) for which a 
MATCH treatment subprotocol is available. Questions regarding interpretation of 
tumor testing results for potential APEC1621B study patients (such as whether a 
specific mutation would be considered actionable for the study) should be directed 
to the APEC1621SC and APEC1621B study chairs. 
 
The treatment assignment to a MATCH to a subprotocol (if a relevant aMOI is 
detected) will be communicated to the enrolling institution via the COG treatment 
assignment mechanism at the time the results of MATCH are returned, upon which 
a reservation to APEC1621B 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 APEC1621B. 
 
3.2 
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. 
 
3.3 
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. 
 
3.4 
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. 
 
 
 

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3.5 
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 2 weeks (14 days) of treatment assignment. The date 
protocol therapy is projected to start must be no later than 7 calendar days after the date of 
enrollment. Patients enrolling onto APEC1621B will have a COG ID obtained through 
their prior enrollment onto the screening protocol or from a prior COG study. Protocol 
therapy must start no later than 7 calendar days after the date of enrollment. Patients who 
are started on protocol therapy prior to study enrollment will be considered ineligible. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated in the eligibility section below. 
 
Note:  No starter supplies will be provided. Drug orders of erdafitinib should be 
placed with CTEP after enrollment and treatment assignment to APEC1621B with 
consideration for timing of processing and shipping to ensure receipt of drug supply 
prior to start of protocol therapy. 
 
3.6 
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 APEC1621SC 
screening protocol.  
 
3.7 
Dose Assignment 
The dose 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 

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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. 
 
4.1 
Inclusion Criteria 
 
 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621B based on the presence 
of an actionable mutation as defined in APEC1621SC. Examples of actionable 
mutations for APEC1621B are listed in Appendix VIII. 
  
 
Age: Patients must be  than 12 months and  21 years of age at the time of 
study enrollment. 
 
 
BSA:  Patients must have a body surface area ≥ 0.53 m2 at enrollment. 
 
 
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 any lesion that 
is at minimum 10 mm in one dimension on standard MRI or CT. 
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. 
 
 
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. 
 
 
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 

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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. 
 
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 

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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 erdafitinib or 
another FGFR inhibitor such as (but not limited to) AZD4547, 
BGJ398, BAY1163877, LY2874455. 
 
 
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) 
-     Hemoglobin  8.0 g/dL at baseline (may receive RBC 
transfusions) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.1.7.1.a 
(may receive platelet or pRBC 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 

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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: 
- 
 QTc interval ≤ 480 milliseconds 
 
 
Adequate Pulmonary Function Defined as: 
- 
Pulse oximetry > 94% on room air if there is clinical indication for 
determination (e.g. dyspnea at rest). 
 
 
Patients must be able to swallow intact tablets.  
 
 
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.  
 
4.2 
Exclusion Criteria 
 
 
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 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, while receiving study treatment and for 3 months after the 
last dose of erdafitinib. Male subjects (with a partner of child-bearing potential) must 
use a condom with spermicide when sexually active and must not donate sperm from 
the first dose of study drug until 3 months after the last dose of study drug. 
 
 
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.  See Appendix 

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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. 
 
 
CYP2C9 Agents: Patients who are currently receiving drugs that are 
strong inducers or moderate inhibitors of CYP2C9 are not eligible. See 
Section 7.5.2. 
 
 
Infection:  Patients who have an uncontrolled infection are not eligible. 
 
 
Patients who have received a prior solid organ transplantation are not eligible. 
 
 
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. 
 
 
A history of cardiovascular diseases: Unstable angina, myocardial infarction, or 
known congestive heart failure Class II-IV within the preceding 12 months; 
cerebrovascular accident or transient ischemic attack within the preceding 3 
months, pulmonary embolism within the preceding 2 months. 
 
A history of any of the following: sustained ventricular tachycardia, ventricular 
fibrillation, Torsades de Pointes, cardiac arrest, Mobitz II second degree heart 
block or third degree heart block; known presence of dilated, hypertrophic, or 
restrictive cardiomyopathy. 
 
 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
 
Patients with significant ophthalmologic conditions (uncontrolled glaucoma, 
central serous retinopathy, history of retinal vein occlusion or retinal detachment, 
excluding patients with longstanding findings secondary to existing conditions) 
are not eligible, to be confirmed with baseline ophthalmologic exam. All patients 
must have a baseline ophthalmologic exam, including fundoscopy to confirm no 
significant ophthalmologic conditions are present. 
 
 
5.0 
TREATMENT PROGRAM 
 
5.1 
Overview of Treatment Plan 
 
Treatment Schedule Table 
Days 1-28 
4.7 mg/m2 erdafitinib once daily, with 
maximum of 8 mg per day 
Day 28 
Evaluation 
 
Erdafitinib tablets will be given orally once daily. A cycle of therapy is considered to be 
28 days.  A cycle may be repeated up to a total duration of therapy of 2 years (maximum 
26 cycles). On Day 1 of Cycle 2, the dose of erdafitinib should be held until a pre-dose 
plasma sample can be obtained. In order to obtain the 24-hour time point, the dose 
on Day 2, Cycle 2 should also be held until plasma sample is obtained. 

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Erdafitinib is provided by NCI. Do not use commercial supply. 
 
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 (maximum 26 cycles) 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).  
 
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, and according to the dosing 
nomogram (see Appendix IV).  If vomiting occurs within 30 minutes of erdafitinib 
administration, then the dose can be repeated once. If a dose is missed, it can be taken up 
to 6 hours after the scheduled time. If it has been more than 6 hours since the missed dose, 
then that dose should be skipped. The next dose should be taken at the usual time 
 
Please refer to Section 7.3 for specific supportive care guidelines.  
 
Since the adult RP2D (8 mg PO once daily) is below the MTD (at least 12 mg PO once 
daily) the starting dose as per standard Pediatric MATCH routine (described in additional 
detail in Section 11.2.1 of the screening protocol APEC1621SC) will be the adult RP2D 
adjusted for BSA, which is 4.7 mg/m2/day (8 mg/1.7 m2) up to a maximum daily dose of 8 
mg PO once daily.  
 
 
Therapy Delivery Map 
See Appendix V for therapy delivery map for Cycle 1 and subsequent cycles. 
 
Intra-Patient Escalation 
Intrapatient dose escalation is not allowed. 
 
5.2 
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. 
  
5.3 
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 CTCAE V5.0.  A copy of 
the CTCAE V5.0 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. 
 
5.4 
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.  
 
 
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 < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 

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levels that meet initial eligibility criteria or baseline within 7 days. See 
Section 6.3, and 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 1 visual disturbance that persists for ≥ 4 weeks  
 
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. 
 
Hyperphosphatemia will be reported as a DLT if a dose modification is 
required (as described in Section 6.4 for serum phosphate of 7.0 or greater) 
 
 
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/mm3 or ANC < 1000/mm3). 
 
 
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. 
  
6.1 
Dose Modifications for Hematological Toxicity 
 
 
If a patient experiences hematological toxicity as defined in Section 5.4.2, 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 as outlined in 
the dosing nomogram table in Appendix IV.  Doses reduced for toxicity will not 
be re-escalated, even if there is minimal or no toxicity with the reduced dose.  
 

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If toxicity does not resolve to meet eligibility parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
 
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. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.4.1, the treatment will be held. If the toxicity resolves to meet eligibility 
parameters or baseline within 14 days of drug discontinuation, the patient may 
resume treatment at a reduced dose as outlined in the dosing nomogram table in 
Appendix IV. Doses reduced for toxicity will not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose.  
 
 
If a non-hematologic dose-limiting toxicity as defined in Section 5.4.1 does not 
resolve to meet eligibility or baseline parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. Any Grade 1 
visual disturbance that persists for ≥ 4 weeks and does not resolve to meet 
eligibility or baseline parameters within ≥ 4 weeks of drug discontinuation must 
be removed from protocol therapy. 
 
 
If non- hematologic dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol therapy. 
  
6.3 
Dose Modifications for Hepatic Adverse Events 
 
 
If a patient experiences Grade 3 ALT/AST/GGT, treatment will be held. If toxicity 
resolves to meet eligibility criteria within 7 days, the drug may be resumed at the 
same dose. Grade 3 ALT/AST/GGT that persists ≥ 7 days will be considered dose-
limiting and require dose modification per Section 6.2. See Appendix XI for values 
that represent thresholds between CTCAE grades. 
 
 
If a patient experiences Grade 4 ALT/AST/GGT, the patient must be removed from 
protocol therapy. See Appendix XI for values that represent thresholds between 
CTCAE grades. 
 
6.4 
Guidelines for the Management of Elevated Phosphate Levels 
Guidelines for the clinical management of elevated serum phosphate levels are presented 
below. 
 
Guidelines for Management of Serum Phosphate Elevation 
Serum Phosphate 
Level 
Study Drug Management 
Medical Management 
All subjects in the 
study 
Continue erdafitinib treatment. 
  
Restriction of phosphate intake to 600 – 
800 mg/day. 

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5.6-6.9 mg/dL 
(1.8-2.3 mmol/L) 
Continue erdafitinib treatment. 
  
Restriction of phosphate intake to 600 – 
800 mg/day. 
May consider sevelamer:  
Children 1-2 years: sevelamer 100-140 
mg/kg/day divided TID titrated to desired 
phosphate level 
Children > 2 years: sevelamer initial dose: 
400 or 800 mg TID with food; titrate to 
desired phosphate level at monthly 
intervals in 1200 mg/day increments (ie, 
400 mg at each meal) up to a maximum of 
1,600 mg PO TID with food 
7.0-9.0 mg/dL 
(2.3-2.9 mmol/L) 
Withholda erdafitinib treatment until serum 
phosphate level returns to <5.5 mg/dL (or 
baseline). 
  
Then re-start treatment at the same dose. 
  
A dose reduction may be implemented for 
persistentb hyperphosphatemia (≥7 mg/dL) lasting 
> 1 week if clinically necessary 
Restriction of phosphate intake to 600 – 
800 mg/day. 
  
Children 1-2 years: sevelamer 100-140 
mg/kg/day divided TID until phosphate 
level is <5.5 mg/dL. 
Children > 2 years: sevelamer initial dose: 
400 or 800 mg TID with food; titrate at 
monthly intervals in 1200 mg/day 
increments (ie, 400 mg at each meal) up to 
a maximum of 1,600 mg PO TID with 
food until phosphate level is <5.5 mg/dL. 
  
>9.0 mg/dL 
(>2.9 mmol/L) 
Withholda erdafitinib treatment until serum 
phosphate level returns to <5.5 mg/dL (or 
baseline). 
  
Re-start treatment at the reduced dose outlined in 
Appendix IV. 
  
 
Restriction of phosphate intake to 600 – 
800 mg/day. 
  
Sevelamer:  
Children 1-2 years: 100-140 
mg/kg/day divided TID  
Children > 2 years: initial dose: 400 or 800 
mg TID with food; titrate at monthly 
intervals in 1200 mg/day increments (ie, 
400 mg at each meal) up to a maximum of 
1,600 mg PO TID with food 
AND 
Acetazolamide 5-7.5 mg/kg/dose (up to 
250 mg/dose) BID or TID only until serum 
phosphate level returns to <5.5 mg/dL. 
>10.0 mg/dL 
(>3.2 mmol/L) 
and/or significant 
alteration in 
baseline renal 
function and/or 
Grade 3 
hypercalcemia 
Erdafitinib should be discontinued permanently. 
(In situations where the subject is having clinical 
benefit and the study chair agrees that re-starting 
drug is in the best interest of the subject, the drug 
may be re-introduced at  the reduced dose level 
outlined in Appendix IV if appropriatec. Follow 
other recommendations described above.) 
Medical management as clinically 
appropriate.  
Note: These are general guidelines that are based on emerging data and consensus experience of participating 
investigators and/or the experts in the field. The treating physicians must use clinical judgment and local standard of 
care to decide the best way to manage phosphate elevation. If sevelamer hydrochloride is not available, the use of other 
phosphate binders (non‐calcium containing) based on the local standard is recommended. These guidelines will be 
updated based on emerging data. Additional information on phosphorous in foods by class of food can also be found 
at www.permanente net/homepage/kaiser/pdf/42025.pdf. Additional information for phosphate management 
and diet can be found the National Kidney Foundation website (http://www kidney.org/atoz/content/phosphorus.cfm) 
a. Drug interruptions for hyperphosphatemia suggested to be 7 days duration 

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b. Persistent hyperphosphatemia is considered to be more than 1 sequential phosphate value of  >=7 mg/dL 
 
  
6.5 
 Guidelines for the Management of Dry Skin and Skin Toxicity 
 Guidelines for the management of dry skin are provided below. 
 
General prophylaxis: 
-        Avoid unnecessary exposure to sunlight and excessive use of soap. 
-        Avoid bathing in excess; use tepid rather than hot water.  
-        Use moisturizers regularly; apply thick, alcohol-free and oil-in-water based emollient cream 
on exposed and dry areas of the body.  
-        Avoid perfumed products, bubble bath, perfumed soaps, and take breaks from shaving.  
-        Use broad spectrum sunscreen with a skin protection factor (SPF) ≥15. 
-        Wear cotton clothes next to skin rather than wool, synthetic fibers, or rough clothing. 
-        Use occlusive alcohol-free emollient creams (jar or tub) for treatment of mild/moderate 
xerosis. 
-        For scaly areas, use exfoliants (ammonium lactate 12% or lactic acid cream 12%). 
 
Guidelines for Management of Dry Skin 
Grade 
and 
Definition 
Study Drug Management 
Medical Management 
Grade 1: Dry skin 
covering less than 
10% body surface 
area (BSA) and no 
associated erythema 
or pruritus 
Continue study drug at current 
dose.  
Use fragrance free moisturizing cream or ointment BID 
over entire body. 
Use ammonium lactate 12% cream or salicylic acid 6% 
cream BID over dry/scaly/hyperkeratotic areas such as 
palms and soles. 
Grade 2: Dry skin 
covering 10 to 30% 
BSA and associated 
with 
erythema 
or 
pruritis with limited 
instrumental 
activities of daily 
living (IADL) 
Continue study drug at current 
dose. 
  
Use fragrance free moisturizing cream or ointment BID 
over entire body. 
Use ammonium lactate 12% cream or salicylic acid 6% 
cream BID over dry/scaly/hyperkeratotic areas such as 
palms and soles. 
Use zinc oxide 13-40% at night for areas with fissures. 
Grade 3: Dry skin 
covering >30% BSA 
and associated with 
pruritis; 
limiting 
self-care activities of 
daily living (ADL) 
Hold study drug (for up to 14 
days), with weekly reassessments 
of clinical condition. 
When resolves to ≤ Grade 1 or 
baseline, restart at 1 dose level 
below in consultation with the 
Study Chair. 
Use topical steroid ointment or cream* BID and zinc 
oxide 13-40% at night for areas with fissures. 
Grade 4: Dry skin 
with life-threatening 
consequences, 
urgent 
intervention 
indicated 
  
Discontinue study drug.  
Evaluation and therapy as clinically indicated 
*Topical Steroid Ointments: Clobetasol 0.05%, Betamethasone 0.05%, Fluocinonide 0.05% 
  
 
 

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6.6 
Dose Modifications for Dermatology/Skin Disorders 
 
Grade  
Action 
Grade 1 or 2  
 
• 
Maintain dose 
Intolerable Grade 2; 
Grade 3  
 
• 
Hold erdafitinib until resolution to ≤ tolerable Grade 2 and dose reduce as 
per Section 6.2.  
 
6.7 
Guidelines for Management of Nail Toxicity (Onycholysis, Onychodystrophy, and 
Paronychia) 
 
General Prophylaxis: 
-          Good hygienic practices, keep fingers and toes clean. 
-          Keep nails trimmed 
-          Use gloves for housecleaning and gardening to minimize damage and prevent infection 
-          Nail polish and imitation fingernails should not be worn until the nails have grown out and 
returned to normal 
-          Wearing comfortable shoes (wide sized shoes with room for the toes) 
-          Trimming nails but avoiding aggressive manicuring 
 
 Guidelines for Management of Nail Discoloration/Loss/Ridging (Onycholysis/Onychodystrophy) 
Grade 
and 
Definition 
Study Drug Management 
Medical Management 
Grade 
1: 
Asymptomatic; 
clinical or diagnostic 
observations 
only, 
intervention 
not 
indicated 
Continue study drug at current dose, 
Over the counter nail strengthener OR poly-urea urethane 
nail lacquer (Nuvail) OR diethylene glycol monoethylether 
nail lacquer daily (Genadur) 
Grade 
2: 
Symptomatic 
separation of the nail 
bed from the nail 
plate or nail loss, 
limiting instrumental 
ADLs 
Continue study drug at current dose. 
Consider holding study drug if no improvement in 
1 to 2 weeks. 
When resolves to         ≤ Grade 1 or baseline, restart 
at same or at a reduced dose (Appendix IV) in 
consultation with the Study Chair. 
For signs of infection (periungal edema/erythema/ tenderness 
and/or discharge), obtain bacterial cultures, and then start the 
following:  
 
• 
treatment with oral antibiotic for 2 weeks (cefadroxil 15 
mg/kg/dose (up to 500 mg/dose) every 12 hours, 
ciprofloxacin 15 mg/kg/dose (up to 500 mg/dose) every 
12 hours, or sulfamethoxazole/trimethoprim (TMP) 6 to 
12 mg TMP/kg/day in divided doses every 12 hours; 
maximum single dose: 160 mg TMP/dose) 
AND 
• 
topical antifungal lacquer daily for 6+ weeks (ciclopirox 
olamine 8% OR efinaconazole 10% OR amorolfine 5% 
weekly OR bifonazole/urea ointment daily) 
Grade 3:  Severe nail 
tip 
pain, 
symptomatic 
separation of the nail 
bed from the nail 
plate or nail loss, 
significantly limiting 
IADLs 
Hold study drug (for up to 14 days), with weekly 
reassessments of clinical condition. 
When 
resolves 
to 
eligibility 
or 
baseline 
parameters, restart at a reduced dose (Appendix 
IV)  below in consultation with the Study Chair. 
Silver nitrate application weekly AND topical antibiotics 
AND vinegar soaks.a 
For signs of infection (periungal edema/erythema/ tenderness 
and/or discharge), obtain bacterial cultures, and then start the 
following: treatment with oral antibiotic for 2 weeks 
(cefadroxil 15 mg/kg/dose (up to 500 mg/dose) every 12 
hours, ciprofloxacin 15 mg/kg/dose (up to 500 mg/dose) 
every 12 hours, or sulfamethoxazole/trimethoprim (TMP) 6 
to 12 mg TMP/kg/day in divided doses every 12 hours; 

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maximum single dose: 160 mg TMP/dose).  
 
For cases of severe/refractory infection consider intravenous 
antibiotics.  
 
Consider dermatological and/or surgical evaluation. 
Grade 
4: 
life-
threatening 
consequences, 
urgent intervention 
indicated 
Discontinue study drug 
Evaluation and therapy as clinically indicated 
  
  
a       Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day. Examples of 
topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B 
   
Guidelines for Management of Paronychia 
Grade 
and 
Definition 
Study Drug Management 
Medical Management 
Grade 1: Nail fold 
edema or erythema; 
disruption 
of 
the 
cuticle 
Continue study drug at current dose. 
Topical antibiotics AND vinegar soaksa 
Grade 2: Nail fold 
edema or erythema 
with pain; associated 
with discharge or 
nail plate separation; 
limiting instrumental 
ADL 
  
Continue study drug at current dose. 
Consider study drug holding if no improvement in 
1 to 2 weeks. 
When resolves to ≤Grade 1 or baseline, restart at 
same or 1 dose level below in consultation with the 
Study Chair. 
  
Topical antibiotics AND vinegar soaksa AND topical 
antifungal lacquer daily for 6+ weeks (ciclopirox olamine 8% 
OR efinaconazole 10% OR amorolfine 5% weekly OR 
bifonazole/urea ointment daily). 
 
For signs of infection (periungal edema/erythema/tenderness 
and/or discharge), obtain bacterial cultures, and then start the 
following: treatment with oral antibiotic for 2 weeks 
(cefadroxil 15 mg/kg/dose (up to 500 mg/dose) every 12 
hours, ciprofloxacin 15 mg/kg/dose (up to 500 mg/dose) 
every 12 hours, or sulfamethoxazole/trimethoprim (TMP) 6 
to 12 mg TMP/kg/day in divided doses every 12 hours; 
maximum single dose: 160 mg TMP/dose). 
Grade 3: Limiting 
self-care 
ADLs, 
surgical 
intervention, 
or 
intravenous 
antibiotics indicated 
Hold study drug (for up to 14 days), with weekly 
reassessments of clinical condition.    
  
  
  
When 
resolves 
to 
eligibility 
or 
baseline 
parameters, restart at a reduced dose (Appendix 
IV) in consultation with the Study Chair. 
Vinegar soaksa AND consider nail avulsion 
For signs of infection (periungal edema/erythema/tenderness 
and/or discharge), obtain bacterial cultures, and then start the 
following: treatment with oral antibiotic for 2 weeks 
(cefadroxil 15 mg/kg/dose (up to 500 mg/dose) every 12 
hours, ciprofloxacin 15 mg/kg/dose (up to 500 mg/dose) 
every 12 hours, or sulfamethoxazole/trimethoprim (TMP) 6 
to 12 mg TMP/kg/day in divided doses every 12 hours; 
maximum single dose: 160 mg TMP/dose) ). 
For cases of severe/refractory infection consider intravenous 
antibiotics. 
 
Consider dermatological and/or surgical evaluation. 
Grade 
4: 
life-
threatening 
consequences, 
urgent intervention 
indicated 
Discontinue study drug. 
Evaluation and therapy as clinically indicated 
a    Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day. Examples of 
topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B 
 

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Dose Modifications for Visual Disturbances 
 
Grade  
Immediate Action 
Subsequent Action 
Grade 1 
Hold erdafitinib until an ophthalmologic exam can be 
completed (if possible, within 7 days). 
• 
If the diagnosis is keratitis or retinal abnormality 
such as central serous retinopathy (CSR)/retinal 
pigment epithelial detachments (RPED) withhold 
erdafitinib until signs and symptoms have 
resolved. For retinal pathology perform OCT as 
appropriate and consider referral to a retinal 
specialist for further evaluation. 
 
• 
Follow 
specific 
treatment 
as 
per 
the 
ophthalmologist’s recommendation. 
 
• 
If the toxicity resolves to < Grade 1 within 4 weeks 
according to ophthalmologic exam, resume 
erdafitinib therapy at the reduced dose (Appendix 
IV) level after consultation with the study chair per 
Section 6.2. Refer to Appendix IV for dose 
reduction information. 
 
• 
Monitor for recurrence every 1-2 weeks for a 
month and as clinically appropriate thereafter.  
 
• 
If there is no evidence of eye toxicity, resume 
erdafitinib therapy at the same dose level. 
Grade 2 
 
Hold erdafitinib until ophthalmologic exam is 
completed (if possible, within 7 days). 
• 
If the diagnosis is keratitis or retinal abnormality 
such as CSR/RPED, hold erdafitinib until signs 
and symptoms have resolved, stabilized. For 
retinal pathology perform OCT as appropriate and 
consider referral to a retinal specialist for further 
evaluation. 
 
• 
Monitor for recurrence every 1-2 weeks for a 
month and as clinically appropriate thereafter. 
 
• 
Follow 
specific 
treatment 
as 
per 
the 
ophthalmologist’s recommendation. 
 
• 
If there is no evidence of eye toxicity, resume 
erdafitinib therapy at the same dose level. 
 
• 
If the Ophthalmology exam is normal and the 
toxicity resolves to < Grade 1 within 4 weeks or 
according to ophthalmologic exam, resume 
erdafitinib therapy at the reduced dose level 
(Appendix IV) after consultation with the study 
chair per Section 6.2. 

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Grade 3  
 
Immediately stop erdafitinib and promptly refer 
subject to an ophthalmologist for evaluation with an 
ophthalmologic exam 
• 
Hold erdafitinib until eye exam is completed. If 
vision change is determined to be unrelated to 
erdafitinib, contact the study chair to discuss 
restarting of erdafitinib. Otherwise ≥ Grade 3 
visual disturbance will be considered a DLT and 
require a dose reduction as per Section 6.2 if 
resolves within 4 weeks. 
 
• 
Follow 
specific 
treatment 
as 
per 
the 
ophthalmologist’s recommendation. 
 
• 
Monitor for recurrence every 1-2 weeks for a 
month and as clinically appropriate thereafter. 
 
• 
If recurs, consider permanent discontinuation. 
Grade 4 
Permanently discontinue erdafitinib and promptly 
refer subject to an ophthalmologist for evaluation 
with an ophthalmologic exam 
• 
Refer to Section 13.0 for reporting guidelines; 
monitor resolution of eye finding until complete 
resolution, stabilization, or other off-study criteria 
are met (see Section 10.1) 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Please see COG Supportive Care guidelines at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. See Section 
7.5 for drugs that should not be used concomitantly due to potential interactions with 
erdafitinib. See below for recommendations on management of specific toxicities associated 
with erdafitinib. 
 
 
Nausea and vomiting: 
Nausea and vomiting has been observed frequently in adult patients treated with 
erdafitinib. It is recommended to provide all patients a 5-HT₃-Receptor blocker (e.g., 
ondansetron or granisetron) at the start of treatment to be used as needed or 
prophylactically.  In the event of breakthrough nausea/vomiting, additional 
antiemetics may be added as needed.  
 
Mucositis: 
For grade 1 mucositis, it is recommended to use conservative measures such as non-
alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. For grade ≥ 2 mucositis, topical analgesic mouth treatments (i.e., local 

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anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) may be used with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (e.g. Kenalog in Orabase®). Agents containing 
hydrogen peroxide, iodine, and thyme derivatives may worsen mouth ulcers and 
should not be used. 
 
Systemic antifungal agents should be avoided unless a fungal infection is diagnosed. 
In particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, voriconazole, etc.) should be avoided due to their strong inhibition of 
CYP3A4 metabolism, therefore leading to higher erdafitinib exposure. Topical 
antifungal agents are preferred if an infection is diagnosed. 
 
7.4 
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. 
 
7.5 
Concomitant Medications 
 
 
CYP3A4 inhibitors or inducers: Strong CYP3A4 inhibitors or inducers are not 
permitted on study (See Appendix II for list of agents). Note: CYP3A4 inducing 
anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable 
dose, are allowed. No grapefruit juice, Seville oranges, or grapefruit can be 
consumed while on erdafitinib. 
 
 
CYP2C9 inhibitors or inducers: Moderate CYP2C9 inhibitors or strong CYP2C9 
inducers are not permitted on the study.  
 
 
CYP3A4 substrates: Until further data become available, concomitant use of 
erdafitinib with CYP3A4 substrates with narrow therapeutic indices should be 
avoided. 
 
 
Co-administration of erdafitinib with other serum phosphate altering agents may 
affect serum phosphate concentrations. Avoid co-administration of serum 
phosphate altering agents if reasonable alternatives exist. 
 
 
Concomitant administration of erdafitinib with P-glycoprotein (P-gp) substrates 
may increase their systemic exposure if administered concurrently.  
 
 
P-glycoprotein: Concomitant administration of erdafitinib with P-glycoprotein 
(P-gp) substrates may increase their systemic exposure if administered 
concurrently. Oral narrow therapeutic index P-gp substrates such as digoxin 
should be taken at least 6 hours before or after erdafitinib to minimize the 
potential for interactions 
 
 
OCT2: Erdafitinib was shown to be an OCT2 inhibitor in vitro. Until further data 
are available, consider alternative agents that are not OCT2 substrates. 
Metformin is an example of an OCT2 substrate. 
 
 

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7.6 
Pharmacogenomic considerations  
The exposure of erdafitinib is predicted to increase by 50% in subjects with the CYP2C9 
*3/*3 genotype. Therefore, monitor for increased adverse reactions in subjects who are 
known or suspected to have CYP2C9*3/*3 genotype. Dose changes are guided by serum 
phosphate levels in all subjects irrespective of genotype.  
 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
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). 
 
 
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 
Tumor Disease Evaluation 4-A, 4-B,  
X 
 
Every other cycle x 3 then q 
3 cycles 4 
Bone Marrow Aspirate and/or biopsy5,6 
X6 
 
 
EKG 
X 
 
 
Ophthalmologic exam10 
X 
 
X 
Every cycle during the first 4 
cycles of treatment, then 
every 3 cycles afterward10 
Plain radiograph tibial growth plate 
(Bone X-Ray Tests)11 
X 
 
Prior to cycles 2, 5 
and every 6 months 
Medication Diary7 
 
Weekly 
X 
Pharmacokinetics (optional)8 
 
 
 
Circulating Tumor DNA (ctDNA-
optional)9 
 
 
Cycle 5, Day 1 and (for 
patients receiving ≥ 5 cycles 

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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 greater thrombocytopenia then CBCs should be checked every 3 to 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 is 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 the start of therapy 
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 the start of therapy. 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 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. 
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 weekly during cycle 1, after completion of 
each treatment cycle and uploaded into RAVE. 
8 
See Section 8.4 for details of PK and plasma protein 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 for details of the ctDNA studies. 
Note that a ctDNA sample is scheduled to be obtained on the APEC1621SC screening protocol prior to 
the initiation of treatment on this subprotocol.  
10 
Patients are required to have a baseline ophthalmological exam including fundoscopy, prior to the first 
dose of study medication, patients with significant ophthalmologic exams should refer to Section 4.2.9. 
Additionally, an ophthalmological exam should be performed every cycle for the first 4 cycles of 
treatment, then every 3 cycles afterward.  
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. 
 
8.2 
Monitoring for Specific Toxicities 
 
 
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 

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radiographs of the same tibial growth plate will be obtained prior to cycles 2, 
5 and every 6 months thereafter. 
• 
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 erdafitinib 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 erdafitinib. 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 erdafitinib or not. 
 
8.3 
Radiology Studies 
 
 
Bone Age/Knee MRI 
All tibial radiographs and knee MRIs (if obtained) should be submitted for review. 
 
 
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 
submitted for review include baseline (pre-study) evaluations as well as all end of 
cycle tumor disease evaluations which occurred while the patient was on the 
subprotocol therapy study. 
 
 
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. 
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 sFTP or may be emailed to DataSubmission@QARC.org.  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 

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Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
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 
                                          
8.4 
Pharmacology and Plasma Protein Binding (Optional) 
 
 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of JNJ-42756493 
(erdafitinib) in children. Pharmacokinetic analysis will be conducted at a 
centralized laboratory using validated assays. 
 
Erdafitinib is avidly bound to plasma proteins (fraction of unbound approx. 
0.36%), preferentially to alpha-1 acid glycoproteins (AGP). Therefore, in addition 
to the PK samples on Day 1 of Cycle 2, an additional sample will be collected for 
the assessment of the binding of erdafitinib to plasma proteins pre-dose and 2 h 
after the erdafitinib dose. In the same samples the concentration of alpha-1 acid 
glycoprotein will be determined. 
 
 
 
 
 
 
 
 
 

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will not exceed 2 hours. 
 
Please Note: If an amber polypropylene screwtop cryotube is not 
available to protect the samples from light, a clear polypropylene 
screwtop cryotube may be wrapped in black tape. Ensure that the 
sample identification is not covered by the tape. Clear polypropylene 
screwtop cryotube must be wrapped before transfer of the plasma to 
the tube to minimize the time of exposure to light. 
 
 
Sample Labeling 
Each sample must be labeled with the patient’s study registration number, the 
study I.D# (APEC1621B), and the date and time the sample was drawn.  Data 
should be recorded on the Pharmacokinetic Study Form, which must accompany 
the sample(s). 
 
 
Institutional Sample Shipping Information  
Institutional Sample Shipping Instructions: 
Samples should be batched per patient and shipped frozen on dry ice monthly. 
Frozen samples must be shipped Monday through Wednesday via overnight 
courier. Do not ship samples on Thursdays, Fridays, weekends, or holidays. 
 
Notify Diana Lozano via email at dl2595@cumc.columbia.edu and the study 
assigned research coordinator when samples are shipped and include the tracking 
number.  
 
Attn:  Diana Lozano 
161 Fort Washington Ave-Room 706 
Columbia University-Pediatric Oncology 
New York, NY 10032 
Phone: (212) 3056-2486 
Email: dl2595@cumc.columbia.edu  
 
 
Sample Analysis 
Samples will be analyzed at the locations below, for sample shipment 
information please see Section 8.4.6 
 
Plasma PK Sample Analysis Shipping: 
Naomi Teekamp PhD 
Alex J. AttemaProject Manager- PRA Health Sciences 
Bioanalytical Laboratory NL / Quality Control Laboratory – Early Development 
Services 
Amerikaweg 18 
9407 TK Assen 
The Netherlands 
Telephone: +31 59 230 3474+31 (0) 592.303.421 
E-mail: teekampnaomi@prahs.com  AttemaAlex@prahs.com 
 
Protein binding Sample Analysis Shipping: 
Jo‐Anne Jensen 
Sample Management, Department of Bioanalysis 
Janssen Research & Development, 

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Building 017 Room 035a Division of Janssen Pharmaceutica N.V. 
 
Turnhoutseweg 30 
B‐2340 Beerse 
Tel: +32 14 60 3335 
Fax: +32 14 60 5110 
Email: bioansup@its.jnj.com 
8.5 
Circulating Tumor DNA Study (Optional)   
 
 
Sampling Schedule   
An initial sample was previously requested at time of enrollment onto the 
pediatric MATCH 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 
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. 

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• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results. 
• 
Store blood in a Streck tube at room temperature until shipment. 
 
 
Sample Processing 
Samples do not need to be processed at the collection site. 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621B), 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). 
 
 
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 APEC1621B-Peds MATCH* 
 
 
700 Children’s Drive, WA1340 
 
 
Columbus, OH 43205 
 
 
Phone: (614) 722-2865 
 
 
Fax: (614) 722-2897 
 
 
Email: BPCBank@nationwidechildrens.org 
 
* Packages must be labeled “Peds MATCH” in order to expedite processing at the 
BPC. Be sure to include the room number. Ship samples by FedEx Priority 
Overnight using a FedEx shipping label obtained through the COG FedEx account 
 
 
 
9.0 
 AGENT INFORMATION 
 
9.1 
Erdafitinib 
 
 
 
 
 
 
 
(01-30-2022) 
(Balversa®, NSC# 781558, IND# 134661  
  
 
Source and Pharmacology: 
 
Erdafitinib is a highly selective and potent oral pan-fibroblast growth factor 
receptor (FGFR) tyrosine kinase inhibitor with high affinity and low nanomolar 
inhibitory activity for all FGFR family members, FGFR 1, 2, 3 and 4. The FGFR 

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are tyrosine kinases that are present in many types of endothelial and tumor cells 
and are shown to play an important role in tumor cell growth, survival, and 
migration as well as in maintaining tumor angiogenesis. Over-expression of 
FGFRs, or inappropriate activation through point mutation, chromosomal 
translocation, or aberrant splicing, has been implicated in many forms of human 
malignancies. Erdafitinib is FDA approved for the treatment of adult patients with 
locally advanced or metastatic urothelial carcinoma that has susceptible FGFR3 or 
FGFR2 genetic alterations.  
 
 
 
 
Pharmacokinetics 
Absorption of erdafitinib was estimated to be near complete. Following single and 
multiple once-daily administration, erdafitinib exposure (Cmax and AUC) increased 
in a dose-proportional manner across the dose range of 0.5 to 12 mg. Multiple dose 
erdafitinib PK was time independent and steady state was achieved after 2 weeks 
of daily administration. With a once daily dose regimen, mean (coefficient of 
variation [CV%]) steady state accumulation ratio for AUC from time 0 to 24 hours 
after daily dosing (AUCτ) was 4.07 (32.0%), corresponding to a mean effective 
half-life (t1/2) of 58.9 hours. Erdafitinib can be administered with or without food 
due to lack of effect of concomitant food intake. Estimated clearance of erdafitinib 
consisted of metabolism (67%), of which primarily by CYP2C9 (39%) and 
CYP3A4 (20%), renal clearance (13%), and intestinal secretion (21%). Excretion 
of erdafitinib was primarily in feces (68.7%), in the form of unchanged drug 
(14.1% to 20.8% of total dose) and M6 (approximately 24%). Erdafitinib was 
excreted to a lesser extent in urine (18.7%), with unchanged drug being the major 
entity (13.3%). Unchanged erdafitinib was the major drug-related moiety in 
plasma; there were no circulating metabolites.  
 
Potential Drug Interactions 
Erdafitinib is a weak time-dependent inhibitor and weak inducer of CYP3A4.  
Until further data become available, concomitant use of erdafitinib with CYP3A4 
substrates with narrow therapeutic indices should be avoided. 
Co-administration with a moderate CYP2C9 or strong CYP3A4 inhibitor 
increased erdafitinib exposure and may lead to increased drug-related toxicity. The 
use of moderate inhibitors of CYP2C9 and strong inhibitors of CYP3A4 are not 
permitted for the duration of the study.   
 
The impact of strong CYP2C9 or CYP3A4 inducers (such as rifampin) on 
erdafitinib was not clinically studied. The concomitant use of strong CYP2C9 and 
CYP3A4 inducers with erdafitinib should be avoided as co-administration may 
significantly decrease erdafitinib exposure. Caution should be exercised for 
concomitant administration of erdafitinib and moderate CYP2C9 or CYP3A4 
inducers as this may result in decreased erdafitinib exposure.  
 
Co-administration of erdafitinib with other serum phosphate altering agents may 
affect serum phosphate concentrations. Avoid co-administration of serum 
phosphate altering agents if reasonable alternatives exist. 
 
Concomitant administration of erdafitinib with P-glycoprotein (P-gp) substrates 
may increase their systemic exposure if administered concurrently. Oral narrow 
therapeutic index P-gp substrates such as digoxin should be taken at least 6 hours 

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before or after erdafitinib to minimize the potential for interactions. 
 
Erdafitinib was shown to be an OCT2 inhibitor in vitro. PK simulations with 
metformin, an OCT2 substrate, predicted a lack of clinically relevant interaction 
with erdafitinib. However, until further data are available, consider alternative 
therapies that are not OCT2 substrates.   
 
No clinically significant QT prolongation or cardiovascular effects have been noted 
to date. Clinical trials revealed no effects of erdafitinib on cardiac repolarization or 
other electrocardiographic parameters. 
 
Acid lowering agents (e.g., antacids, H2-antagonists, or proton pump inhibitors) are 
not expected to affect the bioavailability of erdafitinib. Erdafitinib may be co-
administered with an acid lowering agent. 
 
Pharmacogenomics:  
The exposure of erdafitinib is predicted to increase by 50% in subjects with the 
CYP2C9 *3/*3 genotype, estimated to be 0.4% to 3% of the population among 
various ethnic groups. Therefore, monitor for increased adverse reactions in 
subjects who are known or suspected to have CYP2C9*3/*3 genotype. Dose 
changes are guided by serum phosphate levels in all subjects irrespective of 
genotype; therefore, the implications of higher exposures of erdafitinib including 
safety may be addressed.  
 
Patient Care Implications 
Patients should have a baseline ophthalmological exam including fundoscopy, 
prior to the first dose of study medication. Additional ophthalmological exams 
should be performed every cycle for the first four cycles of treatment and then 
every 3 cycles afterward, manage as in accordance with the “Dose Modifications” 
table in Section 6.8. 
                                           
 
Female subjects (of child-bearing potential and sexually active) must use medically 
acceptable methods of birth control prior to study entry and for the duration of the 
study, and for at least 3 months after the last dose of study drug. Male subjects (with 
a partner of child-bearing potential) must use a condom with spermicide when 
sexually active and must not donate sperm from the first dose of study drug until 3 
months after the last dose of study drug. Medically acceptable methods of 
contraception that may be used by the subject and/or his/her partner include hormonal 
prescription oral contraceptives, contraceptive injections, contraceptive patch, 
intrauterine device, true sexual abstinence, and surgical sterilization (e.g., confirmed 
successful vasectomy or tubal ligation). True sexual abstinence is an acceptable 
method of contraception and is defined as refraining from heterosexual intercourse 
during the entire period of the study, including up to 3 months after the last dose of 
study drug is given. 
 
All subjects should be closely monitored with special attention to cardiovascular 
function and evidence of disturbance of phosphate homeostasis and bone pathology 
and ocular symptoms until sufficient clinical experience is obtained. 
 

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EYE DISORDERS - Blurred vision; Eye disorders - Other (blepharitis); Eye disorders - Other (blindness unilateral); 
Eye disorders - Other (corneal erosion); Eye disorders - Other (corneal infiltrates); Eye disorders - Other (eyelid 
edema); Eye disorders - Other (foreign body sensation in eyes); Eye disorders - Other (lagophthalmos); Eye disorders 
- Other (macular degeneration); Eye disorders - Other (metamorphopsia); Eye disorders - Other (ocular hyperemia); 
Eye disorders - Other (xanthopsia); Eye pain; Night blindness; Papilledema; Photophobia; Vision decreased  
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Dysphagia; Gastrointestinal 
disorders - Other (intestinal obstruction); Salivary duct inflammation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; General disorders 
and administration site conditions - Other (general physical health deterioration); Non-cardiac chest pain; Pain 
INFECTIONS AND INFESTATIONS - Herpes simplex reactivation; Infections and infestations - Other (clostridum 
difficile colitis); Infections and infestations - Other (lower respiratory tract infection); Infections and infestations - 
Other (oral herpes); Sepsis; Urinary tract infection 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; GGT increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (metastases to spine) 
NERVOUS SYSTEM DISORDERS - Lethargy; Somnolence 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Pleural effusion; Respiratory, 
thoracic and mediastinal disorders - Other (respiratory distress) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Eczema; Hyperkeratosis; Rash 
maculo-papular; Skin and subcutaneous tissue disorders - Other (cutaneous calcification); Skin and subcutaneous 
tissue disorders - Other (skin exfoliation); Skin and subcutaneous tissue disorders - Other (skin lesion); Skin and 
subcutaneous tissue disorders - Other (skin toxicity); Skin atrophy; Skin hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Hypotension; Thromboembolic event 
 
Note: Erdafitinib 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. 
 
 
 
Formulation and Stability 
Erdafitinib is a yellow powder.  Tablet excipients include mannitol, 
microcrystalline cellulose, meglumine, croscarmellose sodium and  magnesium 
stearate.  Tablets are coated with Opadry AMB II. The agent is available as 3 mg 
(yellow), 4 mg (orange), and 5 mg (brown) film coated tablets.  
 
The approximate dimensions of the round tablets are in the table below: 
Strength 
Diameter (mm) 
Thickness (width) (mm) 
3 mg 
7.7 + 0.2 
3.7 + 0.4 
4 mg 
8.2 + 0.2 
4.2 + 0.4 
5 mg 
8.7 + 0.2 
4.6 + 0.4 
 
Erdafitinib tablets are provided in 30 count bottles made of high density 
polyethylene (HDPE), with an induction seal and child resistant cap.  Tablets must 
be dispensed in the original container. 
 
Storage 
Store intact bottles at controlled room temperature 15°C to 30°C (59°F to 86°F). 
Tablets must be dispensed in the original container. 

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If a storage temperature excursion is identified, promptly return erdafitinib to 15°C 
to 30°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Stability 
Shelf-life dating is printed on the bottle label. 
 
 
Guidelines for Administration 
See Treatment (Section 5.0) and Dose Modification (Section 6.0) sections of the 
protocol. Administer erdafitinib orally once a day with or without food, at 
approximately the same time each day. Tablets must be swallowed whole, with 
approximate 8 ounces of water.  Do not crush or chew. If vomiting occurs within 
30 minutes of erdafitinib administration, then the dose can be repeated once. If a 
dose is missed, it can be taken up to 6 hours after the scheduled time. If it has been 
more than 6 hours since the missed dose, then that dose should be skipped. The 
next dose should be taken at the usual time. 
              
 
Supplier 
Erdafitinib is supplied by Johnson & Johnson and distributed by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. Do not use commercial supply. 
 
 
Obtaining the Agent 
NCI supplied agent may be requested by the eligible participating investigator (or 
their authorized designee) at each participating institution. The CTEP assigned 
protocol number must be used for ordering all CTEP supplied investigational agents. 
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA form 1572 (Statement of 
Investigator), NIH Biosketch, Agent Shipment Form, 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 erdafitinib (JNJ-
42756493) should be placed with CTEP after enrollment and treatment 
assignment to APEC1621B with consideration for timing of processing and 
shipping to ensure receipt of drug supply prior to start of protocol therapy.  
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, and a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.  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. 

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Agent Accountability 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP forms page.  Store 
and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
                                         
 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP IAM 
account and the maintenance of an “active” account status, a “current” password, 
and active person registration status. Questions about IB access may be directed to 
the PMB IB coordinator via email. 
 
 
 
 
 
 
Useful Links and Contacts  
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent management.htm    
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account:  
   
  https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email: PMBAfterHours@mail.nih.gov  
• 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/   
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
 Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 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. 

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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.  
 
10.2 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
Patients who are off subprotocol therapy will initially be followed on the therapeutic 
subprotocol for a 30-day period. During follow-up on the therapeutic subprotocol 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). Upon completion of subprotocol 
follow-up period, the patient 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); consent is withdrawn or the 
patient dies or is lost to follow-up. 
 
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
APEC1621B will require a minimum of 20 evaluable patients and a maximum of 49 
patients, allowing for 15% inevaluability. Assuming an enrollment rate of 4-9 biomarker 
positive patients per year, the primary cohort of this subprotocol is expected to be 
completed within 2.7-6 years. 
 
11.2 
Dosing Considerations  
 
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 erdafitinib to be 
used in this study. As there is no prior pediatric phase 1 data for erdafitinib, study 
investigators have reviewed relevant data with the pharmaceutical partner to 
identify a drug specific dosing plan for testing in children with recurrent/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 this arm. Since the adult RP2D (8 mg PO once daily) is below the MTD 
(at least 12 mg PO once daily) the starting dose  will be the adult RP2D adjusted 
for BSA, which is 4.7 mg/m2/day (8 mg/1.7 m2) up to a maximum daily dose of 8 
mg PO once daily. The dosing for erdafitinib will follow the general Pediatric 
MATCH subprotocol guidelines as below: 
 

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11.4 
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.16 Decision making for A’Hern design 
cohorts will follow rules described above. 
 
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.   
 
11.5 
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 the first 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. 
 
11.6 
Evaluability for Toxicity 
All eligible patients who receive at least one dose of protocol therapy will be considered in 
the evaluation of toxicity. 
 
11.7 
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.     
 
 
 
 

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show opposite responses, the progressive disease takes precedence. 
 
12.3 
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 
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. 
 
 Definitions 
 
 Evaluable for objective response:  
Eligible patients who receive exhibit objective disease progression and 
who have received 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 
 
 Evaluable Non-Target Disease Response: 
  
Eligible patients who have evaluable but not measurable disease and 
have received at least one dose of protocol therapy, have lesions present 
at baseline that are evaluable but do not meet the definitions of 
measurable disease, will be considered evaluable for non-target disease 
response. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
 Disease Parameters 
 
 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 

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 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes with 
≥ 10 to < 15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the 
next largest lesion that can be measured reproducibly should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
 
 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 

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The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
 Clinical lesions:   
Clinical lesions will only be considered measurable when they are 
superficial (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.  
 
 Chest x-ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
 Conventional CT and MRI:  
 This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (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.  
 
 PET-CT:   
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use 
with RECIST measurements.  However, if the site can document that the 
CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-
CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
 Tumor markers:  
Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to 
be considered in complete clinical response.  
 
 Cytology, Histology:  
These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 

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Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
 FDG-PET:  
While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
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.17 
 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 

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sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
 Overall Response Assessment 
 
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-
No 
PR 

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CR/Non-
PD/not 
evaluated 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
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 
 
 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. 
 
12.5 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 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 

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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. 
 
 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 
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 
 
 
 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 

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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) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
 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 
 
 
 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. 
 
12.6 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
 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.  

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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 
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. 
 
 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. 
 
 
12.7 
Response Criteria for Patients with CNS Tumors 
 
 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
 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. 
 
 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 

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(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. 
 
 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 
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.  
 
 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. 
 
 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
 
 

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 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 
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. 
 
 
12.8 
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 Criteria18, with modification from the Lugano classification.19 
 
 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. 
 
 
 

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 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. 
 
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)19 
 
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. 
 
 Evaluation of organ enlargement19  
 
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 

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increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
12.9 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 
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. 
 
 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 
 
 
 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). 
 

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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.  
 
 
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. 
 
13.1 
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 

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listed in this definition. 
 
 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.  
 
Any medical documentation supporting an expedited report (eg, H & P, 
admission and/or notes, consultations, ECG results, etc.) MUST be faxed 
within 48-72 hours to the NCI. NOTE: English is required for supporting 
documentation submitted to the numbers listed below in order for the NCI to 
meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents 
supplied under a CTEP IND to: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 
(310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 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 APEC16-
21B COG Study Assigned Research Coordinator.  ALWAYS include the ticket 
number on all faxed and emailed documents. 
 
13.2 
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 5.0 of the NCI CTCAE.  
The descriptions and grading scales found in the current version 5.0 of the CTCAE 
will be used for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE v5.0.  A copy of the CTCAE v5.0 can be downloaded 
from the CTEP website (http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE v5.0. 
 
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 

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specific adverse events that require special monitoring; and/or 
• 
There are any protocol-specific exceptions to the reporting requirements.  
 
• 
Any medical event equivalent to CTCAE v5.0 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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 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.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
 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). 
 
 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. 
 
13.6 
Specific Examples for Expedited Reporting 
 
 Reportable Categories of Death 
• Death attributable to a CTCAE v5.0 term.  
• 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. 
 
 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 

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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. 
 
 Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Death 
Neonatal”, 
the 
Pregnancy 
Information 
Form, 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/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 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in 
an expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 
 
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. 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. 
 
 
 

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 Death Neonatal 
Neonatal death, defined in CTCAE v5.0 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.  
 
13.7 
Special Reporting Situations 
In accordance with the protocol the following special situations, which are safety events of 
interest for a J&J medicinal product that require expediting reporting and/or safety 
evaluation with or without an SAE include: 
• 
Drug exposure during pregnancy (maternal) 
• 
Suspected abuse/misuse of erdafitinib product 
The following Special Situations should be reported if associated with an SAE or as defined 
within the protocol  
• 
Overdose of erdafitinib product 
• 
Exposure to erdafitinib product from breastfeeding  
• 
Inadvertent or accidental exposure to erdafitinib product 
• 
Any failure of expected pharmacological action (i.e., lack of effect) of erdafitinib  
• 
Critical Treatment Deviations as defined in CTMB Audit Guidelines: 
o Any finding identified before or during an audit that is suspected to be 
fraudulent activity 
o Incorrect agent/treatment/intervention used 
• 
Suspected transmission of any infectious agent via administration of a medicinal 
product  
These safety events may not meet the definition of an adverse event; however, from a 
COLLABORATOR perspective, they are treated in the same manner as adverse events. 
Special Situations should be recorded on the appropriate CRF. 
 
13.8 
Product Quality Compliant (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or delivery system. 
Not all PQCs involve a subject. Lot and batch numbers are of high significance and need 
to be provided upon request. 
 
Examples of PQC include but are not limited to: 
• 
Function Problem: e.g. altered delivery rate in a controlled release product 
• 
Physical Defect: e.g. abnormal odor, broken or crushed tablets/capsules 

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• 
Potential Dosing Device Malfunction: e.g. autoinjector button not working, needle 
detaching from syringe 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  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 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
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 quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31.  This 
is not a responsibility of institutions participating in this trial. 
 
Note:  This 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.   
 
14.3 
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 

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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. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order as described in the IP Option to Collaborator (http://ctep.cancer.gov
/industryCollaborations2/intellectual property.htm). Additionally, all Clinical 
Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 

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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. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
 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. 
 
 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 
1. 
Porta R, Borea R, Coelho A, et al.: FGFR a promising druggable target in cancer: Molecular biology 
and new drugs. Crit Rev Oncol Hematol 113:256-267, 2017 
2. 
Bange J, Prechtl D, Cheburkin Y, et al.: Cancer progression and tumor cell motility are associated 
with the FGFR4 Arg(388) allele. Cancer Res 62:840-7, 2002 
3. 
Liang G, Chen G, Wei X, et al.: Small molecule inhibition of fibroblast growth factor receptors in 
cancer. Cytokine Growth Factor Rev 24:467-75, 2013 
4. 
Weiss J, Sos ML, Seidel D, et al.: Frequent and focal FGFR1 amplification associates with 
therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 
2:62ra93, 2010 
5. 
Jones DT, Hutter B, Jager N, et al.: Recurrent somatic alterations of FGFR1 and NTRK2 in 
pilocytic astrocytoma. Nat Genet 45:927-32, 2013 
6. 
Singh D, Chan JM, Zoppoli P, et al.: Transforming fusions of FGFR and TACC genes in human 
glioblastoma. Science 337:1231-5, 2012 
7. 
Missiaglia E, Selfe J, Hamdi M, et al.: Genomic imbalances in rhabdomyosarcoma cell lines affect 
expression of genes frequently altered in primary tumors: an approach to identify candidate genes 
involved in tumor development. Genes Chromosomes Cancer 48:455-67, 2009 
8. 
Karkera JD, Martinez Cardona G, Bell K, et al.: Oncogenic Characterization and Pharmacologic 
Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the 
Selective FGFR Inhibitor Erdafitinib. Mol Cancer Ther, 2017 
9. 
Perera TP, Jovcheva E, Mevellec L, et al.: Discovery and pharmacological characterization of JNJ-
42756493 (erdafitinib), a functionally selective small molecule FGFR family inhibitor. Mol Cancer 
Ther, 2017 
10. 
Nishina T, Takahashi S, Iwasawa R, et al.: Safety, pharmacokinetic, and pharmacodynamics of 
erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients 
with advanced or refractory solid tumors. Invest New Drugs, 2017 
11. 
Loriot Y, Necchi A, Park SH, et al.: Erdafitinib in Locally Advanced or Metastatic Urothelial 
Carcinoma. New England Journal of Medicine 381:338-348, 2019 
12. 
Central serous retinopathy includes: chorioretinopathy, retinal detachment, retinal oedema, 
detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium, 
retinopathy and vitreous detachment.,  
13. 
Eye disorders includes, but is not limited to eye disorder with redness and irritation of the eye, 
maybe associated with increased tearing of the eyes, itchy eyes, and inflamed eyes.,  
14. 
Nail disorder includes, but is not limited to, onycholysis, onychalgia, onychoclasis, nail dystrophy, 
nail loss, nail bed bleeding, nail bed inflammation, nail discomfort, nail discoloration, and nail 
ridging.,  
15. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
16. 
Agresti A,Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
17. 
Sandlund JT, Guillerman RP, Perkins SL, et al.: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. Journal of Clinical Oncology 33:2106-2111, 2015 
18. 
Sandlund JT, Guillerman RP, Perkins SL, et al.: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
19. 
Cheson BD, Fisher RI, Barrington SF, et al.: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 

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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 
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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everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
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 

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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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Cycle 1  
See Section 6.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
 
Required Observations in Cycle 1  
*All baseline studies must be performed prior to starting protocol therapy unless otherwise 
indicated below. For information related to pre-study observations please refer to Section 8.1. 
Studies on Day 1 may be obtained within 72 hours prior to the start of the subsequent cycle. * 
Please refer to Section 8.1 for the specific timing of these observations. 
 
 
 
 
 
 
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) 
 
 
 
 
Treatment Details: Cycle 1 
 
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).  
 
 
 
 
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. 
   
  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.  
h. 
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. 

  
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Subsequent Cycles 
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 
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- Bone marrow aspirate and/or biopsy should only be performed 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.  
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. 
Pharmacokinetics - see Section 8.4 for details of PK/plasma protein studies in Cycle 2. 
l. 
Ophthalmology exam - Patients should have a baseline ophthalmological exam including fundoscopy, prior to 
the first dose of study medication, patients with significant ophthalmologic exams should refer to Section 4.2.9. 
Additionally, an ophthalmological exam should be performed every cycle for the first four cycles of treatment and 
then every 3 cycles afterward. 
m. 
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 
 
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) 
 
 
 
 
 
 
 
 
 
Treatment Details: Subsequent Cycles 
 
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).  

  
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APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621B EXPANSION COHORTS 
Target tumor types considered for biomarker-positive expansion cohorts and biomarker-negative 
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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APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS FOR SUBPROTOCOL FOR APEC1621B 
INCLUSION 
VARIANTS 
  
  
  
Hotspots 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
FGFR1 
COSM4771556 
SNV 
p.K656M 
3 
FGFR1 
COSM35673 
SNV 
p.K656E 
3 
FGFR1 
COSM19176 
SNV 
p.N546K 
3 
FGFR1 
COSM302229 
SNV 
p.N546K 
3 
FGFR1 
COSM48380 
SNV 
p.T141R 
3 
FGFR1 
PM_COSM1456955 
SNV 
p.T141A 
3 
FGFR2 
COSM49173 
SNV 
p.K659N 
3 
FGFR2 
COSM683054 
SNV 
p.K659N 
3 
FGFR2 
COSM49175 
SNV 
p.K659M 
3 
FGFR2 
PM_B7 
SNV 
p.K659N 
3 
FGFR2 
COSM36909 
SNV 
p.K659E 
3 
FGFR2 
COSM29836 
SNV 
p.A648T 
3 
FGFR2 
COSM36912 
SNV 
p.N549K 
3 
FGFR2 
COSM36902 
SNV 
p.N549K 
3 
FGFR2 
PM_COSM3665555 
SNV 
p.N549S 
3 
FGFR2 
COSM250083 
SNV 
p.N549H 
3 
FGFR2 
PM_COSM4604460  
SNV 
p.N549D 
3 
FGFR2 
COSM36913 
SNV 
p.I547V 
3 
FGFR2 
COSM250081 
MNV 
p.V395D 
3 
FGFR2 
COSM915493 
SNV 
p.C382Y 
3 
FGFR2 
COSM36906 
SNV 
p.C382R 
3 
FGFR2 
COSM36904 
SNV 
p.Y375C 
3 
FGFR2 
COSM29824 
SNV 
p.G305R 
3 
FGFR2 
COSM49170 
SNV 
p.P253R 
3 
FGFR2 
COSM537801 
SNV 
p.P253L 
3 
FGFR2 
PM_COSM4994845  
SNV 
p.S252L 
3 
FGFR2 
COSM36903 
SNV 
p.S252W 
3 
FGFR3 
PM_COSM27138 
INS 
p.R248_S249insC 
3 
FGFR3 
COSM714 
SNV 
p.R248C 
2 
FGFR3 
PM_COSM732 
INS 
p.R248_S249insL 
3 
FGFR3 
COSM29431 
SNV 
p.S249T 
3 
FGFR3 
COSM715 
SNV 
p.S249C 
2 
FGFR3 
PM_COSM722 
SNV 
p.A369A 
3 
FGFR3 
COSM716 
SNV 
p.G370C 
3 
FGFR3 
COSM17461 
SNV 
p.S371C 
3 
FGFR3 
PM_B6 
indel 
p.Y373C 
2 
FGFR3 
COSM718 
SNV 
p.Y373C 
3 

  
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FGFR3 
COSM24842 
SNV 
p.G380R 
3 
FGFR3 
COSM51545 
SNV 
p.G380E 
3 
FGFR3 
OM3151 
SNV 
p.A393T 
3 
FGFR3 
COSM721 
SNV 
p.A391E 
3 
FGFR3 
COSM296687 
SNV 
p.R399C 
3 
FGFR3 
COSM29438 
SNV 
p.D641N 
3 
FGFR3 
COSM719 
SNV 
p.K650E 
3 
FGFR3 
COSM726 
SNV 
p.K650Q 
3 
FGFR3 
COSM720 
SNV 
p.K650M 
3 
FGFR3 
COSM731 
SNV 
p.K650T 
3 
FGFR3 
COSM3993567 
SNV 
p.K652N 
3 
FGFR3 
COSM24802 
SNV 
p.G697C 
3 
FGFR3 
COSM732992 
SNV 
p.K715M 
3 
FGFR4 
PM_B1 
SNV 
p.N535D 
3 
FGFR4 
BT122 
SNV 
p.N535K 
3 
FGFR4 
BT120 
SNV 
p.N535K 
3 
FGFR4 
PM_B4 
SNV 
p.A554D 
3 
FGFR4 
PM_B5 
SNV 
p.G649D 
3 
 
 
 
 
 
Fusions 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
FGFR1 
FGFR1-ADAM32.F17A14 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
BCR-FGFR1.B4F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
CNTRL-FGFR1.C40F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
CUX1-FGFR1.C11F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1OP-FGFR1.F5F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1OP-FGFR1.F6F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1OP-FGFR1.F7F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
LRRFIP1-FGFR1.L8F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
MYO18A-FGFR1.M33F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
TRIM24-FGFR1.T11F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
BAG4-FGFR1.B2F6 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
BAG4-FGFR1.B1F8 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
ZMYM2-FGFR1.Z17F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
TPR-FGFR1.T22F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1OP2-FGFR1.F4F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
WHSC1L1-FGFR1.W14F5 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FN1-FGFR1.F22F3 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FN1-FGFR1.F23F3 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FN1-FGFR1.F23F4 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FN1-FGFR1.F28F5 
Fusion 
FGFR1 Gene Fusion 
2 

  
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FGFR1 
FN1-FGFR1.F22F4 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
SQSTM1-FGFR1.S6F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
ERVK3_1-FGFR1.E3F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-NTM.F1N2 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-PLAG1.F1P2.COSF1108 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-PLAG1.F1P3.COSF1110 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-TACC1.F17T7.COSF1362 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-TACC1.F18T7 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-ZNF703.F14Z2.COSF720 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
WHSC1L1-FGFR1.W1F2 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
ERLIN2-FGFR1.E8F2 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-PLAG1.F2P2.COSF1111 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
FGFR1-PLAG1.F2P3.COSF1113 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
CPSF6-FGFR1.C8int8F10 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR1 
RANBP2-FGFR1.R20F10int9 
Fusion 
FGFR1 Gene Fusion 
2 
FGFR2 
FGFR2-AHCYL1.F17A2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-BICC1.F17B2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-BICC1.F17B3.1 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-BICC1.F17B18 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-CASP7.F17C2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-CCAR2.F17C4 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-CCDC6.F17C1 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-CIT.F17C23 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-COL14A1.F17C34 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-CREB5.F17C8 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-FAM76A.F17F2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
SLC45A3-FGFR2.S1F1 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
SLC45A3-FGFR2.S1F2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
PARK2-FGFR2.P9F11 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
CD44-FGFR2.C1F3 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
CTNNB1-FGFR2.C1F10 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
PDHX-FGFR2.P1F7 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
SNX19-FGFR2.S7F7 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-KCTD1.F17K2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-MGEA5.F17M12 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-NOL4.F17N7 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-OFD1.F17O3 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-PPHLN1.F17P3 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-SHTN1.F17S7 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-TACC3.F17T11 
Fusion 
FGFR2 Gene Fusion 
2 

  
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FGFR2 
FGFR2-TXLNA.F17T6 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-USP10.F17del11U5 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-CCDC6.F17C2 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
FGFR2-AFF3.F17A8.1 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR2 
SNX19-FGFR2.S8F7 
Fusion 
FGFR2 Gene Fusion 
2 
FGFR3 
ETV6-FGFR3.E5F9 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T10.COSF1434 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-BAIAP2L1.F17B2.COSF1346 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T8.COSF1353 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T11.COSF1348 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F15T11 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F16T10.COSF1359 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F16T11.COSF1348 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T13.NGS 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T5 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T6 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T9 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T7.NGS 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-AES.F17A2 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-ELAVL3.F17E2 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F14T11 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T4and5 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T10.1 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T10 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T11 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.TruncatedF17T4 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T7 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T10 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T11.1 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T11.2 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T14 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T11del5 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F18T1 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17ins1T10 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-JAKMIP1.F17J4 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T14.1 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-FBXO28.F17F4 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17intron17T4.1 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17Intron17T9 
Fusion 
FGFR3 Gene Fusion 
2 
FGFR3 
FGFR3-TACC3.F17T4 
Fusion 
FGFR3 Gene Fusion 
2 

  
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APEC1621B 
 
                                                                                                                      
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Page 99 
 
APPENDIX IX: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621B 
(for children from 7 through 13 years of age) 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) 
in children with a cancer that has come back after treatment or is difficult to treat 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is 
being done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because 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 you have.  
 
4. What will happen to me in the study? Children who are part of this study have been “matched” to 
a medicine. We think that this medicine will help you and other kids that have the same kind of 
cancer as you have. If you decide to be treated with this medicine, you will have some tests and 
check-ups done more often than if you weren’t part of this study. We will follow your health after 
you finish the study treatment. 
 
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 for your cancer to 
stop growing, or even shrink, but we don’t know for sure if there is any benefit of being part of this 
study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have more problems, or side 
effects, from a medicine used in this study. There may be risks that we don’t know about yet. 
 
5. Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and your family can also decide to stop being in this study at any time once you start. There may 
be other treatments for your illness that your doctor can tell you about. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
6. We are asking your permission to collect additional blood. If you agree, we will draw two additional 
blood samples from you. This would not change what medicines we would use to treat your tumor 
and would not provide any “benefits” to you. We hope that it might help us learn how to better treat 
other children’s cancers in the future. You do not have to participate if you do not want to.  

  
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INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621B 
(for teens from 14 through 17 years of age) 
1. What is the name of the study? 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 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is being 
done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because 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.  
 
4.  What will happen to me on the study? Your tumor has a mutation that matches erdafitinib, and so 
you have been assigned to erdafitinib. The doctors want to see if erdafitinib will make children with 
your type of cancer get better. We don’t know if erdafitinib will work well to get rid of your cancer. 
That is why we are doing the study. 
 
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 tipifarnib 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. 
 
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 
tipifarnib. Your doctor will talk to you about the risks we know about from tipifarnib. There may 
be other risks from tipifarnib that we don’t know about yet.  
 
 
5.   Will I be paid to be in this study? You will not be paid for being in this study. 
 
6.    Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and your family can also decide to stop being in this study at any time once you start. There may 
be other treatments for your illness that your doctor can tell you about. If you have any questions 
or don’t like what is happening, please tell your parent, the doctor or nurse. 
 
7. We are asking your permission to collect additional blood. If you agree, we will draw two additional 
blood samples from you. This would not change what medicines we would use to treat your tumor 
and would not provide any “benefits” to you. We hope that it might help us learn how to better treat 
other children’s cancers in the future. You do not have to participate if you do not want to.  
 
 
 

  
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APPENDIX X 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 
 
 
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NCI Biosketch (education, 
training, employment, license, 
and certification) 
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GCP training 
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Agent Shipment Form (if 
applicable) 
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CV (optional) 
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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).  
 
Protocol-Specific Requirements For Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
• 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must 
be aligned to an RTI provider. To manage provider associations or to add or remove 
associated providers, access the Provider Association page from the Regulatory section on 
the CTSU members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation. Sites 
must be linked to at least one Imaging and Radiation Oncology Core (IROC) provider to 
participate on trials with an RTI component. Enrolling sites are responsible for ensuring 
that the appropriate agreements and IRB approvals are in place with their RTI provider. An 
individual with a primary role on a treating site roster can update the provider associations, 
though all individuals at a site may view provider associations. To find who holds primary 
roles at your site, view the Person Roster Browser under the RUMS section on the CTSU 
website. 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 

  
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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. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata. To accept the invitation, site staff must either click on the link in the email or log in to 
iMedidata via the CTSU members’ website under Data Management > Rave Home and click accept 
the invitation in the Tasks pane located in the upper right-corner of the iMedidata screen. Site staff 
will not be able to access the study in Rave until all required Medidata and study specific trainings 
are completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right corner of 
the iMedidata screen. If an eLearning is required for a study and has not yet been taken, the link to 
the eLearning will appear under the study name in the Studies pane located in the center of the 
iMedidata screen; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the eLearning link under the study 
name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms, DQP Form Status, and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, forms with current status, 

  
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and timeliness reports. Review the DQP modules on a regular basis to manage specified queries 
and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on the 
DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports modules. 
 
 
 

  
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APPENDIX XI TOXICITY-SPECIFIC GRADING 
Bilirubin 
 
Grade 1: 
≤ 1.5 x ULN 
Grade 2: 
> 1.5 x - 3 x ULN 
Grade 3: 
> 3 x -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