NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) Screening Protocol
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Ann Arbor Stage III Non-Hodgkin Lymphoma, Ann Arbor Stage IV Non-Hodgkin Lymphoma, Histiocytic Sarcoma, Juvenile Xanthogranuloma, Langerhans Cell Histiocytosis, Malignant Glioma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Recurrent Soft Tissue Sarcoma, Refractory Ewing Sarcoma, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Rhabdoid Tumor, Stage III Osteosarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Wilms Tumor
Sponsor: National Cancer Institute (NCI)



                       
 
           
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TABLE OF CONTENTS 
SECTION 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
1 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
STUDY COMMITTEE, CONT. 
7 
COG Operations Staff 
7 
OVERVIEW  
8 
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Aims 
8 
1.2 
Secondary Aims 
9 
1.3 
Exploratory Aims 
9 
2.0 BACKGROUND 
9 
2.1 
Tumor Biopsy in Children with Cancer (Stage 1 Only. As of Amendment #4, tumor samples 
will no longer be submitted for centralized clinical testing.) 
12 
2.2 
Germline Testing in Children with Cancer 
14 
2.3 
Circulating Tumor DNA (ctDNA) 
16 
2.4 
Overview of Proposed Pediatric MATCH Study 
16 
3.0 SCREENING AND STUDY ENROLLMENT PROCEDURES 
17 
3.1 
Study Enrollment 
17 
3.2 
Procedures for Eligibility to Screening Protocol 
20 
3.3 
Genetic Screening Procedures for Eligibility to Subprotocols 
20 
3.4 
Informed Consent/Assent 
22 
3.5 
Eligibility Checklist 
22 
3.6 
Institutional Pathology Report 
22 
3.7 
As of Amendment #4: Institutional Tumor Molecular Profiling Report (Stage 2 of Pediatric 
MATCH only) 
23 
3.8 
Study Enrollment Instructions for Subprotocols 
23 
4.0 PATIENT ELIGIBILITY FOR TARGET SCREENING 
24 
4.1 
Eligibility Criteria for Enrollment onto APEC1621SC 
24 
4.2 
General Inclusion Criteria for Subprotocols 
25 
4.3 
General Exclusion Criteria for Subprotocols 
28 
5.0 SUBMISSION OF EVALUATIONS/MATERIAL AND DATA FOR TARGET SCREENING 
29 
5.1 
Required Clinical, Laboratory and Disease Evaluation 
29 
5.2 
Biopsy Methods and Complication Monitoring 
29 
5.3 
Pathology Guidelines and Specimen Requirements 
30 
5.4 
Imaging Procedures 
30 
5.5 
Genomic Platform and Reporting 
30 
5.6 
APEC1621SC Specimen Studies 
34 
5.7 
APEC1621SC Specimen Shipment 
38 
5.8 
Agent selection 
39 
5.9 
Patients with non-target bearing (biomarker negative) tumors 
40 
6.0 TREATMENT PROGRAM 
40 

                       
 
           
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6.1 
Overview of Treatment Plan 
40 
6.2 
Grading of Adverse Events 
40 
6.3 
Definition of Biopsy-Related Target Toxicity (TT) 
41 
6.4 
Definition of Dose-Limiting Toxicity (DLT) 
41 
7.0 DOSE MODIFICATIONS FOR ADVERSE EVENTS 
42 
8.0 SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
42 
8.1 
Concurrent Anticancer Therapy 
42 
8.2 
Investigational Agents 
42 
9.0 AGENT INFORMATION: GENERAL OVERVIEW 
42 
9.1 
Refer to Subprotocol for agent information. 
42 
10.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
42 
10.1 
Off Study Criteria from APEC1621SC Screening Protocol 
42 
10.2 
Criteria for Removal from Subprotocol Therapy 
42 
10.3 
APEC1621SC Re-screening upon removal from subprotocol therapy 
43 
11.0 STATISTICAL AND ETHICAL CONSIDERATIONS 
43 
11.1 
Sample Size and Study Duration 
43 
11.2 
Dosing Considerations 
45 
11.3 
Subprotocol Study Design 
46 
11.4 
Match Rate Feasibility Analysis 
48 
11.5 
Methods of Analysis 
49 
11.6 
Evaluability for Response 
49 
11.7 
Evaluability for Toxicity 
49 
11.8 
Monitoring of Biopsy Related Adverse Events 
49 
11.9 
Progression free survival (PFS) 
50 
11.10 Correlative Studies 
50 
12.0 EVALUATION CRITERIA 
50 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
50 
12.2 
Progression-Free Survival 
51 
12.3 
Response Criteria for Patients with Solid Tumors 
51 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
54 
12.5 
Response Criteria for Neuroblastoma Patients 
56 
12.6 
Response Criteria for Patients with CNS Tumors 
56 
12.7 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
57 
12.8 
Best Response 
59 
13.0 ADVERSE EVENT REPORTING REQUIREMENTS 
61 
13.1 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
62 
13.2 
Steps to Determine if an Adverse Event is to be reported in an Expedited Manner 
63 
13.3 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements: 
65 
13.4 
Definition of Onset and Resolution of Adverse Events 
65 
13.5 
Other Recipients of Adverse Event Reports 
65 
13.6 
Specific Examples for Expedited Reporting of Biopsy-Related Target toxicities 
66 
14.0 RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
68 
14.1 
Categories of Research Records 
68 
14.2 
Access to RAVE for Data Submission/ Data Reporting 
68 
14.3 
CDUS 
68 
14.4 
CRADA/CTA/CSA 
69 
14.5 
Data and Safety Monitoring Plan 
69 

                       
 
           
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15.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
69 
15.1 
Computed Tomography (CT) with Contrast 
69 
15.2 
CT during PET/CT 
70 
15.3 
[18F] Fluorodeoxyglucose (FDG) PET 
70 
REFERENCES 
71 
APPENDIX I: EXAMPLES OF Pediatric MATCH Agent Classes and Linked Genetic Alterations. 
74 
APPENDIX II: APEC1621SC Target Histologies for Expansion Cohorts 
76 
APPENDIX III: Levels of Evidence for Subprotocol Agents and Gene Variants as aMOI 
77 
APPENDIX IV: Performance Status Scales/Scores 
78 
APPENDIX V: Biospecimen Flow Diagram USED FOR STAGE 1 of pediatric MATCH TRIAL at 
nationwide children’s hospital 
79 
APPENDIX VI: APEC1621SC Youth Information Sheets 
80 
APPENDIX VII: CTEP and CTSU RegistraTion Procedures 
82 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about 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. 
 
OVERVIEW 
 
The Pediatric MATCH (Molecular Analysis for Therapy Choice) study, (referred to as Pediatric MATCH 
in the remainder of this document), will match targeted agents with specific molecular changes identified 
using genomic sequencing technologies in refractory/recurrent tumors from children and adolescents with 
cancer. Pediatric MATCH will build upon experience from the adult NCI MATCH clinical trial.  Pediatric 
MATCH will be a national trial under a single IND and will be led by NCI and the Children’s Oncology 
Group (COG), a member of the NCI National Clinical Trial Network (NCTN).   
Pediatric MATCH will employ an analytically validated next-generation sequencing targeted assay of more 
than 4,000 different mutations (SNVs, indels, copy number alterations, and gene fusions) across more than 
140 genes. This assay will be coupled to a computer algorithm that uses pre-existing definitions and 
prioritization of target-agent pairs to assign patients by actionable mutation results to a targeted treatment.   
As of Amendment #4: Starting in 2022, Pediatric MATCH will move to a new screening model, called 
Stage 2, in which tumor molecular profiling reports from CLIA-certified clinical laboratories are 
reviewed to determine molecular eligibility to Pediatric MATCH treatment protocols. Centralized tumor 
testing will no longer be performed as part of the study. The Stage 2 review process will utilize the same 
definitions for clinical actionability of tumor mutations as used throughout Pediatric MATCH. 
The primary endpoint for Pediatric MATCH will be objective response rate.  The study will use a trial 
design with the flexibility to open and close arms.  The study drugs included in this trial will include agents 
that have at least an adult recommended phase 2 dose and that have shown some activity against tumors 
with a particular genetic alteration(s). Patients with recurrent or refractory tumors enrolled on study will 
have tumor molecular profiling reports that are believed (in the opinion of the treating clinician) to confer 
eligibility to a Pediatric MATCH treatment arm. If confirmed by Pediatric MATCH review, the patient will 
be offered treatment on Pediatric MATCH.  
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To utilize clinical and biological data to screen for eligibility to phase 2 pathway-
targeting specific subprotocols of pathway-targeting agents in pediatric patients 
with advanced solid tumors, non-Hodgkin lymphomas, and histiocytic disorders. 
 

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1.1.2 
To determine the proportion of pediatric patients whose advanced tumors have 
pathway alterations that can be targeted by select anti-cancer drugs. (Completed 
as of Amendment #4. patients enrolled on or after Amendment 4 will not be 
included in this analysis as screening of unselected patients will no longer be 
conducted.) 
 
1.2 
Secondary Aims 
 
1.2.1 
To obtain preliminary information on the response rate to targeted therapy in 
patients whose tumors lack actionable alterations as defined for the MATCH study, 
for selected agents for which efficacy is observed in the primary matched cohort. 
 
1.3 
Exploratory Aims 
1.3.1 
To increase knowledge of the genomic landscape of advanced pediatric solid 
tumors, non-Hodgkin lymphomas, and histiocytic disorders. 
1.3.2 
To describe the genomic changes that occur in advanced pediatric cancers between 
the time of initial diagnosis and relapse, in cases for which paired tumor specimens 
are available. 
1.3.3 
To explore approaches to diagnosing and profiling genomics of advanced pediatric 
cancers through evaluation of circulating tumor DNA 
1.3.4 
To determine the frequency and spectrum of germline cancer susceptibility 
mutations in children with relapsed solid tumors and non-Hodgkin lymphomas and 
assess the feasibility of return of those results in the NCTN group setting  
 
Note: patients enrolled on or after Amendment 4 will not be included in return of 
results analysis as clinical germline testing will no longer be conducted. 
2.0 
BACKGROUND 
The current approach to treatment of recurrent pediatric tumors is histology based, with patients 
directed to on- or off-protocol therapy depending on: 1) available clinical evidence for activity of 
a particular agent or regimen; 2) in the absence of clinical evidence, preclinical rationale supporting 
use of an agent/regimen; and 3) the availability of clinical trials for which the patient would be 
eligible. For some relatively common tumor types, phase 2 studies based on histologic diagnosis 
would commonly be used at recurrence. However, only a minority of pediatric phase 2 studies 
include rare tumor diagnoses. Phase 1 studies, which are generally not histologically driven, are 
recommended when there is no curative option with acceptable quality of life. It is uncommon for 
studies of recurrent pediatric tumors to be based on mutation status or other non-histologic criteria, 
although there are occasional exceptions such as studies with crizotinib in ALK-positive tumors. 
Although there are effective treatments for a few tumor types at relapse, such as Wilms tumor, the 
outcome following recurrence is generally poor. In addition, objective response rates in early phase 
trials of new agents remain unsatisfyingly low, generally <10%. Thus there is a strong rationale for 
considering new clinical trial designs that maximize the chance of benefit for patients enrolled onto 
early-phase studies by improving our ability to direct patients to the trials of the agents to which 
their tumors are most likely to respond. 
 
One potential strategy is the use of molecular profiling to detect tumor mutations that may be 
predictive of response to “molecularly targeted” agents. Knowledge of the spectrum of mutations 
found in different tumor types has improved significantly over the past decade,1 with a 

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corresponding increase in the subsequent development of agents targeting those mutations. To date, 
however, only a relatively small number of targeted agents have been approved, and experience 
with many of these drugs for pediatric patients is limited, emphasizing the need for clinical trials 
to evaluate both the efficacy of specific agents as well as the benefit of molecular profiling for this 
purpose. 
 
The number of genomic tests that can be used to molecularly profile tumors has continued to 
increase with advances in sequencing technologies. The spectrum of tests that are being utilized in 
the clinic for tumor analyses include: (1) targeted analyses of genetic alterations in individual genes 
(e.g. BRAF), (2) mutation panels evaluating a set of cancer genes of interest or members of specific 
biologic groups or genetic pathways (e.g. MAPK signaling pathway genes), and (3) unbiased 
genome-scale tests (e.g. whole exome or genome sequencing, RNA-sequencing). As for other types 
of clinical tests, the determination of the best methods for genomic characterization of tumors and 
assignment of molecularly-targeted therapies will require consideration of test cost, turnaround 
time, reproducibility, information yield, and other factors affecting feasibility in the clinical setting.  
 
Previous studies have attempted to quantify the number of potentially targetable mutations in a 
variety of tumor types in order to inform the design of clinical trials involving molecular profiling.  
Preliminary results from clinical genomic analyses of pediatric solid tumor patients have been 
reported to show mutations of potential clinical relevance in a fraction of patients using either tumor 
whole exome sequencing of newly-diagnosed patients (as part of the Baylor College of Medicine 
BASIC3 study) or mutation panel-based testing of relapsed/refractory tumors (in the Dana-Farber 
Cancer Institute iCAT study).2,3 Of note, only perhaps 10-20% of these alterations appear 
“targetable” (“druggable”) by current FDA-approved or investigational targeted agents. 
Importantly, a recent genomic analysis of relapsed neuroblastoma has revealed the presence of 
clonal evolution of targetable mutations in MAPK pathway genes in the relapsed tumors (not 
present in the pre-therapy tumor), providing further rationale for testing relapsed tumor samples as 
opposed to diagnostic (pre-therapy) tumor specimens to maximize diagnostic yield in prospective 
clinical trials utilizing molecular profiling.4 
 
Although they served to demonstrate the feasibility of genomic testing in the context of clinical 
trials, early studies evaluating the clinical benefit of molecular profiling were limited by the lack 
of availability of molecularly targeted agents. A common conclusion of early feasibility studies of 
clinical molecular profiling for relapsed/refractory cancers has been the small proportion of patients 
who go on to receive molecularly-targeted therapies (either on or off study) based upon those 
results. In the example of the SAFIR01/UNICANCER study of patients with metastatic breast 
cancer, for example, targeted therapy could be recommended in only 55 of 423 patients (13%), and 
only 43 patients actually received targeted therapy. Of these, 4 (9%) had an objective response, and 
9 others (21%) had stable disease for more than 16 weeks.5 These studies emphasize the need for 
clinical trials in which a selection of targeted investigational agents are available corresponding to 
the spectrum of targetable mutations that can be detected in the patient population being enrolled. 
 
Several such studies are being conducted under National Cancer Institute (NCI)-sponsored 
protocols. The “Molecular Profiling-Based Assignment of Cancer Therapy for Patients With 
Advanced Solid Tumors (NCI-MPACT)” trial is a pilot study designed to test whether patients 
whose tumors contain gene mutations or amplifications in one of three genetic pathways (DNA 
repair, PI3K, or RAS/RAF) are more likely to benefit if treated with agents targeting that pathway 
than if treated with agents that do not.6 Only patients with such mutations are entered onto the 
study; patients are then randomized to receive either the study drug identified to work on their 
tumor’s pathway, or a study drug targeting one of the other pathways. Of note, the investigators 
plan to enroll approximately 800 subjects in order to be able to randomize 180. A different approach 

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is being taken in the “Molecular Analysis for Therapy Choice” (NCI-MATCH) study, which 
utilizes a basic strategy of testing patient tumors for molecular targets under a screening protocol, 
then directing patients to one of many separate phase 2 studies that have molecular eligibility 
criteria. These studies involve many thousands of patients. For example, NCI-MATCH proposed 
to screen 3000 patients and enter 1000 on clinical trials studying 15-30 different drugs.7  
 
The adult NCI-MATCH study mutation panel underwent extensive validation testing prior to the 
opening of the study in August 2015. This testing revealed an observed sensitivity of 97% and 
specificity of >99% for the assay. Over the first 3 months of the adult NCI-MATCH 795 patients 
enrolled for screening, 739 biopsies were submitted, and sequencing was completed for 645 
specimens (87%). Approximately 9% of patients had an actionable mutation as defined for the 
study, with 5% meeting molecular eligibility for assignment to one of the 10 treatment arms. This 
rate will likely increase as additional study arms are opened, with recent match rates reported as 
~20 to 25%. The reported median turnaround time (TAT) was 27 days but increased from 14 days 
in the first month to 36 days in the last month, corresponding to a marked increase in study accrual. 
More recently (for subjects enrolled after May 30, 2016) the estimated median TAT has decreased 
to 15 days (Barb Conley, personal communication) despite an increase in study accrual to 100-120 
subjects per week.  This improved TAT reflects several modifications of the adult MATCH 
pipeline, including additional staffing and moving to a more high-throughput sequencing 
instrument. A third sequencing laboratory has also been selected.10 
 
As of Amendment #4, NCI-MATCH study screening update prior to Stage 2 of Pediatric 
MATCH: In 2020, the feasibility of the centralized molecular screening approach utilized for 
the adult NCI-MATCH study was further confirmed with testing results reported for nearly 6000 
patients. Of note, in the later stages of NCI-MATCH, the study protocol was modified to move 
from a centralized testing model to allow the use of clinical molecular testing results from 
approved clinical laboratories.8  
   
Given the relatively small number of pediatric patients with recurrent solid or central nervous 
system tumors, and the relative infrequency of targetable mutations in those tumors, multi-
institutional efforts will be required to determine whether molecular profiling and target-directed 
therapy will lead to improvements in patient outcomes. We propose a pediatric version of the NCI 
Molecular Analysis for Therapy Choice protocol, (Pediatric MATCH), as an initial step. 
 
 

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2.1 
Tumor Biopsy in Children with Cancer (Stage 1 Only. As of Amendment #4, tumor 
samples will no longer be submitted for centralized clinical testing.) 
 
Tumor biopsies are a fundamental component of the management of childhood cancer 
patients. A variety of procedures are utilized to obtain tumor tissue for diagnosis and risk-
based therapy stratification, including open biopsies and resections, “minimally-invasive” 
surgeries (e.g. laparoscopy and thoracoscopy), and percutaneous biopsies.9 Increasingly, 
molecular characterization of tumor tissue obtained by biopsy is being performed as part 
of the pathologic tumor evaluation, focusing specifically on histology-specific biomarkers 
or more broadly on potentially-targetable alterations (particularly in the context of relapsed 
and refractory tumors). 
 
Although the majority of the reports in the medical literature on complication rates of 
specific biopsy procedures describe adult oncology patients, ample pediatric data do exist 
to support the general safety of tumor biopsy as well as that of specific biopsy procedures. 
In a recent report describing 1025 biopsy procedures (43% open, 6% minimally invasive, 
50% percutaneous; median age 12.7 years, age range 0-33 years) targeting diverse non-
CNS anatomic locations performed over a decade at a single pediatric institution, NCI 
CTCAE v.4.0 grade 3 or 4 adverse events were reported in 32 of 1025 (3.1%) patients.10 
Twenty-four of these 32 events were post-operative transfusions; the majority of these 
patients were anemic before the biopsy procedure and only 8 of 24 had clearly documented 
blood loss post-procedure. It was judged that the biopsy procedure may have contributed 
to two deaths noted within 30 days of the procedure; the first a child with progressive NHL 
and pre-operative sepsis and multiorgan system failure and the second a patient who had a 
presumed intratumoral hemorrhage after open biopsy of a hepatoblastoma. CTCAE grade 
3 or 4 adverse events believed to be related to anesthesia were reported in 2 of 1025 (0.2%) 
cases; of note, nearly 94% of children underwent general anesthesia for their biopsy 
procedure in this series. In total, Serious Adverse Events related to biopsy procedures, 
including anesthesia, were reported in < 2% of children. Data for endoscopic and 
skin/subcutaneous biopsies were not reported, based on the authors’ assessment that those 
procedures are “likely to be associated with an even lower rate of adverse events”. 
Complication rates similar to those described by Interiano et al. (SAE rate < 2%) have also 
been reported in the context of specific disease indications, such as biopsy of localized 
neuroblastoma (2%; age < 20 years).11  
 
Numerous studies have reported data regarding the safety of percutaneous biopsies of non-
CNS tumors in pediatric patients.12-16 In these cohorts (n >1100 patients), CTCAE grade 3 
or 4 adverse events were observed in 0 to 3.4% of procedures, with SAEs in < 2% (. The 
percutaneous biopsies were performed on the spectrum of anatomical sites that are 
routinely sampled in pediatric oncology patients: renal13,17 (n=177, age < 21 years), lung12 
(n=64, mean age 10 years, range <1 to 20 years, assorted abdominal16 (n=105, median age 
3.9 years, range <1 to 14 years).and soft-tissue sites18 (n=205, mean 11 years, range 4-18 
years), and multiple sites including musculoskeletal and lymph nodes in addition to 
thoracic/abdominal tumors (n=415, median 9-10 years, range <1 to 33 years).14,15  
 
Minimally-invasive surgical (MIS) procedures have also become increasingly utilized for 
tumor biopsy in pediatric patients.19,20 The majority of pediatric data on MIS complication 
rates reported to date focus on thoracoscopy21, a common method of sampling pediatric 
lung tumors: SAEs have been reported in <1% of procedures, with conversion to open 
biopsy performed in 3% of cases, n=333 patients (Guye et al. n=139, mean 9.2 years, range 
<1 to 17 years; Rothenberg et al. n=194, range < 1 to 18 years). 22,23 Laparoscopic 

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procedures are also routinely used to biopsy or resect abdominal tumors in children24,25, 
including adrenal tumors (e.g. neuroblastoma) and renal tumors, with reported rates of 
SAEs < 2% and conversion to open procedures in ~5% of laparoscopic adrenalectomy 
cases26-29 (Al-Shanafey et al27. n=29, median age 3 years; range < 1 to 13 years; Leclair et 
al28. n=145, median age 6.8 months, range < 1 to 9 years; Nerli et al29. n=18, mean age 5.8 
years, range 1 to 15 years; Skarsgard et al30. n=20, mean age 6.4 years, range 1-18 years) 
and similar reported risks for nephrectomy.30,31 Of note, these data are for more extensive 
laparosopic procedures (resections) than biopsies. 
 
Several types of surgical procedures are routinely performed to biopsy CNS tumors in 
pediatric patients. Although data regarding major adverse events are available for such 
procedures in children, they have been limited to smaller cohorts and have not generally 
reported following CTCAE grading criteria. A recent review of SEER data (n=5533 cases) 
reported a 30-day mortality rate of <2% after craniotomy in patients from 1 to 21 years of 
age (median age 10 years).32 Neuroendoscopic biopsies are frequently utilized for 
intraventricular or periventricular tumors33, often in conjunction with procedures to relieve 
symptomatic hydrocephalus (e.g. endoscopic third ventriculostomy or septostomy). A 
study of neuroendoscopic biopsies (with or without or without a CSF diversion procedure) 
in 49 pediatric patients (mean age 12 years, range <1 to 21 years) reported major adverse 
events in 3/49 procedures (6%).34 A recent larger multi-institutional nationwide study of 
pediatric neuroendoscopic biopsies in Japan (n=206, age < 15 years) has described a similar 
frequency of major adverse events of 5-6% and also noted no difference in complication 
rates between the pediatric cohort and a larger cohort of adult patients.35 Stereotactic biopsy 
is another method of CNS tumor sampling for pediatric patients. In one series of 99 children 
(< 7 years of age), a complication rate of 5% was reported using a frame-based approach.36 
Stereotactic techniques are often used for cases in which deep or brainstem lesions are 
biopsied.37 Although a majority of the publications describing this procedure provide only 
a broad view of the complication rate (e.g. “no mortality or permanent morbidity” in 106 
children with brainstem masses (< 18 years of age) 38, more recent data have provided 
additional detail into the feasibility of these procedures. In the largest series reported to 
date (n=130, mean age 6 years, range 1 to 16 years), stereotactic biopsy of pediatric pontine 
gliomas resulted in transient worsening of neurologic deficit in 5 patients (3.9%) but no 
permanent deficits, major complications, or deaths.39 In total, it is estimated that SAEs 
occur in between 2 and 5% of CNS biopsies performed in children. 
 
In summary, a variety of procedures are currently in routine use to obtain tumor biopsies 
in pediatric patients. Such procedures are increasingly being used in the clinical care of 
children with relapsed and refractory tumors in order to facilitate clinical molecular testing. 
Published case series have revealed an estimated overall major complication rate of SAEs 
of < 2% for biopsy of non-CNS tumors and slightly higher for CNS tumors, with some 
variability depending on the specific procedure and tumor site. For children with relapsed 
or refractory cancer, this level of risk appears commensurate with the potential for direct 
benefit in the context of the precision oncology Pediatric MATCH study. The risk of 
complications from the procedure is significantly lower than what has been observed for 
children of similar clinical status participating on phase I trials, for whom dose-limiting 
(severe, life threatening or fatal) toxicities in the range of 15 to 25% have been reported.40,41 
Moreover, although additional data will be required to further evaluate the overall response 
rates for novel molecularly-targeted therapeutics in biomarker positive patients, data such 
as that reported for the pediatric phase I crizotinib study (in which responses were observed 
in 12/27 (44%) patients with known activating ALK aberrations)42 suggest that utilizing a 
genotypically-driven approach may result in higher response rates than the historical rate 

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of 5 to 10% for pediatric phase I trials.40,41 In this context, utilization of the proposed range 
of biopsy procedures in order to make Pediatric MATCH broadly accessible to children 
with relapsed or refractory solid tumors and non-Hodgkin lymphomas appears justified. In 
particular, we believe that it is critically important to include children with CNS tumors, 
given both the clinical need for these patients and the observed rate of potentially 
actionable mutations in their tumors. For example, no effective chemotherapy options exist 
for children with high grade gliomas- extremely poor prognosis tumors known to harbor 
recurrent genetic alterations that are theoretically targetable by agents being prioritized for 
Pediatric MATCH43, including mutations in MAPK pathway mutations as well as fusions 
involving BRAF, NTRK and FGFR genes. 
 
2.2 
Germline Testing in Children with Cancer  
The Pediatric MATCH study proposes to sequence tumor DNA obtained from patients with 
relapsed or refractory solid tumors and non-Hodgkin lymphomas using a panel of selected 
genes in order to assign targeted therapies based on the actionable mutations detected in 
each patient’s tumor. The genetic alterations identified by such tumor sequencing can 
represent either somatic (tumor-specific) mutations or germline (constitutional) variants.44-
47 Although bioinformatic methods can be used to attempt to distinguish between these two 
possibilities, current methods are not adequate for this purpose.45 Hence, the determination 
of whether a variant is somatic or germline requires the analysis of a patient-matched non-
malignant tissue sample, most frequently blood, in addition to a tumor specimen. 
 
Specific tumor types are known to be associated with underlying germline cancer 
susceptibility genes (e.g. retinoblastoma and RB1; adrenocortical carcinoma and TP53; 
atypical teratoid-rhabdoid tumor and SMARCB1/SMARCA4).9 Recently, next-generation 
sequencing studies (including whole exome sequencing) of diverse cohorts of childhood 
cancer patients have revealed that approximately 10% of unselected patients harbor a 
pathogenic or likely pathogenic germline variant, as defined by the American College of 
Medical Genetics,48 in a cancer susceptibility gene.3,45,49,50 Importantly, many of the 
germline cancer gene variants revealed by this testing were not previously associated with 
the specific tumor type diagnosed in the patient, as has also been observed in adult cancer 
patients.47 Although most germline cancer variants are not considered targetable (with 
some exceptions, such as the use of PARP inhibitors in patients with germline 
BRCA1/BRCA2 variants) and thus not the primary focus in precision oncology trials, their 
identification can offer potential clinical benefit by guiding genetic counseling and 
preventive care of both the patient and their family.51-53 
 
Rationale for germline testing approach for Stage 1 of Pediatric MATCH (patients 
enrolled from start of study in July 2017 through 12/31/21): 
 
A number of the genes that are included on the current version of the Oncomine Cancer 
Panel (ThermoFisher/Life Technologies) are known to be germline cancer susceptibility 
genes (see list of examples below), in addition to being targeted by somatic mutations. 
Additional germline cancer susceptibility genes are being added to the revised version of 
the panel that we will utilize for the Pediatric MATCH study.  
 
A. Genes with full coding sequence analyzed: APC, ATM, BAP1, BRCA1, BRCA2, 
CDKN2A, CDH1, MSH2, NF1, NF2, PTCH1, PTEN, RB1, SMAD4, SMARCB1, 
STK11, TP53, TSC1, TSC2, VHL, WT1 
B.  Genes with hotspots analyzed: ALK, CDK4, CHEK2, EGFR, EZH2, GATA2, 
HNF1A, HRAS, KIT, MET, MLH1, PDGFRA, RET 

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The value of the Pediatric MATCH study – to patients and families as well as the scientific 
community – will be maximized by parallel sequencing of germline (blood) DNA using 
the same panel as for the tumor sequencing. This will allow determination of which 
mutations of interest (MOIs) and actionable mutations of interest (aMOIs) may represent 
germline variants in cancer susceptibility genes so that the patient and family can receive 
appropriate counseling and follow-up care. Equally important, it will clarify which variants 
detected in tumor DNA are NOT present in the germline, thereby relieving patients, 
families and oncologists of concern about germline risk and avoiding unnecessary 
workups. We believe that this germline testing is indicated, given: (i) the frequency of 
pathogenic and likely pathogenic germline cancer susceptibility variants in childhood 
cancer patients, (ii) the probability of detecting such variants (if present) using the selected 
study mutation panel, (iii) the clinical relevance of reporting those variants for the care of 
both childhood cancer patients and families, (iv) the ability of the COG to devise an 
efficient and responsible plan for return of these results to patients/families and their 
oncologists, (v) the reduction in recommendations for follow-up genetic evaluation for the 
majority of subjects with tumor only results, and (vi) the need to develop best clinical 
practice for responding to germline variants given the likelihood that systematic evaluation 
for inherited cancer susceptibility will likely become a routine part of pediatric oncology 
practice in the near future. Finally, we anticipate that this germline testing will provide rich 
scientific information about inherited predisposition to childhood cancer, including among 
children who are not found to have targets for therapy by tumor-focused sequencing. 
 
The purpose of Pediatric MATCH study germline testing is to determine which of the 
variants that are being identified by tumor sequencing may actually be germline in nature 
and not to provide a comprehensive cancer susceptibility evaluation. This will be 
emphasized to the oncologists and within the informed consent document, which will also 
describe the potential risks of germline sequencing, namely: (i) anxiety related to the 
performance of genetic testing or the identification of a germline cancer susceptibility 
variant, and (ii) the risk of loss of privacy of genetic information resulting from such 
testing. Recent data suggest that the vast majority of parents of childhood cancer patients 
believe that the potential benefits of clinical genomic testing (including both somatic and 
germline results of clinical relevance) outweigh these risks. As one example, the parents 
of only ~10%  of newly-diagnosed childhood cancer patients eligible for the BASIC3 
clinical and tumor germline exome sequencing study (which, unlike the Pediatric MATCH 
study, does not offer the potential benefit of availability of investigational molecularly-
targeted agents) have reported declining study enrollment due to concerns about either 
anxiety from genetic testing results or privacy risks54 [and DW Parsons, personal 
communication]. Interviews of parents of BASIC3 study subjects have provided further 
evidence for this positive risk-benefit calculation in the context of a childhood cancer 
diagnosis. 55 
 
In summary, current evidence and experience with the identification and reporting of 
germline cancer susceptibility variants for childhood cancer patients provide strong support 
for a Pediatric MATCH study approach in which blood samples are also analyzed in order 
to provide information about the somatic or germline nature of the variants identified 
through tumor sequencing. This approach simplifies the follow-up evaluation by the 
oncologist for the majority of subjects with tumor only findings and offers potential clinical 
benefit to study subjects and their families, including those patients who will not qualify to 
receive study therapy due to lack of a targetable mutation.  
 

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As of Amendment #4: Germline testing in Stage 2 of Pediatric MATCH (for patients 
enrolled starting in 2022): 
 
In Stage 2 of Pediatric MATCH no centralized tumor testing will be performed as the study 
will rely exclusively on review of tumor molecular profiling results from outside clinical 
laboratories. Accordingly, no tumor mutations will be reported by Pediatric MATCH 
laboratories that could represent germline cancer susceptibility variants, eliminating the 
need for parallel (centralized) clinical testing of patient blood samples to determine the 
somatic or germline nature of variants included in tumor reports. Patient blood samples 
will be collected for research studies only. 
 
2.3 
Circulating Tumor DNA (ctDNA) 
One appealing alternative approach to tumor sequencing for identifying gene variants 
includes sequencing circulating tumor (ct) DNA found in patient plasma, also known as 
liquid biopsy studies. This approach also allows for quantification and serial tracking of 
ctDNA, which could be used to assess disease burden and treatment response. Liquid 
biopsy technologies have demonstrated superior detection and quantification rates 
compared to assays for circulating tumor cells.56 Furthermore, ctDNA can be reliably 
extracted from plasma using commercially available kits making it feasible for any clinical 
or research laboratory to draw and ship appropriate samples for ctDNA studies. The 
integrity of ctDNA can be further enhanced by the use of specialized blood tubes, such as 
Streck Cell-Free DNA BCT tubes, widely employed for circulating fetal DNA studies and 
increasingly utilized in ctDNA assays. Many reports have now demonstrated the clinical 
utility of detecting and quantifying circulating tumor DNA from patients with solid 
tumors.56,57 These assays have been used to assess disease burden, track disease response 
to therapy, identify clonal evolution, and predict relapse after remission. However, the 
application of cell free DNA technologies has yet to be applied systematically in pediatric 
solid tumors. In this study, we propose to collect plasma samples from patients prior to 
therapy to aid in ongoing studies to develop and assess ctDNA analysis strategies in solid 
tumors. 
2.4 
Overview of Proposed Pediatric MATCH Study 
The Pediatric MATCH study will consist of a screening protocol to screen for eligibility to 
pathway-targeting specific subprotocols. This screening protocol will specify subject 
eligibility; details and logistics of tumor acquisition and molecular analysis as well as of 
reporting; response and adverse event evaluation criteria and stopping rules; the schedule 
of required observations; and the overall statistical plan. Consent for participation in the 
screening protocol will include consent and assent for: 
 
• 
tumor genetic analysis and return of tumor sequencing results in Stage 1 of the trial 
• 
As of Amendment #4: review of submitted tumor molecular profiling results 
from outside laboratories in Stage 2 of the trial 
• 
concept of molecularly targeted therapy, if match is identified 
• 
possibility of assignment of patients with non-target-bearing tumors to selected 
agents that have demonstrated activity in target-bearing tumors  
• 
optional research studies including further genomic characterization of tumor and 
blood samples and analysis of an archived specimen obtained prior to treatment 
(and prior to relapse/progression), if available 
 
Individual agent-specific subprotocols will be developed for each treatment agent/regimen. 
Some subprotocols may include more than one primary cohort (each with different 

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molecular eligibility criteria). The subprotocols will contain any additional treatment-
specific eligibility criteria and the treatment plan including monitoring for adverse events, 
as well as pharmaceutical information, etc. There will be an agent-specific consent for each 
subprotocol that details the specific risks of the agent. 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every 
patient with a known or suspected neoplasm needs to be offered participation in 
APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix VII for detailed CTEP Registration Procedures for 
Investigators and Associates, and Cancer Trials Support Unit (CTSU) Registration 
Procedures including: how to download site registration documents; requirements 
for site registration, submission of regulatory documents and how to check your 
site’s registration status. 
 
3.1.2 
IRB Approval 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies 
open to the National Clinical Trials Network (NCTN) and NCI Community 
Oncology Research Program (NCORP) Research Bases. In addition, U.S.-based 
sites must accept the NCI CIRB review to activate new studies at the site after 
March 1, 2019. Local IRB review will continue to be accepted for studies that are 
not reviewed by the CIRB, or if the study was previously open at the site under the 
local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific 
regulations. 
 
Sites participating through the NCI CIRB must submit the Study Specific 
Worksheet 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 

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automatically communicated to the CTSU Regulatory Office, but sites are required 
to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to 
establish site preferences for applying NCI CIRB approvals across their Signatory 
Network. Site preferences can be set at the network or protocol level. Questions 
about establishing site preferences can be addressed to the CTSU Regulatory 
Office by email (CTSURegPref@ctsu.coccg.org) or by calling 1-888-651-CTSU 
(2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on 
the IRB/REB approval) must meet the following criteria for the site to be able to 
have an Approved status following processing of the IRB/REB approval record: 
• 
Have an active CTEP status; 
• 
Have an active status at the site(s) on the IRB/REB approval (applies to 
US and Canadian sites only) and on at least one participating 
organization’s roster; 
• 
If using NCI CIRB, be active on the NCI CIRB roster under the 
applicable CIRB Signatory Institution(s) record; 
• 
Include the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; 
• 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and 
• 
Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
• 
Compliance with all applicable protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix VII. 
 
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. 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 

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approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. 
 
3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or the Theradex 
Interactive 
Web 
Response 
System 
(IWRS) 
for 
retrieval 
of 
patient 
registration/randomization assignment. OPEN will populate the patient enrollment 
data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:  
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems;  
• 
To perform enrollments or request slot reservations:  Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an 
Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DLT) is required for the study, the 
registrars must hold the OPEN Registrar task on the DLT for the site; 
and 
• 
Have an approved site registration for the protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the Institutional Review Board (IRB) number 
used on the site’s IRB approval on their Form Food and Drug Administration 
(FDA) 1572 in the Registration and Credential Repository (RCR). If a DTL is 
required for the study, the IVR or NPIVR must be assigned the appropriate OPEN-
related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 

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3.2 
Procedures for Eligibility to Screening Protocol 
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 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.  
 
3.3 
Genetic Screening Procedures for Eligibility to Subprotocols 
 
3.3.1 
Screening approach for Stage 1 of Pediatric MATCH (patients enrolled from 
start of study in July 2017 through 12/31/21): 
 
Tumor and blood samples will be obtained from patients who enroll in the study 
through December 31, 2021. The results of the evaluation of the tumor specimens 
will determine if the patient's tumor has an actionable Mutation of Interest (aMOI) 
for which a MATCH treatment subprotocol is available. 
• 
A tumor sample for screening is obtained from enrolled patients (see 
Section 5.2, Biopsy Methods, for additional information). 
• 
A blood sample is obtained for germline testing. 
• 
Tumor and blood samples are submitted to the COG Biopathology 
Center (BPC) at Nationwide Children’s Hospital in Columbus, Ohio 
for pre-analytic processing, including DNA and RNA extraction, and 
quality control. 
• 
FFPE specimens for immunohistochemistry (IHC) testing will be 
forwarded from the Biopathology Center to the MDACC clinical 
laboratory. 
• 
The nucleic acid analytes (DNA/RNA) will be forwarded from the 
Biopathology Center to one of the CLIA-certified laboratories in the 
MATCH study-specific network for molecular profiling (MDACC, the 
NCI Molecular Characterization Laboratory (Frederick, MD) and 
Dartmouth) to assess for the presence of specific, pre-defined 
actionable mutations, amplifications or translocations of interest 
(aMOIs).  
• 
The laboratories will report whether or not an aMOI for patient 
assignment to one of the clinical trial subprotocols has been detected to 
the NCI informatics pipeline (MATCHbox). 
• 
The automated rules engine in MATCHbox will generate a list of 
potential treatment assignments (TA) and the highest priority TA will 
be determined. 
• 
The highest priority TA (or notification if no match was available) will 
be sent to the COG Operations Office. This will then be made 
available to the registering site via CTSU OPEN/Medidata Rave, with 
an email sent as notification of available TA (or if no match was 
available) approximately 14 days after receipt of the patient’s tumor 
sample at the BPC. The BPC does not provide testing results: any 

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inquiries about treatment assignments or results should be 
directed to the COG study chair and COG research coordinator. 
• 
Patient is assessed for subprotocol eligibility and patient/family 
consents to treatment with the indicated agent in the trial subprotocol. 
• 
If the patient is ineligible for the highest priority TA, the treatment 
assignment process is repeated, in order of priority, until either all TAs 
are exhausted or the patient is confirmed eligible and is registered to a 
treatment subprotocol. 
• 
In cases where insufficient tumor is obtained for biomarker analysis, 
the enrolling site will be notified by the BPC and given the option of 
providing an additional tumor sample for screening. 
• 
When each new treatment subprotocol is added, the informatics 
process will review previous test results for subjects who have been 
enrolled on the screening protocol within the past two years and report 
if there is a new treatment assignments (i.e. if there are any patients 
with a mutation that is an aMOI for the new subprotocol).  
3.3.2 
As of Amendment #4: Screening approach for Stage 2 of Pediatric MATCH 
(for patients enrolled starting 2022): 
A clinical tumor molecular profiling report from a CAP/CLIA-approved 
laboratory will be submitted for patients who enroll in the study. The treating 
COG site will indicate which molecular alteration in the submitted report they 
believe to be actionable and the open Pediatric MATCH study arm for which the 
patient is thought to be eligible.  
 
NOTE: patients should only be enrolled in APEC1621SC if the treating 
clinician/site believes that the tumor molecular profiling report submitted 
for review contains an actionable mutation for an open Pediatric MATCH 
treatment subprotocol. 
 
The results of the evaluation of this report by the Pediatric MATCH Molecular 
Review Committee (MRC) will determine if the patient's tumor has an actionable 
Mutation of Interest (aMOI) for which a MATCH treatment subprotocol is 
available. The levels of evidence used to define mutation actionability will remain 
as defined from the start of the study (Appendix III). The MRC will be composed 
of oncologists and molecular pathologists with specific expertise in interpretation 
of genomic testing results, including the screening protocol COG study chair, vice 
chair, and pathologists. 
• 
The MRC will generate a list of potential treatment assignments (TA) 
and the highest priority TA will be determined. 
• 
The highest priority TA (or notification if no match was available) will 
be sent to the COG Operations Office. This will then be made available 
to the registering site via CTSU OPEN/Medidata Rave, with an email 
sent to the treating institution as notification of available TA (or if no 
match was available) within one week after submission of the patient’s 
tumor molecular testing report. 
• 
Patient is assessed for subprotocol eligibility and patient/family consents 

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to treatment with the indicated agent in the trial subprotocol. 
• 
If the patient is ineligible for the highest priority TA, the treatment 
assignment process is repeated, in order of priority, until either all TAs 
are exhausted or the patient is confirmed eligible and is registered to a 
treatment subprotocol. 
3.4 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternatives 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.  
 
3.5 
Eligibility Checklist 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist, documenting that the patient meets the criteria in 
Section 4.1 for study enrollment.  A signed copy of the checklist will be uploaded into 
RAVE immediately following enrollment. 
 
NOTE: For enrollment onto the APEC1621SC screening protocol, patients do not need to 
meet all criteria described in Section 4.2 for subprotocol eligibility. However, patients will 
need to meet all criteria prior to enrollment on any assigned treatment subprotocol.  
Investigators are encouraged to consider these criteria when determining appropriateness 
and timing of enrollment onto the screening protocol. 
 
3.6 
Institutional Pathology Report 
 
3.6.1 
Pathology report submission procedure for Stage 1 of Pediatric MATCH 
(patients enrolled from start of study in July 2017 through 12/31/21): 
Immediately following enrollment, the institutional pathology report from the 
tumor specimen to be submitted for sequencing must be uploaded into RAVE. The 
report must include the associated study number and COG patient registration and 
accession numbers. Personal identifiers, including the patient’s name and initials 
must be removed from the institutional pathology report prior to submission. The 
surgical pathology ID (SPID) from the report will be used by the BPC to link the 
report to the tumor specimen. 
 
3.6.2 
As of Amendment #4: Pathology report submission procedure for Stage 2 of 
Pediatric MATCH (for patients enrolled starting 2022): 
Immediately following enrollment, the institutional pathology report for the same 
tumor specimen analyzed in the submitted molecular profiling report (Section 3.3) 
must be uploaded into RAVE using the same procedures as described for Stage 1 
(Section 3.6.1). 
 

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3.7 
As of Amendment #4: Institutional Tumor Molecular Profiling Report (Stage 2 of 
Pediatric MATCH only) 
Immediately following enrollment, the clinical tumor molecular profiling report which will 
be used to evaluate the tumor specimen treatment assignment must be uploaded into 
RAVE. The report must include the associated study number and COG patient registration 
and accession numbers. Personal identifiers, including the patient’s name and initials must 
be removed from the institutional molecular report prior to submission. 
 
If a patient enrolled on APEC1621SC has clinical molecular tumor profiling performed on 
a sample obtained at a later date (i.e. not the tumor report initially reviewed for Pediatric 
MATCH) this report can be submitted for review by the Molecular Review Committee as 
described above. An institutional pathology report must also be submitted as described in 
Section 3.6 above that corresponds to the same sample as the new molecular profiling 
report. 
 
At the time of APEC1621SC enrollment, the treating COG site must indicate which 
molecular alteration in the submitted report they believe to be actionable and the open 
Pediatric MATCH study arm for which the patient is thought to be eligible. This will be 
indicated in the CRFs in Medidata Rave. 
 
The tumor profiling test submitted must be capable of identifying actionable mutations as 
defined in the relevant treatment subprotocol. It is anticipated that these will most often be 
next-generation sequencing tests of DNA (to identify single nucleotide variants, insertions, 
deletions, and gene amplifications) and/or RNA (to identify gene fusions). Examples of 
such tests would be FoundationOne Heme, TempusxT, CARIS DNA sequencing and 
CARIS RNA sequencing.  
 
Examples of report types that cannot be submitted for review and cannot be used to 
determine eligibility for Pediatric MATCH treatment subprotocols include: 
• 
Immunohistochemistry (IHC) reports 
• 
Cytogenetics reports 
• 
Fluorescence in situ hybridization (FISH) reports 
 
Any questions about whether a specific report is acceptable or mutation is actionable can 
be referred to the COG study chair and vice chair (Drs. Parsons and Janeway) who will 
consult with the Molecular Review Committee (MRC) as required. 
 
3.8 
Study Enrollment Instructions for Subprotocols 
Patients may be enrolled on the APEC1621SC screening protocol if they meet the 
eligibility criteria in Section 4.1. Patients who give informed consent for the protocol in 
order to eligibility assessments are not considered enrolled and should not be enrolled until 
the eligibility assessments are completed and they are determined to meet all eligibility 
criteria. 
 
Patients must be enrolled onto a therapeutic subprotocol within 2 weeks (14 days) of 
treatment assignment. Subprotocol therapy must start no later than 7 calendar days after 
the date of enrollment to the subprotocol. 
 
Note:  Drug orders should be placed with CTEP with consideration for timing of 
processing and shipping to ensure receipt of drug supply prior to start of protocol 
therapy onto a subprotocol. No starter supplies will be provided and agents can be 

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ordered only after the patient is registered to a subprotocol. 
 
3.8.1 
Reassignment Request (if unable to enroll within 2 week timeframe): 
The treating team may email PedsMATCHOps@childrensoncologygroup.org and 
the 
APEC1621SC 
study 
co-chairs 
(dwparson@texaschildrens.org, 
seibelnl@mail.nih.gov) with a request for a single treatment re-assignment for any 
patient who was previously matched to a therapeutic subprotocol arm, but were 
unable to enroll during the original specified reservations window. The request can 
be made within a year of the ‘Pediatric MATCH-Reservation expiration date’ 
stipulated in the original treatment assignment email when the patient was 
assigned. The treatment re-assignment request is subject to slot availability on the 
therapeutic subprotocol at the time of the request.  
 
 
4.0 
PATIENT ELIGIBILITY FOR TARGET SCREENING 
 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01).  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 
Eligibility Criteria for Enrollment onto APEC1621SC 
 
4.1.1 
Age: Patients must be ≥ 12 months and ≤ 21 years of age at the time of study 
enrollment. 
 
4.1.2 
Diagnosis: Patients with recurrent or refractory solid tumors, including non-
Hodgkin lymphomas, histiocytoses (e.g. LCH, JXG, histiocytic sarcoma), and 
CNS tumors are eligible.  Patients must have had histologic verification of 
malignancy at original diagnosis or relapse except in patients with intrinsic brain 
stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations 
of CSF or serum tumor markers including alpha-fetoprotein or beta-HCG. In cases 
where patient enrolls prior to histologic confirmation of recurrent disease, patient 
is ineligible and should be withdrawn from study if histology fails to confirm 
recurrence. Please Note: Patients with Hodgkin lymphoma and plexiform 
neurofibroma are not eligible.  
 
4.1.3 
Tumor Testing Requirement: Tumor sample availability requirement for Stage 1 
of Pediatric MATCH (patients enrolled from start of study in July 2017 through 
12/31/21) :  
Patients must have an FFPE tumor sample available for MATCH study testing 
from a biopsy or surgery that was performed at any point after initial tumor 
recurrence/progression, or be planned to have a procedure to obtain such a sample 
that is considered to be of potential benefit by the treating clinicians including but 
not limited to the procedures listed in Section 5.2 below. A tumor sample from a 
clinically performed diagnostic (pre-treatment) biopsy will be acceptable for 
enrollment onto Pediatric MATCH only for children with high-grade gliomas of 
the brainstem (diffuse intrinsic pontine gliomas) or thalamus. 
  

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Please note: Samples that have been decalcified using standardly utilized acid-
based decalcification methods are not generally suitable for MATCH study 
testing; the nucleic acids will have been degraded in the decalcification 
process.  
 
4.1.4 
Tumor molecular profiling report availability requirement for Stage 2 of Pediatric 
MATCH (patients enrolled starting 2022):  
In Stage 2 of the study, no tumor samples will be submitted for centralized clinical 
tumor profiling. Instead, a tumor molecular profiling report from a CAP/CLIA-
approved testing laboratory must be submitted for review by the Molecular Review 
Committee (MRC) as described in Section 3.8.  
 
This molecular profiling must have been performed on a tumor sample that 
was obtained at any point after initial tumor recurrence/progression and must 
be accompanied by a pathology report for the same tumor specimen as 
specified in Section 3.7. A molecular profiling report for a diagnostic (pre-
treatment) tumor sample will be acceptable for enrollment onto Pediatric MATCH 
only for children with high-grade gliomas of the brainstem (diffuse intrinsic 
pontine gliomas) or thalamus. In the event that molecular profiling reports are 
available from multiple timepoints, the most recent report should be prioritized for 
study submission.  
4.1.5 
Performance Status: Karnofsky ≥ 50% for patients > 16 years of age and Lansky 
≥ 50 for patients ≤ 16 years of age). Note: Neurologic deficits in patients with CNS 
tumors must have been stable for at least 7 days prior to study enrollment. Patients 
who are unable to walk because of paralysis, but who are up in a wheelchair, will 
be considered ambulatory for the purpose of assessing the performance score. 
4.1.6 
Disease Status: Patients must have radiographically measurable disease (Refer 
to Section 12). Measurable disease based on imaging obtained less than or 
equal to 56 days prior to 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. 
 
4.2 
General Inclusion Criteria for Subprotocols 
NOTE: patient does not need to meet all subprotocol criteria at time of enrollment onto the 
APEC1621SC screening protocol, but will need to meet all criteria prior to enrollment on 
any assigned treatment subprotocol. Patients must be enrolled onto a subprotocol within 2 

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weeks (14 days) of treatment assignment. 
 
4.2.1 
Performance Status: (See Section 4.1.4) 
 
4.2.2 
Disease Status: At the time of treatment with subprotocol specified therapy, 
the patients must have radiographically measurable disease. (See Section 12). 
Patients with neuroblastoma who do not have measurable disease but have MIBG+ 
evaluable 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. 
 
4.2.3 
Prior Therapy: At the time of enrollment onto a subprotocol, the following 
general criteria for initiation of therapy will be required: 
4.2.3.1 Patients must have fully recovered from the acute toxic effects of all prior 
anticancer therapy and must meet the following minimum duration from 
prior anticancer directed therapy prior to enrollment to the subprotocol. If 
after the required timeframe, the numerical eligibility criteria are met, e.g. 
blood count criteria, the patient is considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anticancer agents known to be 
myelosuppressive.  
See https://www.cogmembers.org/site/disc/devtherapeutics/def
ault.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.≥ 21 days after the last 
dose of cytotoxic or myelosuppressive chemotherapy (42 days if 
prior nitrosourea).  
 
b. Anticancer 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/devtherapeutics/def
ault.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 

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recovered to Grade ≤ 1. 
 
d. Corticosteroids: 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. Neulasta) or 7 days for short-acting growth 
factor. For agents that have known adverse events occurring beyond 7 
days after administration, this period must be extended beyond the 
time during which adverse events are known to occur.  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 Hematopoietic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoietic Growth Factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
≥ 50% of the pelvis; ≥ 42 days if other substantial BM radiation.  Note: 
Radiation may not be delivered to “measurable disease” tumor site(s) 
being used to follow response to subprotocol treatment. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): 
≥ 
42 
days 
after 
systemically 
administered 
radiopharmaceutical therapy. 
4.2.4 
Organ Function Requirements 
4.2.4.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 
- 
Platelet count ≥ 100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. 
Patients with known bone marrow metastatic disease will be 
eligible for study provided they meet the blood counts in 4.2.4.1.a 
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  

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4.2.4.2 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 utilizing child length and stature data published 
by the CDC.58 
 
4.2.4.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT) ≤ 135 U/L.  (For the purpose of this study, the ULN for 
SGPT is 45 U/L.)  
 
4.2.5 
Patients must be able to swallow intact capsules/tablets, unless otherwise specified 
in the subprotocol to which they are assigned. 
 
4.2.6 
Agent specific limitations on prior therapy will be included with specific treatment 
subprotocols.  
 
4.3 
General Exclusion Criteria for Subprotocols 
 
4.3.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies, or because 
there is currently no available information regarding human fetal or teratogenic 
toxicities. Pregnancy tests must be obtained in females who are post-menarcheal. 
Males or females of reproductive potential may not participate unless they have 
agreed to use an effective contraceptive method. 
4.3.2 
Concomitant Medications 
 
4.3.2.1 Corticosteroids: At the time of consent and enrollment to regimen specific 
subprotocols, patients receiving corticosteroids who have not been on a 
stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment to the subprotocol will not be eligible. If used to modify 
immune adverse events related to prior therapy, ≥ 14 days must have 
elapsed since last dose of corticosteroid. 
 
4.3.2.2 Investigational Drugs: Patients must meet criteria for prior therapy 
(Section 4.2.3) at the time of consent and enrollment to a subprotocol. 

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Other investigational agents may not be administered to patients while 
they are receiving study drug as part of a subprotocol (See Section 8). 
 
4.3.2.3 Anticancer Agents: Patients must meet criteria for prior therapy (Section 
4.2.3) at the time of consent and enrollment to a subprotocol. Other 
investigational agents may not be administered to patients while they are 
receiving study drug as part of a subprotocol (See Section 8). 
 
4.3.2.4 Anti-GVHD agents post-transplant: Patients who are receiving 
cyclosporine, tacrolimus or other agents to prevent graft-versus-host 
disease post bone marrow transplant are not eligible. 
 
4.3.3 
Infection: Patients who have an uncontrolled infection are not eligible. 
 
4.3.4 
Patients who have had a prior solid organ transplant are not eligible. 
4.3.5 
Additional agent specific criteria will be included with specific treatment 
subprotocols. 
 
 
5.0 
SUBMISSION OF EVALUATIONS/MATERIAL AND DATA FOR TARGET 
SCREENING  
 
5.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility (see Section 4.0) must be 
performed within 7 days prior to enrollment unless otherwise indicated. Platelet count 
should be obtained within 48 hours prior to biopsy. For treatment subprotocols, imaging 
studies and other required testing must be obtained as required by the subprotocol. 
 
The following studies are required pre-study and then until the patient is enrolled onto a 
subprotocol or until the patient is off study as defined in Section 10.1.  
 
STUDIES TO BE OBTAINED 
Pre-Study/ Enrollment 
History 
X 
Physical exam with vital signs 
X 
Performance Status 
X 
Blood sample (K2 EDTA tube) for genomics 
research, if available 
X 
Relapsed tumor sample for genomics research, if 
available 
X 
Blood sample (Streck tube) for ctDNA research, if 
available 
X 
Diagnostic (pre-relapse) tumor sample for 
additional genomics research, if available 
X 
Note: All Follow-up data, which includes all anti-cancer therapies received after 
enrollment must be submitted in accordance with the Case Report Forms (CRFs) schedule. 
 
5.2 
Biopsy Methods and Complication Monitoring 
 
Stage 1 of Pediatric MATCH (patients enrolled from start of study in July 2017 
through 12/31/21) 
 
 

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5.2.1 
Examples of biopsy procedures.  
 
 
 
           
No biopsies performed exclusively for research purposes will be utilized to obtain 
tumor samples for the Pediatric MATCH study. Procedures such as those listed 
below are routinely used to obtain tumor tissue in patients for whom the procedure 
is deemed to offer potential clinical benefit. Decision about the indication for 
biopsy in an individual patient will be made by the treating clinicians. 
• 
Percutaneous biopsy, including image-guided studies 
• 
Excisional biopsy of readily accessible lesions (e.g. cutaneous or 
subcutaneous lesions, superficial lymph nodes) 
• 
Laparoscopic or thoracoscopic biopsy 
• 
Needle biopsy, including stereotactic biopsy, of CNS tumors 
• 
Endoscopic biopsy of CNS tumors 
• 
Other minimally-invasive biopsy procedures 
 
5.2.2 
Biopsies of patients with high-grade gliomas of the brainstem and thalamus. 
 As children with diffuse intrinsic pontine gliomas (DIPG, brainstem gliomas) 
generally progress following initial standard radiation therapy, tumor samples 
from clinically performed diagnostic (pre-treatment) biopsies will be acceptable 
for enrollment onto Pediatric MATCH for children with such tumors. 
 
5.2.3 
In the event that multiple post-recurrence/progression tumor samples are available, 
the sample from the most recent procedure should be prioritized for study testing. 
 
5.2.4 
Any complications associated with tumor samples for Pediatric MATCH:   biopsy 
or biopsy-related anesthesia or imaging procedures performed after consent to this 
study will be reported and tracked as outlined in Section 6.3. 
 
As of Amendment #4: Stage 2 of Pediatric MATCH (patients enrolled starting 
1/01/22): Starting in Stage 2 of Pediatric MATCH, no tumor samples are being submitted 
for central clinical testing as part of the study and no biopsy-related complications will be 
reported or tracked. 
 
5.3 
Pathology Guidelines and Specimen Requirements 
Before entering patients on this trial, clinicians should discuss this protocol with their 
pathologist and provide them with the protocol and list of the required materials that will 
need to be submitted.  
 
It is the responsibility of the Principal Investigator at the institution to ensure that the 
pathologist is informed and to request that all patient specimens be forwarded to the COG 
Biopathology Center (BPC), as required. The BPC will NOT request materials. 
 
5.4 
Imaging Procedures 
The use of imaging to facilitate biopsies will be decided by the clinical site and may include 
the following baseline imaging: FDG-PET, CT scan, or MRI which will be used for tumor 
disease evaluation. Should CT scan be needed for biopsy, the number of scans for each 
procedure will be limited to the minimum number needed to safely obtain a biopsy.  
 
5.5 
Genomic Platform and Reporting 
 
Genomic platform and reporting for Stage 1 of Pediatric MATCH (patients enrolled 
from start of study in July 2017 through 12/31/21) 

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The Pediatric MATCH study will employ an analytically validated next-generation 
sequencing targeted assay of more than 4,000 different mutations of interest (MOIs; SNVs, 
indels, copy number alterations, gene fusions) across more than 140 genes (see Appendix 
I for gene list). This assay will be coupled to a computer algorithm (MATCHbox), that was 
initially developed for the adult NCI MATCH study and will be further optimized for the 
pediatric study, that uses pre-existing definitions of actionable mutations of interest 
(aMOIs) and prioritization of target-agent pairs, combined with clinical criteria specific to 
each subprotocol, to assign patients by actionable mutation results to a targeted treatment. 
The aMOIs (a subset of MOIs) and subprotocol-specific clinical criteria for use in the 
MATCHbox algorithm will be defined for each agent/subprotocol at the time of 
subprotocol development. The sequencing assays will be performed in one of the NCI 
MATCH CLIA-approved laboratories that are performing tumor sequencing for the adult 
MATCH study.  
 
A Platform and Sequencing Committee was formed to evaluate and recommend a plan for 
the testing to be performed on Pediatric MATCH. The committee reviewed available 
options for sequencing platforms and determined that an adaptation of the ThermoFisher 
Oncomine panel developed for the adult MATCH study would be preferred. The committee 
then reviewed the contents of the current version of the panel being used for adult MATCH 
at both the gene and variant level, reviewed the pediatric literature for specific 
genes/variants (including CNVs, SNVs, indels, and fusions) relevant to high-priority 
Pediatric MATCH agents that would need to be included, and have provided these 
recommendations as the next version of the platform is currently  being developed (e.g. the 
version of the platform that will be utilized for Pediatric MATCH). For example, the 
committee provided specific information about the spectrum of ALK and FGFR4 
mutations observed in pediatric cancers and recommended inclusion of the full coding 
sequences of SMARCA4 and SMARCB1 (INI1) in anticipation of a potential EZH2 
inhibitor arm of the study. The lead investigator for each subprotocol developed will work 
with the Target and Agent Prioritization committee and Platform Sequencing and Analysis 
committee in order to define the relevant genes and aMOIs within those genes for that 
subprotocol at the time of protocol development. 
 
An extensive validation of the mutation panel being used for the adult NCI MATCH study 
has previously been performed to establish the performance of this test, including treatment 
assignment using MATCHbox.  In addition, analytic performance plans have now been 
developed in order to further confirm the performance of the mutation panel using (1) 
pediatric tumor samples harboring genetic alterations that have previously been identified 
by testing in clinical laboratories and (2) blood samples harboring germline genetic 
alterations that have previously been identified by testing in clinical laboratories. These 
plans include a full assay system fit-for-purpose experiment in which clinical blood and 
tumor specimens will be obtained from either core needle biopsies, tumor resections, or 
archived FFPE specimens collected according to study protocols.  This effort will test the 
entire MATCH specimen workflow system from sample collection, clinical database 
tracking, specimen shipment, central pre-analytic processing, nucleic acid extraction and 
quantity/quality checks, IHC testing, nucleic acid shipment, NGS testing in the laboratory 
network, NGS assay verification and reporting, MATCHbox treatment selection and 
reporting.  
 
Sequencing of matched patient blood samples using the same cancer gene mutation panel 
will be performed in parallel with tumor sequencing in order to allow the somatic (tumor-
specific) or germline nature of mutations detected by the panel to be determined. A 

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germline results report, separate from the tumor report, will be generated by a clinical 
genomics lab with the appropriate expertise and experience to interpret a hereditary cancer 
panel and returned to treating physicians as soon as possible after the tumor reports are 
provided. Note: study treatment assignment will be based exclusively on results of tumor 
sequencing. Results obtained from sequencing of blood samples will not impact the process 
of tumor analysis or be separately used to determine study treatment assignment. 
 
The treatment assignment algorithm (MATCHbox) will identify the first priority study for 
each patient based on the predefined set of genetic and clinical criteria for each subprotocol. 
If more than one molecular abnormality is identified as actionable for treatment on a 
Pediatric MATCH subprotocol, the one with the greater level of evidence that tumors 
harboring the variant will respond will be used to assign treatment (see Appendix III for 
variant level of evidence definitions). For SNV/indels, if more than one actionable 
mutation of interest (aMOI) is present with equivalent level of evidence, then the 
abnormality with the higher allele frequency (must be > 15% higher than the next lower 
allele frequency) will be used to assign treatment. If two variants are equivalent using these 
2 parameters, the patient will be assigned to the subprotocol with fewer patients, or 
randomized between subprotocols if numbers of patients on the relevant subprotocols are 
equal. If a subject is not able to receive that therapy, based for example on subprotocol-
specific exclusion criteria, then they will be assigned to the second priority agent (if 
applicable), and so on in an iterative manner.  
 
The mutation panel is anticipated to be updated approximately every 12 months over the 
course of the study, to include additional genes/variants as needed based on new data in 
the literature and novel agents of interest. This will be performed in conjunction with the 
adult NCI MATCH study team and include input on priority genes and variants to be 
included to serve the pediatric MATCH study.  
 
As of Amendment #4: Genomic platform and reporting for Stage 2 of Pediatric 
MATCH (patients enrolled starting 1/01/22): 
 
In Stage 2 of Pediatric MATCH centralized tumor and blood testing will not be performed 
and the MATCHbox informatics platform will not be used as part of the treatment 
assignment process. Patient assignment to treatment subprotocols will be made after 
confirmation (by the Pediatric MATCH Molecular Review Committee, MRC) of the 
presence of an actionable mutation (aMOI) in a submitted tumor molecular profiling report 
from a CLIA-certified laboratory. Levels of evidence for mutation actionability will remain 
as defined from the start of the study. Prioritization of treatment assignments (in the event 
that the patient is eligible for more than one treatment subprotocol based upon their outside 
molecular testing results) will follow the same procedures described above for Stage 1 of 
the study. 
 
5.5.1 
Tumor and Germline Mutation Reporting 
 
Tumor and germline mutation reporting for Stage 1 of Pediatric MATCH (patients 
enrolled from start of study in July 2017 through 12/31/21): 
 
• 
A blood sample is drawn for germline sequencing from each child who 
participates in Pediatric MATCH, contingent upon parental permission/child 
assent/young adult participant consent, and sent from the COG study site to the 
COG Biopathology Center (BPC) for DNA extraction. 

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• 
The informed consent form includes specific language explaining that the 
germline sequencing results are not utilized for determination of subprotocol 
eligibility and are not intended to replace a comprehensive genetic evaluation (if 
clinically indicated) but are being used for the sole purpose of determining which 
somatic mutations are present in the germline and which are not present in the 
germline, thereby permitting further evaluation of clinically relevant germline 
mutations and alleviating concerns about somatic mutations that are not present 
in the germline. 
• 
Germline DNA is sent from the BPC to one of the designated CLIA/CAP-certified 
laboratories that is conducting tumor sequencing for the study. DNA/RNA 
extracted from the patient’s tumor sample is also sequenced in the same laboratory 
as per study procedures. 
• 
The sequencing laboratory analyzes the germline DNA using the same mutation 
panel that is being used to sequence tumor samples. 
• 
The sequencing laboratory sends the resulting germline and tumor sequence data, 
including the tumor mutation report (listing both aMOIs and MOIs), to a COG-
designated certified clinical genomics laboratory with the appropriate expertise 
and experience to interpret a hereditary cancer panel. The Baylor College of 
Medicine (BCM) and Children’s Hospital of Los Angeles (CHLA) genetics 
laboratories have been selected to perform this interpretation. 
• 
The tumor (somatic) sequencing results are used to determine potential eligibility 
for Pediatric MATCH study subprotocols as per study procedures (if an aMOI is 
identified). This notification of a potential match (or lack of a match) is sent to 
the site from COG as described above in (Section 3.3) 
• 
A tumor sequencing report (including both aMOIs and MOIs) and a tumor 
immunohistochemistry report are separately provided to the treating clinician by 
the tumor testing laboratories as soon as they are available, without any delay 
related to germline sequence analysis or reporting. This is currently done by fax. 
• 
The germline sequencing results are not utilized for determination of subprotocol 
eligibility. 
• 
The clinical genomics laboratory then generates a germline report for the specific 
purpose of determining if any of the aMOIs and MOIs included in the tumor 
sequencing report may represent pathogenic or likely pathogenic germline 
variants in cancer susceptibility genes based on ACMG/AMP variant guidelines, 
and for informing oncologists which variants included in the tumor report are not 
present in the germline.  
• 
If a pathogenic or likely pathogenic germline aMOI or MOI is identified in the 
blood sample but was not reported in the tumor analysis (due to tumor sequencing 
failure or more focal tumor sequencing coverage issues) it will be included in the 
germline report. 
• 
No confirmatory mutation testing (using an orthogonal platform) of germline 
variants identified will be performed (note this is not required by ACMG next-
generation sequencing guidelines).  
• 
If insufficient tumor DNA is available for sequencing (and therefore no tumor 
DNA sample is sent from the BPC to the sequencing laboratory) no germline 

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DNA will be sent from the BPC to the sequencing laboratory and no germline 
analysis will be performed. 
• 
The germline report will be provided to the treating institution by the clinical 
genomics laboratory, with a goal of return within one month of processing the 
blood sample for analysis. This is currently accomplished by placing a copy of 
the report in a shared secure location (Sharefile) to which the institutional PI has 
access. An email will be sent to the institutional PI automatically when a new 
germline report is available.  
• 
The germline report will include language stating that further genetic evaluation, 
including confirmatory or additional genetic testing as clinically indicated, should 
be guided by the patient’s oncologist in consultation with appropriate specialists. 
• 
Examples of tumor and germline reports will be provided on the protocol 
webpage. 
• 
The clinical genomics laboratories doing the germline reporting (BCM and 
CHLA) will have the capacity to do targeted mutation testing of variants identified 
in Pediatric MATCH, so that this can be performed (outside of the MATCH 
protocol) for family members desiring clinical follow-up as part of routine 
medical care if that is requested. Contact information for the BCM and CHLA 
laboratories will be provided to participating oncologists and included in the 
germline reports. 
• 
The Germline Reporting committee is committed to developing education 
materials and central genetics expertise to support the oncologists receiving 
germline reports and provide information about local genetics resources for 
families desiring further evaluation. 
• 
Contact information for a Pediatric MATCH study resource to answer questions 
about both tumor and germline study testing and provide additional referral 
information (as indicated) will be posted on the COG protocol homepage.  
As of Amendment #4: Tumor and germline mutation reporting for Stage 2 of Pediatric 
MATCH (patients enrolled starting 1/01/22): 
 
• 
In Stage 2 of Pediatric MATCH centralized tumor and blood testing will not be 
performed and no clinical testing reports will be issued.  
• 
Any questions about whether a specific report is acceptable or mutation is 
actionable can be referred to the COG study chair and vice chair (Drs. Parsons 
and Janeway) who will consult with the Molecular Review Committee (MRC) as 
required. 
 
5.6 
APEC1621SC Specimen Studies  
 
5.6.1 
Blood Sample for Genomic Research (required if available): 
 
5.6.1.1 Sample collection and handling instructions 
4 mL blood in EDTA will be collected after enrollment. If blood in an 
EDTA tube is collected over the weekend or on the day before a holiday, 
the sample should be stored in a refrigerator until shipped on the next 

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business day. 
 
5.6.1.2 Labeling 
Label each blood collection tube with the patient’s name, date of birth, 
COG patient ID, specimen type (blood) and the date and time the sample 
was drawn.   
 
Record the exact date and time each sample is drawn on the CRF.  
 
5.6.1.3 Shipping 
Refer to Section 5.7 for shipping details. 
 
5.6.2 
Relapsed Tumor for Genomic Research (required if available): 
 
5.6.2.1 Sample collection and handling instructions 
Block or 20-30 (5 µm) unstained slides from tumor collected after 
relapse/recurrence. If slides are submitted in place of a block, the slides 
should be cut sequentially from one block and include the following: 
 
• 
1 unstained charged slide (the first) for H&E 
• 
6 unstained charged slides for IHC 
• 
15-25 unstained, air-dried (preferably uncharged) slides for 
macrodissection and nucleic acid extraction 
 
Note: If relapsed tumor sample is available but quantity does not meet 
the criteria above, the available tumor may still be submitted for 
research. 
 
Note: Send a block or slides from the most recent procedure if multiple 
post-recurrence/progression tumor samples are available. If a patient 
relapses after enrollment and another biopsy occurs for clinical reasons, 
this tissue may also be submitted for genomic research.      
 
5.6.2.2 Labeling 
Label blocks and slides with the COG patient ID, specimen type (P for 
primary or M for metastatic), surgical pathology ID and block number 
from the corresponding pathology report, and section number of the 
sequentially cut section (slides).  In addition, the patient’s name, date of 
birth, and the collection date must be labeled on the specimen. 
 
Note: Stage 2 samples will not require patient’s name and DOB. 
 
The corresponding unredacted pathology report must be labeled with the 
patient’s name, date of birth and BPC number. 
 
Complete the APEC1621SC MATCH Genomic Research Tumor 
Specimen Transmittal Form and the site contact information form.   The 
site contact information form must be included with each shipment of 
specimens for genetic research Include the transmittal form, the pathology 
report, and the site contact information form with the shipment  

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New York State Institutions must complete the Non-Permitted Laboratory 
Test Request Approval Form. The Non-Permitted Laboratory Test 
Request Approval Form must be submitted with the MATCH Genomic 
Research Tumor Specimen Transmittal Form. The Non-Permitted 
Laboratory Test Request Approval Form can be found on the protocol 
page. 
 
Note: Stage 2 will no longer require the Non-Permitted Laboratory 
Test Request Approval Form to be submitted. 
 
5.6.2.3 Shipping 
Refer to Section 5.7 for shipping details. 
 
5.6.3 
Circulating Tumor (ctDNA) DNA Study (required if available): 
 
5.6.3.1 Sample collection and handling instructions 
One blood sample for ctDNA extraction will be collected from all patients 
after enrollment onto APEC1621SC, into Streck Cell-Free DNA BCT 
tubes. Please note that this sample must be collected prior to start of 
subprotocol therapy. Streck Cell-Free DNA BCT tubes may be ordered via 
the BPC Kit Management application. (https://kits.bpc-apps.nchri.org/).  
 
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  
 
Record the exact date and time each sample is drawn on the CRF.  
 
 
 
 
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 (i.e. 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. 

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• 
Hold the tube with the stopper in the uppermost position so that the 
tube contents do not touch the stopper or the end of the needle during 
sample collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 
• 
Remove tube from adapter and immediately mix by gentle inversion 
8 to 10 times. Inadequate or delayed mixing may result in inaccurate 
test results.  
• 
Store blood in Streck tube at room temperature until shipment, 
completion of the case report form must occur before shipment. 
 
5.6.3.2 Labeling 
Label each blood collection tube with the patient’s name, date of birth, 
COG patient ID, specimen type (blood) and the date and time the sample 
was drawn.   
 
Complete the APEC1621SC ctDNA specimen transmittal form and 
include the transmittal form and corresponding unredacted pathology 
report with the shipment. 
 
Note: Stage 2 samples will not require patient’s name or DOB.  
 
5.6.3.3 Shipping 
Refer to Section 5.7 for shipping details. 
5.6.4 
Diagnostic (Pre-Therapy) Tumor Sample for Additional Genomics Research 
(required, if available): 
 
5.6.4.1 Sample collection and handling instructions 
After enrollment, one block or 10-20 (5 µm) unstained slides from a tumor 
sample obtained at the time of original diagnosis (pre-therapy), will be 
collected if available. If slides are submitted in place of a block, the slides 
must be cut sequentially from one block with the first slide an unstained 
charged slide for H&E.  
 
5.6.4.2 Labeling 
Label blocks and slides with the COG patient ID, specimen type (P for 
primary or M for metastatic), surgical pathology ID and block number 
from the corresponding pathology report, and section number of the 
sequentially cut section (slides).  In addition, the patient’s name, date of 
birth, and the collection date must be labeled on the specimen. 
 
Complete the APEC1621SC Diagnostic Tumor specimen transmittal 
form and include the transmittal form and corresponding unredacted 
pathology report with the shipment. 
 

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5.6.4.3 Shipping 
Refer to Section 5.7 for shipping details. 
 
5.7 
APEC1621SC Specimen Shipment 
 
Stage 1 ONLY: Blood samples should be shipped the same day as collection. Ship both 
EDTA and Streck tubes at room temperature on Monday through Friday for Tuesday 
through Saturday delivery. 
 
Ship blood by FedEx Priority Overnight using the COG FedEx account. Ship blood for 
Saturday delivery if shipped on Friday. 
 
• 
If blood for genomics research (EDTA) is collected 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.  
• 
Blood sample for ctDNA (Streck tube) must remain at room temperature if it 
cannot be shipped the day of collection. 
 
Ship blocks or slides on Monday through Thursday by FedEx Priority Overnight using the 
COG FedEx account; do not send blocks or slides for Saturday delivery. 
 
Include the specimen transmittal form, site contact information form and a copy of the 
corresponding pathology report (when sending tissue).  The copy of the unredacted 
pathology report sent to the BPC must include the patient’s name, and date of birth, and 
BPC number.  
 
As of Amendment #4 and after Stage 2 accrual begins: pathology report must be 
redacted and uploaded to RAVE. The redacted report must include the COG patient 
ID and the patient BPC number. The site contact information form must be 
completed in RAVE and sent with all specimens. Please send a copy of the redacted 
report to the BPC with any tissue submitted. 
 
Shipping Address: 
 
COG Biopathology Center 
APEC1621SC-Peds MATCH* 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
Ship samples by FedEx Priority Overnight using a FedEx shipping label obtained through 
the COG FedEx account. 
 
*Labeling is extremely important for this project. Packages must be labeled 
“APEC1621SC-Peds MATCH” in order to ensure appropriate processing at the BPC.  
 
 

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5.8 
Agent selection 
 
Rationale for agent selection approach for Stage 1 of Pediatric MATCH (patients 
enrolled from start of study in July 2017 through 12/31/21): 
 
The study Target and Agent Prioritization (TAP) committee will review target and agent 
pairs for inclusion in the Pediatric MATCH Trial. TAP committee membership includes 
pediatric oncologists with expertise in cancer genomics, with representation from the COG 
disease committees relevant to the trial patient population, in addition to NCI/CTEP, FDA, 
and adult NCI MATCH study leadership. In preparation for the study, the TAP committee 
compiled a comprehensive list of targeted agent classes that could be considered for 
inclusion, then conducted a formal review process (with two primary reviewers for each 
target/agent pair) that culminated in a written review that was presented to the committee 
with a recommended priority score that was then voted on by the committee. Based on this 
ranking, the committee leadership determined the top priority target-agent pairs by 
assessing factors including (1) the level of evidence linking the biomarker to response to 
the agent (see Appendix III), (2) the ability of the proposed MATCH assay to detect the 
biomarker, (3) the frequency of the relevant genetic alterations in pediatric cancers, and (4) 
the suitability of each target-agent pair for the planned trial design and endpoints. Appendix 
I details the initial list of prioritized agent classes, the genes and types of alterations relevant 
to each drug, the estimated frequency of actionable alterations for each drug, and the tumor 
types known to be most frequently mutated.  
 
As part of their process the TAP committee also evaluates the available data regarding 
blood brain barrier penetration for each potential study agent. In cases in which it is known 
from previous clinical studies that adequate levels of the agent cannot be achieved in the 
CNS to induce tumor responses, the TAP committee may recommend that children with 
CNS tumors not receive that agent. In general, however, given the known extent of 
disruption of the blood brain barrier in CNS tumors, the goal will be to treat children with 
both CNS and non-CNS tumors with each study agent (presuming that they have a defined 
targetable agent). 
 
A subset of TAP committee members have participated (and continue to participate) in a 
series of calls led by CTEP with numerous pharmaceutical companies whose portfolios 
include the prioritized classes of agents. The company representatives formally present the 
relevant agent or class of agents and engage in discussion with the TAP committee 
members. Based upon this review process (including additional preclinical and clinical 
information from each company) the TAP committee then recommends specific agents for 
inclusion for the study. Refer to the ‘APEC1621-Master Version Control protocol’ for 
agents that have been recommended for inclusion. The rationale for the selection of each 
agent will be described in detail in each subprotocol. 
 
Over the course of the study, the TAP committee will continue to meet on a quarterly basis 
to evaluate whether additional target-agent pairs should be discussed and reviewed by the 
committee in order to determine suitability for inclusion in the study. If a high priority 
agent is nominated by a TAP committee member then ad hoc reviews will also be 
conducted as required. 
 
As of Amendment #4: Rationale for agent selection approach for Stage 2 of Pediatric 
MATCH (for patients enrolled starting 1/01/22): 
 

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No additional agents will be selected for study in Stage 2. 
 
5.9 
Patients with non-target bearing (biomarker negative) tumors 
It is anticipated that a minority of children with relapsed or refractory cancer will have an 
actionable mutation of interest (aMOI) for which a study agent is available. An important 
question to address for select agents, should a significant signal of activity be observed in 
pediatric patients, is whether the signal is truly confined to biomarker positive patients. In 
order to provide data relevant to this question of agent specificity, for select agents that 
have demonstrated preliminary signs of activity (defined as ≥ 3 CR/PRs) in biomarker 
positive patents, patients with non-target bearing (biomarker negative) tumors may be 
enrolled on an independent stratum. These biomarker negative cohorts may either be 
histology-specific (if ≥ 3 responses are observed in a specific histology, see Section 11.2.3 
for additional details) or histology-agnostic (if ≥ 3 responses are observed, but not in any 
one histology), and will preferentially enroll patients to the earliest opened cohort when 
possible within slot availability/cohort suspension constraints. Patients in the biomarker 
negative cohorts will not be counted for purposes of determining the primary objective 
(response rate to targeted agents in patients whose tumors bear the target).  
 
A recommendation regarding whether each particular agent is appropriate for potential 
inclusion of biomarker negative subjects (presuming the bar for observed responses in 
biomarker positive subjects has been met) will be made in the corresponding subprotocol 
based on the recommendation of the TAP committee. This decision will be based upon a 
number of factors, including (1) specific mechanism of action of the agent, (2) potential 
promiscuity of the targeted molecular pathway, (3) degree of permissiveness of the agent-
target interaction, (4) available preclinical data in non-target-bearing tumor models, and 
(5) available clinical data for patients with non-target-bearing tumors. The same factors 
utilized in assessing evidence to support a link between a biomarker and response to the 
agent (see Appendix III) will be applied to assess evidence for response in a biomarker 
negative population. The concept for each individual subprotocol in which a biomarker 
negative population is proposed will describe the evidence supporting potential activity of 
that agent in a biomarker negative population. 
 
 
6.0 
TREATMENT PROGRAM 
 
6.1 
Overview of Treatment Plan 
 
Refer to subprotocol. 
 
6.2 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to version 5.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE). All appropriate treatment areas should 
have access to a copy of version 5.0 of the CTCAE. A copy of the CTCAE 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 
dose -limiting toxicity attributable to subprotocol therapy should be reported as defined in 
the subprotocol. 
 
 
 

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6.3 
Definition of Biopsy-Related Target Toxicity (TT) 
 
Tracking of biopsy-related target toxicity in Stage 1 of Pediatric MATCH (patients 
enrolled from start of study in July 2017 through 12/31/21): 
 
Biopsy related target toxicity (TT) will be defined as: 
• 
Any Grade 4 or Grade 5 toxicity or complication associated with tumor samples 
for pediatric MATCH, that is probably or definitely attributable to any biopsy or 
biopsy-related anesthesia or imaging procedure that occurs within 14 days of a 
biopsy performed after enrollment on this study 
• 
Any Grade 3 toxicity or complication associated with tumor samples for pediatric 
MATCH,  that is probably or definitely attributable to any biopsy or biopsy-related 
anesthesia or imaging procedure that occurs within 14 days of a biopsy performed 
after enrollment on this study and which in addition meets any of the following 
criteria: 
o An adverse event that results in any inpatient hospitalization in which an 
unplanned intervention is administered (i.e. any hospitalization for other 
than planned observation) or prolongation of existing hospitalization for 
≥ 48 hours 
o Permanent adverse sequelae 
o A life-threatening adverse event 
o Other important medical events (IMEs) that may not result in death, be life 
threatening, or require hospitalization but may be considered a serious 
when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
 
These target toxicities will require expedited reporting via CTEP-AERS as outlined in 
Table A of Section 13.  
 
As of Amendment #4: Tracking of biopsy-related target toxicity in Stage 2 of Pediatric 
MATCH (for patients enrolled starting 1/01/22): 
 
Starting in Stage 2 of Pediatric MATCH, no tumor samples are being submitted for clinical 
testing as part of the study and no biopsy-related complications will be reported. 
 
6.4 
Definition of Dose-Limiting Toxicity (DLT) 
Dose-limiting hematological and non-hematological toxicities will be defined any of the 
following events that are at least possibly related to subprotocol therapy, as specified in 
each subprotocol. The DLT observation period for the purposes of determining safety and 
feasibility of the protocol directed therapy will be the first cycle of therapy as defined in 
the subprotocol.   
 
Unless otherwise specified in the subprotocol, the standard definition of DLT will be: 
Non-Hematological DLT: 
• 
Any ≥ Grade 3 non-hematological toxicity attributable to protocol therapy.  
Specific exclusions and additional non-hematologic DLTs will be outlined in 
each subprotocol.  

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7.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
Dose modifications for dose-limiting toxicity will be detailed in the subprotocols. 
 
 
8.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
8.1 
Concurrent Anticancer Therapy 
Patients may receive concurrent cancer therapy while enrolled on the screening portion of 
APEC1621SC, but must meet criteria for prior therapy (Section 4.2.3) at the time of 
consent and enrollment to a subprotocol. Concurrent cancer therapy, including 
chemotherapy, radiation therapy, immunotherapy, or biologic therapy may NOT be 
administered to patients while they are receiving study drug as part of a subprotocol. If 
these treatments are administered the patient will be removed from protocol therapy. 
 
8.2 
Investigational Agents 
Patients may receive investigational agents while enrolled on the screening portion of 
APEC1621SC, but must meet criteria for prior therapy (Section 4.2.3) at time of consent 
and enrollment to a subprotocol. No other investigational agents may be given while the 
patient is enrolled on an APEC1621 subprotocol and receiving protocol directed therapy.  
 
 
9.0 
AGENT INFORMATION: GENERAL OVERVIEW 
 
9.1 
Refer to Subprotocol for agent information. 
 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
10.1 
Off Study Criteria from APEC1621SC Screening Protocol 
 
a) 
Two years from the date of patient enrollment onto APEC1621SC if not enrolled 
onto a subprotocol. 
b) 
Two years from the date of technical failure resulting in inability to yield sequencing 
results and no further plan to obtain additional tumor sample [STAGE 1 ONLY, does 
not apply after Amendment #4] 
c) 
The fifth anniversary of the most recent date of patient enrollment onto a 
subprotocol. 
d) 
Death 
e) 
Lost to follow-up 
f) 
Withdrawal of consent for any further required observations or data submission. 
g) 
Physician determines it is not in the patient’s best interest. 
h) 
Histologic diagnosis of recurrent malignancy not confirmed within one month of 
enrollment.  
 
10.2 
Criteria for Removal from Subprotocol Therapy  
 
a) 
Each subprotocol will outline specific criteria for removal from subprotocol therapy. 
Removal from subprotocol therapy does not constitute removal from the 
APEC1621SC screening protocol. 
 

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Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations 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. Patients 
who are removed from protocol therapy in subsequent cycles should have the 
necessary observations to ensure adequate clinical care.  
 
Patients who are off subprotocol therapy will continue to be followed on the APEC1621SC 
screening protocol. Follow-up data submission will occur until one of the Off Study criteria 
outlined in Section 10.1 is met. Ongoing adverse events, or adverse events that emerge 
after the patient is removed from subprotocol therapy, but within 30 days of the last dose 
of subprotocol investigational agent, must be followed and reported in the subprotocol via 
RAVE and CTEP-AERS (if applicable). Serious adverse events that occur during the 
follow-up period (more than 30 days after the last administration of investigational agent) 
and have an attribution of possible, probable, or definite require reporting per Footnote 1 
of Table A.  Follow-up data will be required unless consent is withdrawn. 
 
10.3 
APEC1621SC Re-screening upon removal from subprotocol therapy 
Patients who are removed from subprotocol therapy may be assigned to another MATCH 
treatment subprotocol if the Molecular Review Committee (MRC) identified an actionable 
mutation for that subprotocol in the tumor profiling report(s) reviewed for that patient. If a 
tumor profiling report is available from a later date or becomes available while the patient 
is enrolled on APEC1621SC that report can be submitted for review by the MRC. The 
treatment assignment process is repeated, in order of priority, until all potential treatment 
assignments are exhausted. 
 
The treating team will need to complete a re-screen step in OPEN, to indicate that they 
would like the patient to be considered for assignment to a new MATCH treatment 
subprotocol (if available).  
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 
 
Sample size and study duration for Stage 1 of Pediatric MATCH (patients enrolled 
from start of study in July 2017 through 12/31/21): 
 
The expected accrual rate is 200-300 patients per year, of which 10% or 30 patients/year 
are expected to have an actionable mutation of interest (aMOI) for which a study agent is 
available. A total of 1500 enrollments is planned during Stage 1.  
 
As of Amendment #4: Sample size and study duration for Stage 2 of Pediatric MATCH 
(patients enrolled starting 2022 ): 
 
It is anticipated that 50 patients per year will enroll on the screening protocol, of whom 
50% (25 patients per year) will be eligible for enrollment on the primary cohorts of a 
treatment subprotocol.   
 
It is noted that as of Amendment #4, there are no sample size goals associated with the 
screening study. APEC1621SC serves to support subprotocols. The ceiling in the table 

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11.2 
Dosing Considerations 
If a pediatric RP2D dose has been established, the patient will be treated at that dose.  
 
11.2.1 Pediatric MATCH Sub-arm Dosing in the Absence of Pediatric Phase 1 Data 
If there is no prior pediatric phase 1 data, study investigators will review 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 these arms.  In 
general, the dosing for the Pediatric MATCH subprotocols will follow the 
guidelines below: 
 
• 
For agents where the adult RP2D is below the adult MTD, the adult RP2D 
(normalized to body surface area or body weight) will be used for evaluation 
in the Pediatric MATCH, understanding that further dose optimization may be 
required in a future pediatric study.   
• 
For drugs for which the adult RP2D is at the adult MTD, the pediatric 
subprotocol will evaluate an initial cohort of patients at a dose level 
approximately 30% below the adult MTD and then complete the study using 
the adult RP2D, assuming that both dose levels are tolerated. Rules for 
determining tolerability of these dose levels are described in Section 11.2.2. 
 
11.2.2 Determination of Recommended Phase 2 Dose (RP2D)/Tolerable Dose 
For drugs for which the adult RP2D is the adult MTD, the pediatric subprotocol 
will evaluate an initial cohort of patients using a modified rolling 6 design starting 
at a dose level approximately 30% below the adult MTD and then completing the 
study using the adult RP2D, assuming that both dose levels are tolerated. The DLT 
evaluation period for the purpose of dose escalation will be cycle 1 of therapy. 
Accrual will be suspended to assess tolerability when a cohort of six has enrolled 
at the starting dose level. 
 
The rolling six phase 1 trial design will be used for the conduct of this study. 59 
Two to six patients can be concurrently enrolled onto a dose level, dependent upon 
(1) the number of patients enrolled at the current dose level, (2) the number of 
patients who have experienced DLT at the current dose level, and (3) the number 
of patients entered but with tolerability data pending at the current dose level.  
Accrual is suspended when a cohort of six has enrolled or when the study endpoints 
have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in 
the cohort, the number of DLTs observed, and the number of participants at risk 
for developing a DLT (i.e., participants enrolled but who are not yet assessable for 
toxicity). For example, when three participants are enrolled onto a dose cohort, if 
toxicity data is available for all three when the fourth participant entered and there 
are no DLTs, the dose is escalated and the fourth participant is enrolled to the 
subsequent dose level. If data is not yet available for one or more of the first three 
participants and no DLT has been observed, or if one DLT has been observed, the 
new participant is entered at the same dose level. Lastly, if two or more DLTs have 
been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three 

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participants, accrual is only suspended when a cohort of six is filled. When 
participants are inevaluable for toxicity, they are replaced with the next available 
participant if escalation or de-escalation rules have not been fulfilled at the time 
the next available participant is enrolled onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the 
current dose level (ii) at an escalated dose level, (iii) at a de-escalated dose level, 
or whether the study is suspended to accrual: 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
3 
0 
3 
0 
Escalate** 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
4 
0 
4 
0 
Escalate** 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 
5 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Same dose level 
5 
0 
5 
0 
Escalate** 
5 
≥ 2 
0, 1, 2 or 3 
0, 1, 2 or 3 
De-escalate* 
 
 
 
 
 
6 
0 
0, 1, 2, 3, or 4 
2, 3, 4, 5 or 6 
Suspend 
6 
1 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
Suspend 
6 
0 or 1 
5 or 6 
0 or 1 
Escalate** 
6 
≥ 2 
0, 1, 2, 3 or 4 
0, 1, 2, 3 or 4 
De-escalate* 
 
* If six patients already entered at next lower dose level, the recommended dose 
has been defined. 
 
 **If final dose level has been reached, the recommended dose has been reached. 
 
If two or more of a cohort of up to six patients experience DLT at a given dose level, then 
dose escalation will be stopped. 
 
In addition to determination of the RP2D, a descriptive summary of all toxicities will be 
reported. 
 
11.3 
Subprotocol Study Design 
The primary cohort(s) and any biomarker negative expansion cohorts defined below will 
employ single stage A’Hern designs of N=20 and N=10 respectively. The agent will be 
deemed worthy of further study in the relevant subset of patients (i.e. biomarker positive 
in any histology, biomarker positive in a particular histology, etc) if the decision rule is 
met. Operating characteristics are shown below. 
 
 

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11.3.3.1 Histology-Agnostic Biomarker Negative Cohort:  
If at any time ≥ 3 patients in the primary cohort show signs of objective 
response, but there are < 3 responses of the same histology, then a single 
cohort of 10 biomarker negative patients of any histology will be opened. 
If in the course of the study the primary cohort continues to have responses 
such that ≥ 3 responses are observed in the same histology, then biomarker 
negative cohorts will be opened as described in Section 11.3.3.2 and 
biomarker negative patients with that histology will be reallocated to the 
histology-specific cohort. If 2 or more responses are seen in the non-
histology-specific biomarker negative cohort, the regimen will be declared 
active for biomarker negative patients. This will provide a low probability 
(9%) of carrying forward agents with response rates less than 5% and a 
moderately high probability (74%) of identifying agents with response 
rates ≥ 25%. 
 
11.3.3.2 Histology-Specific Biomarker Negative Cohorts:  
If at any time ≥ 3 patients in the primary cohort with the same histology 
show signs of objective response, then 10 patients with the same histology 
but without the biomarker will be enrolled. If 2 or more responses are seen 
in a histology-specific biomarker negative cohort, the regimen will be 
declared active for biomarker negative patients of that histology. Using 
this A’Hern single stage design will assure a low probability (9%) of 
carrying forward agents with response rates less than 5% and provide a 
moderately high probability (74%) of identifying agents with response 
rates ≥ 25%. Up to a total of 3 such biomarker negative cohorts can be 
opened, for a total of 30 biomarker negative patients.  
 
 
For biomarker negative cohorts: If more than one histology-specific cohort 
is opened alongside a histology-agnostic cohort, accrual to the histology-
agnostic cohort will stop if no activity is observed in the histology-specific 
cohorts and activity has not yet been observed in the histology-agnostic 
cohort. 
 
11.3.4 Subprotocol Sample Size: 
Each subprotocol will require a minimum of 20 evaluable patients (or 4 evaluable 
patients if criteria in Section 11.2.2 is met), and a maximum of 96 patients can be 
enrolled, allowing for 15% inevaluability. This maximum could only occur if the 
primary cohort has ≥ 12 responses, with 9 evenly split among 3 histologies and 3 
responses spread amongst other histologies, and the TAP committee has 
determined that it is reasonable to enroll biomarker negative patients. If biomarker 
negative enrollment is not allowed on the subprotocol, the maximum sample would 
be 49 patients, allowing for 15% inevaluability. 
 
11.4 
Match Rate Feasibility Analysis 
 
Stage 1 of MATCH: The match rates will initially be assessed after accrual to 200 
patients or one year after study activation, whichever occurs first, then on a quarterly 
basis. 
 
As of Amendment #4: Stage 2 of MATCH: The match rates will be assessed in 2023 
after one year of Stage 2 operations. 
 

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11.5 
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.61 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.   
 
11.6 
Evaluability for Response 
Any eligible patient who is enrolled and receives at least one dose of protocol therapy on 
any APEC1621 sub-protocol 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 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. 
 
11.7 
Evaluability for Toxicity 
All eligible patients who receive at least one dose of protocol therapy (according to 
subprotocol guidelines) on any APEC1621 subprotocol will be considered in the evaluation 
of toxicity. 
 
11.8 
Monitoring of Biopsy Related Adverse Events 
 
Monitoring of biopsy related adverse events in Stage 1 of Pediatric MATCH (patients 
enrolled from start of study in July 2017 through 12/31/21): 
 
Patients who undergo a biopsy after enrolling on APEC1621SC will be monitored to 
determine whether they experience a biopsy related target toxicity (TT) as defined in 
Section 6.3. Biopsy related target toxicity will be monitored separately for subjects with 
CNS tumors and non-CNS tumors who receive a biopsy for the purpose of obtaining a 
tumor sample for MATCH using the following monitoring rule: If 3 or more of the first 33 
patients who undergo a biopsy after enrolling on MATCH experience a biopsy related 
target toxicity, the data for the relevant cohort of the study (CNS or non-CNS tumors) will 
be sent to the study committee and DSMC for review to determine whether actions are 
required. Otherwise additional monitoring will continue, up to 88 patients who undergo a 
biopsy after enrolling on MATCH. A similar review will be conducted if 5 or more biopsy-
related target toxicities are observed in that cohort. If the true biopsy related target toxicity 
rate is 2%, then the monitoring rule will be tripped with 0.05 probability. If the true 
research-biopsy related target toxicity rate is 10%, then the rule will be tripped with 0.95 
probability. In order to avoid delays and logistical problems due to pausing accrual while 

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each accrued patient’s toxicity data are evaluated, this study will continue to concurrently 
enroll patients without waiting for target toxicity outcomes to be determined for evaluable 
patients. Re-evaluation will occur at 30 days post-biopsy of any biopsy-related target 
toxicities that have been reported in the CNS tumor cohort. 
 
As of Amendment #4: Monitoring of biopsy-related adverse events in Stage 2 of 
Pediatric MATCH (for patients enrolled starting 1/01/22): 
 
Starting in Stage 2 of Pediatric MATCH, no tumor samples are being submitted for clinical 
testing as part of the study and no biopsy-related complications will be captured. 
 
11.9 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of subprotocol 
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. Duration 
of PFS response will be summarized for responders.     
 
11.10 Correlative Studies 
A descriptive analysis of pharmacokinetic (PK) parameters will be performed in specific 
subprotocols to define systemic exposure, drug clearance, and other pharmacokinetic 
parameters. Refer to specific subprotocols for more information on the pharmacokinetic 
(PK) parameters being performed. 
 
Approaches to diagnosing and profiling genomics of tumors through the evaluation of 
Circulating Tumor DNA will also be explored. A next-generation sequencing based assay 
will be utilized to quantify the DNA present in the plasma.  
 
A descriptive analysis of the exploratory aims described in Section 1.3 will be performed 
and will be summarized with simple summary statistics. All of these analyses will be 
descriptive in nature. 
 
 
12.0 
EVALUATION CRITERIA 
 
12.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
The descriptions and grading scales found in version 5.0 of the NCI Common Terminology 
Criteria for Adverse Events v5.0 (CTCAE) will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE.  A copy of the 
CTCAE 
v5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events). 
 
• 
Toxicity and Adverse events probably or definitely attributable to tumor biopsy 
on this protocol will be tabulated as part of APEC1621SC Screening Protocol. 

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• 
Toxicity and Adverse events related to administration of APEC1621 
subprotocol directed protocol therapy will be tabulated according to the 
subprotocol. 
• 
Toxicity and Adverse events that occur related to therapy prior to administration 
of APEC1621 subprotocol directed therapy or in participants who do not enroll 
on a subprotocol will not be collected. 
 
12.2 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
12.3 
Response Criteria for Patients with Solid Tumors  
 
All APEC1621 sub-protocols will use the same response criteria and interval of 
response assessment. Tumor disease evaluations will be performed at the end of every 
other cycle x 3, then every 3 cycles.  In addition to the scheduled scans, a confirmatory 
scan should be obtained the 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/histiocytosis (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).62  Key points are 
that 5 target lesions are identified and that changes in the largest diameter (unidimensional 
measurement) of the tumor lesions but the shortest diameter of malignant lymph nodes are 
used in the RECIST v 1.1 criteria. 
 
12.3.1 
Definitions 
 
12.3.1.1 Evaluable for objective response:                                                                          
Eligible patients who receive at least one dose of protocol therapy will be 
considered evaluable for response. Evaluable patients who demonstrate a 
complete or partial response confirmed by central review before receiving 
non-protocol anti-cancer therapy will be considered a responder. All other 
evaluable patients will be considered non-responders. 
12.3.1.2 Evaluable Non-Target Disease Response:  
Eligible patients who have lesions present at baseline that are evaluable but 
do not meet the definitions of measurable disease and have received at least 
one dose of protocol therapy will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 

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12.3.2 Disease Parameters 
 
12.3.2.1 Measurable disease: Measurable lesions are defined as those that can 
be accurately measured in at least one dimension (longest diameter 
to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, 
or ≥10 mm with calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
12.3.2.2 Malignant lymph nodes: To be considered pathologically enlarged 
and measurable, a lymph node must be ≥15 mm in short axis when 
assessed by CT scan (CT scan slice thickness no greater than 5 mm).  
At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
12.3.2.3 Non-measurable disease: All other lesions (or sites of disease), 
including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
12.3.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions 
per organ and 5 lesions in total, representative of all involved organs, 
should be identified as target lesions and recorded and measured at 
baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion that can 
be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum 
diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will 
be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
12.3.2.5 Non-target lesions: All other lesions (or sites of disease) including 
any measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the 

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presence, absence, or in rare cases unequivocal progression of each 
should be noted throughout follow-up.  
 
12.3.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
12.3.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph 
nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin 
nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
12.3.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable 
lesions when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable.  
 
12.3.3.3 Conventional CT and MRI:  This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness 
is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, 
the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible 
to prior scans.  
 
12.3.3.4 PET-CT:  At present, the low dose or attenuation correction CT 
portion of a combined PET-CT is not always of optimal diagnostic 
CT quality for use with RECIST measurements.  However, if the site 
can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
or International Pediatric non-Hodgkin Lymphoma Response 
Criteria measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional 
data which may bias an investigator if it is not routinely or serially 
performed.   
12.3.3.5 Tumor markers: Tumor markers alone cannot be used to assess 
response.  If markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete clinical 

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response.  
 
12.3.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response 
or stable disease. 
 
12.3.3.7 FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following 
algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up is a sign of PD based on a new lesion. 
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.63 
 
12.4 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).   

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Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progression). 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 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.     
 
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. 
 

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12.5 
Response Criteria for Neuroblastoma Patients 
 
Please refer to specific subprotocols for response criteria used to assess 
neuroblastoma patients.  Patients who have a positive MIBG scan at the start of 
therapy will be evaluable for MIBG response. The use of 123I for MIBG imaging 
is recommended for all scans. 
 
12.6 
Response Criteria for Patients with CNS Tumors 
 
12.6.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI, for 
CNS tumors. 
 
12.6.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.6.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.6.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
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.. 
 

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• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
Increasing doses of corticosteroids required to maintain stable neurological 
status should be strongly considered as a sign of clinical progression unless in 
the context of recent wean or transient neurologic change due e.g. to radiation 
effects.  
 
12.6.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.6.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.6.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns.   
 
 
Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
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. 
12.7 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
Response and progression will be evaluated in this study using the new international 

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criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria63, with modification from the Lugano classification.64 
 
12.7.1 Evaluation of Measurable Disease 
 
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 Criteria63, with modification from the Lugano 
classification. 64 
 
Disease Parameters 
 
1. 
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). 
 
2. 
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).   
 
3. 
Target lesions: For patients staged with CT, up to six of the largest target nodes, 
nodal masses, or other lymphomatous lesions that are measurable in two diameters 
(longest diameter [LDi] and shortest diameter) should be identified from different 
body regions representative of the patient’s overall disease burden and include 
mediastinal and retroperitoneal disease, if involved. 
 
12.7.2 Evaluation of Measurable Disease 
Complete Response (CR) 
Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
 
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.  
 

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Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)64 
 
Complete Response (CR): 
Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New 
or 
clear 
progression 
of 
preexisting 
non-measured lesions. 
 
12.7.3 Evaluation of organ enlargement 64 
 
Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by >50% in length 
beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
12.8 
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. 
 
12.8.1 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
 

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Table 1: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once ≥ 
28 days from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  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.  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 
 
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 

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CR 
CR 
CR 
CR 
Normal 
CR 
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 
 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
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 data collection packet 
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 of biopsy-related adverse events in Stage 1 of Pediatric MATCH (patients enrolled 
from start of study in July 2017 through 12/31/21): 
 
 
Reporting requirements may include the following considerations if related to biopsy related target 
toxicity: 1) whether the adverse event is considered serious; 2) the grade (severity); and 3) whether 
or not hospitalization or prolongation of hospitalization was associated with the event. 
 

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Any Complications associated with tumor samples for pediatric MATCH: biopsy, biopsy-related 
anesthesia, biopsy related target toxicity or imaging procedures performed after consent to 
this study will be reported and tracked as protocol-related adverse events and graded 
according to NCI CTCAE v5. Any grade complication will be considered a Serious Adverse 
Event if it meets the criteria outlined in Table A.  
 
Biopsy related target toxicities (TT) as defined in Section 6.3 will require expedited reporting 
via CTEP-AERS as outlined in Table A.  
 
Reporting of biopsy-related adverse events in Stage 2 of Pediatric MATCH (for patients 
enrolled starting 1/01/22): 
 
Starting in Stage 2 of Pediatric MATCH, no tumor samples are being submitted for clinical testing 
as part of the study and no biopsy-related complications will be reported. 
 
13.1 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
 
Expedited reporting requirements for SAEs in Stage 1 of Pediatric MATCH (patients 
enrolled from start of study in July 2017 through 12/31/21): 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with biopsy related target toxicities. A Serious 
Adverse Event (SAE) is any adverse event (experience) occurring in ANY of the following 
outcomes only related to biopsy related target toxicities: 
 
1) Death 
 
2) 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. 
3 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
4) A congenital anomaly/birth defect. 
5) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
13.1.1 Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair 
have the primary responsibility for AE identification, documentation, grading, and 
assignment of attribution to the investigational agent/intervention. It is the 
responsibility of the treating physician to supply the medical documentation 
needed to support the expedited AE reports in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via 
routine reporting. Routine reporting is accomplished via the Adverse Event (AE) 
Case Report Form (CRF) within the study database.   

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13.1.2 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page  
https://ctepcore.nci.nih.gov/ctepaers/pages/task. 
 
Send supporting documentation to the NCI by fax (fax# 301-897-7404) and by 
email to the APEC1621SC COG Study Assigned Research Coordinator. 
ALWAYS include the ticket number on all faxed and emailed documents. 
 
Expedited reporting requirements for SAEs in in Stage 2 of Pediatric MATCH (for 
patients enrolled starting 1/01/22): 
 
Starting in Stage 2 of Pediatric MATCH, no tumor samples are being submitted for clinical 
testing as part of the study and no biopsy-related SAEs will be reported. 
 
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 version 5.0 of the NCI CTCAE.  The 
descriptions and grading scales found in 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 specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
• 
Any biopsy related target toxicity equivalent to CTCAE Grade 3, 4, or 5 that 
precipitates hospitalization (or prolongation of existing hospitalization) must be 
reported regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
• 
Any 
biopsy 
related 
target 
toxicity 
results 
in 
persistent 
or 
significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via 
CTEP-AERS. 
• 
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 

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13.6 
Specific Examples for Expedited Reporting of Biopsy-Related Target toxicities 
 
13.6.1 Reportable Categories of Biopsy-Related Target toxicity relating to Death for 
Screening Protocol  
 
• Any death that occurs due to biopsy-related target toxicity should be reported, 
refer to Section 6.3 and Section 11.8 for more information. All other 
occurrences of death (unrelated to biopsy) should be reported in RAVE but 
should not be reported as an SAE. 
 
13.6.2 Reporting of Biopsy-Related Target toxicity relating to Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options 
are available to describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
13.6.3 Reporting of Biopsy-Related Target toxicities relating to 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 
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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. This form is available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf.  If the baby is born with a birth defect or anomaly, then a 
second CTEP-AERS report is required. 
 
 
Any pregnancy loss needs to be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the “Pregnancy, puerperium and perinatal conditions” SOC. Do 
NOT report a pregnancy loss as a Grade 5 event since CTEP-AERS recognizes 
any Grade 5 event as a patient death. 
 
Death Neonatal 
Neonatal death, defined in 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. 
 
13.6.4 Unanticipated Events 
In accordance with OHRP guidelines, Unanticipated Events are defined as 
any event that includes an incident, experience, or outcome that meets the 
following criteria:  
• Unexpected, related to or possibly related to participation in research, 
and anything that suggests that the research places subjects or others 
at a greater risk of harm 
 
For more information please refer to the guidelines on the OHRP website   
(https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-
unanticipated-problems/)  
 
Unanticipated problems warrant consideration of substantive changes in 
the screening protocol or informed consent document in order to protect 
the safety, welfare, or rights of subjects.  In addition, unanticipated 
problems may present unanticipated risks to others (e.g., parents of the 
subjects) in addition to the subjects.  While these events may not have 
caused any detectable harm or adverse effect to subjects or others, they 
nevertheless represent unanticipated problems and should be promptly 
provided to the IRB and DSMC in accordance with HHS regulations at 45 
CFR 46.103(a) and 46.103(b)(5).  
 
 
 

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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: e.g., 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 data form packet. 
 
See separate Data Form Packet, which includes submission schedule. 
 
14.2 
Access to RAVE for Data Submission/ Data Reporting 
Data collection for this study will be done through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support System 
(RSS).  To access Rave via iMedidata, the site user must have an active CTEP-IAM 
account (check at https://ctepcore.nci.nih.gov/iam/index.jsp), appropriate RCR registration 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the COG 
or COGC roster at the enrolling site.  Please refer to Appendix VII for more detailed 
information on the necessary registration procedures. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To 
accept 
the 
invitation, 
site 
users 
must 
log 
into 
the 
Select 
Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, 
and click on the “accept” link in the upper right-corner of the iMedidata page.  Please note, 
site users will not be able to access the study in Rave until all required Medidata and study 
specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation 
and Study Invitation Acceptance).  Additional information on iMedidata/Rave is available 
on the CTSU members’ website under the Rave tab 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, or by email to the COG Study Assigned Data Manager. 
 
14.3 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis.  Reports are due January 31, April 30, July 31 and October 31.  
This is not a responsibility of institutions participating in this trial. 

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14.4 
CRADA/CTA/CSA 
Refer to individual subprotocols. 
 
 
14.5 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
 
14.5.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
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, including adverse events related to 
biopsies and any unanticipated problems, 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 for each study reviewed to change the study or to 
continue the study unchanged. Data and Safety Committee reports for institutional 
review boards can be prepared using the public data monitoring report as posted 
on the COG Web site. 
 
14.5.2 Monitoring by the Study Chair  
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 at regular 
intervals. 
 
 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 
 
 
15.1 
Computed Tomography (CT) with Contrast 
Most, if not all, COG institutions will be using multi-detector helical CT scanners. This is 
preferred in order to decrease scanning time compared to conventional CT, allow image 
acquisition at the time of peak contrast enhancement, reduce/eliminate the need for 
sedation, and reduce image degradation from motion artifact.  The volumetric acquisition 
of helical/spiral CT and the reconstruction of overlapping images increases the conspicuity 
of small lesions and facilitates multi-planar reconstruction for better depiction of certain 
lesions. Sagittal and coronal reconstructed images, as well as images reconstructed using a 
lung algorithm should be submitted where feasible, along with the axial imaging data. CT 

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imaging should be performed with intravenous and oral contrast using age and weight-
based adjustments to kVp and mA, in accordance with institutional practice and 
ALARA/Image Gently guidelines. Timing of protocol therapy administration, response 
assessment studies, and surgical interventions are based on schedules derived from the 
experimental design or on established standards of care. Minor unavoidable departures (up 
to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week 
for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the 
protocol). 
 
MRI may be used as an alternative modality for assessment of non-pulmonary disease sites 
(e.g. abdominal/pelvic disease), provided the institution is able to acquire images using 
phased array surface coils, cardiac gating and respiratory triggering, in order to minimize 
artifacts from cardiac motion, diaphragmatic motion and bowel peristalsis. Pulse sequences 
should include at a minimum axial and coronal T1, axial and coronal fat-saturated FRFSE-
T2 and multi-planar post-gadolinium fat-saturated T1 weighted imaging. If MRI is used 
for imaging of the thorax, abdomen and/or pelvis, an unenhanced CT of the chest should 
still be obtained to evaluate the lungs. 
 
15.2 
CT during PET/CT 
Nearly all PET scanners in use today are integrated PET/CT scanners. However, low 
dose CT scans performed on integrated PET/CT scanners for the purpose of 
attenuation correction are of non-diagnostic quality, are usually performed without 
intravenous contrast, and will not be acceptable for staging or response assessment. 
As noted above, staging CT scans should include intravenous and oral contrast. In 
some instances – particularly for staging – a diagnostic quality CT will have been 
performed prior to the PET/CT. In these cases an additional low-dose CT will still be 
required for attenuation correction of the PET images. Provided that the diagnostic quality 
CT scan has been performed within 14 days of the PET/CT, a repeat diagnostic CT 
examination is not necessary at the time of PET/CT. For post-therapy follow-up scans 
limited to the neck and/or thorax the use of IV contrast alone is sufficient, provided the 
scanning parameters are optimized to achieve diagnostic quality images. Some institutions 
perform the low dose attenuation correction CT with intravenous contrast. Please refer to 
Section 12.3.3.4 for the requirements. 
 
15.3 
[18F] Fluorodeoxyglucose (FDG) PET 
The use of PET scans is optional but highly recommended. If there is positive disease by 
PET scan at diagnosis, PET scans have to be performed at repeat evaluation time points 
until the patient has achieved a CR. 
 
 

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Tang S, Li JH, Lui SL, Chan TM, Cheng IK, Lai KN. Free-hand, ultrasound-guided percutaneous 
renal biopsy: experience from a single operator. Eur J Radiol. 2002;41(1):65-69. 
18. 
Acord M, Shaikh R. Predictors of diagnostic success in image-guided pediatric soft-tissue 
biopsies. Pediatr Radiol. 2015;45(10):1529-1534. 
19. 
Fuchs J. The role of minimally invasive surgery in pediatric solid tumors. Pediatr Surg Int. 
2015;31(3):213-228. 
20. 
Fuchs J, Schafbuch L, Ebinger M, Schafer JF, Seitz G, Warmann SW. Minimally invasive 
surgery for pediatric tumors - current state of the art. Front Pediatr. 2014;2:48. 
21. 
Malkan AD, Loh AH, Fernandez-Pineda I, Sandoval JA. The role of thoracoscopic surgery in 
pediatric oncology. J Laparoendosc Adv Surg Tech A. 2014;24(11):819-826. 
22. 
Guye E, Lardy H, Piolat C, et al. Thoracoscopy and solid tumors in children: a multicenter study. 
J Laparoendosc Adv Surg Tech A. 2007;17(6):825-829. 
23. 
Rothenberg SS. Thoracoscopic pulmonary surgery. Semin Pediatr Surg. 2007;16(4):231-237. 
24. 
Heloury Y, Muthucumaru M, Panabokke G, Cheng W, Kimber C, Leclair MD. Minimally 
invasive adrenalectomy in children. J Pediatr Surg. 2012;47(2):415-421. 

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25. 
Malkan AD, Loh AH, Sandoval JA. Minimally invasive surgery in the management of abdominal 
tumors in children. J Pediatr Surg. 2014;49(7):1171-1176. 
26. 
Al-Shanafey S, Habib Z. Feasibility and safety of laparoscopic adrenalectomy in children: special 
emphasis on neoplastic lesions. J Laparoendosc Adv Surg Tech A. 2008;18(2):306-309. 
27. 
Leclair MD, de Lagausie P, Becmeur F, et al. Laparoscopic resection of abdominal 
neuroblastoma. Ann Surg Oncol. 2008;15(1):117-124. 
28. 
Nerli RB, Reddy MN, Guntaka A, Patil S, Hiremath M. Laparoscopic adrenalectomy for adrenal 
masses in children. J Pediatr Urol. 2011;7(2):182-186. 
29. 
Skarsgard ED, Albanese CT. The safety and efficacy of laparoscopic adrenalectomy in children. 
Arch Surg. 2005;140(9):905-908; discussion 909. 
30. 
Varlet F, Petit T, Leclair MD, et al. Laparoscopic treatment of renal cancer in children: a 
multicentric study and review of oncologic and surgical complications. J Pediatr Urol. 
2014;10(3):500-505. 
31. 
Warmann SW, Godzinski J, van Tinteren H, et al. Minimally invasive nephrectomy for Wilms 
tumors in children - data from SIOP 2001. J Pediatr Surg. 2014;49(11):1544-1548. 
32. 
Hankinson TC, Dudley RW, Torok MR, et al. Short-term mortality following surgical procedures 
for the diagnosis of pediatric brain tumors: outcome analysis in 5533 children from SEER, 2004-
2011. J Neurosurg Pediatr. 2016;17(3):289-297. 
33. 
Constantini S, Mohanty A, Zymberg S, et al. Safety and diagnostic accuracy of neuroendoscopic 
biopsies: an international multicenter study. J Neurosurg Pediatr. 2013;11(6):704-709. 
34. 
Song JH, Kong DS, Shin HJ. Feasibility of neuroendoscopic biopsy of pediatric brain tumors. 
Childs Nerv Syst. 2010;26(11):1593-1598. 
35. 
Miwa T, Hayashi N, Endo S, Ohira T. Neuroendoscopic biopsy and the treatment of tumor-
associated hydrocephalus of the ventricular and paraventricular region in pediatric patients: a 
nationwide study in Japan. Neurosurg Rev. 2015;38(4):693-704. 
36. 
Furlanetti LL, Monaco BA, Cordeiro JG, Lopez WO, Trippel M. Frame-based stereotactic 
neurosurgery in children under the age of seven: Freiburg University's experience from 99 
consecutive cases. Clin Neurol Neurosurg. 2015;130:42-47. 
37. 
Pincus DW, Richter EO, Yachnis AT, Bennett J, Bhatti MT, Smith A. Brainstem stereotactic 
biopsy sampling in children. J Neurosurg. 2006;104(2 Suppl):108-114. 
38. 
Rajshekhar V, Moorthy RK. Status of stereotactic biopsy in children with brain stem masses: 
insights from a series of 106 patients. Stereotact Funct Neurosurg. 2010;88(6):360-366. 
39. 
Puget S, Beccaria K, Blauwblomme T, et al. Biopsy in a series of 130 pediatric diffuse intrinsic 
Pontine gliomas. Childs Nerv Syst. 2015;31(10):1773-1780. 
40. 
Kim A, Fox E, Warren K, et al. Characteristics and outcome of pediatric patients enrolled in 
phase I oncology trials. Oncologist. 2008;13(6):679-689. 
41. 
Lee DP, Skolnik JM, Adamson PC. Pediatric phase I trials in oncology: an analysis of study 
conduct efficiency. J Clin Oncol. 2005;23(33):8431-8441. 
42. 
Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with 
refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 
consortium study. Lancet Oncol. 2013;14(6):472-480. 
43. 
Gajjar A, Bowers DC, Karajannis MA, Leary S, Witt H, Gottardo NG. Pediatric Brain Tumors: 
Innovative Genomic Information Is Transforming the Diagnostic and Clinical Landscape. J Clin 
Oncol. 2015;33(27):2986-2998. 
44. 
Bombard Y, Robson M, Offit K. Revealing the incidentalome when targeting the tumor genome. 
JAMA. 2013;310(8):795-796. 
45. 
Jones S, Anagnostou V, Lytle K, et al. Personalized genomic analyses for cancer mutation 
discovery and interpretation. Sci Transl Med. 2015;7(283):283ra253. 
46. 
Raymond VM, Gray SW, Roychowdhury S, et al. Germline Findings in Tumor-Only Sequencing: 
Points to Consider for Clinicians and Laboratories. J Natl Cancer Inst. 2016;108(4). 
47. 
Schrader KA, Cheng DT, Joseph V, et al. Germline Variants in Targeted Tumor Sequencing 

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Using Matched Normal DNA. JAMA Oncol. 2016;2(1):104-111. 
48. 
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence 
variants: a joint consensus recommendation of the American College of Medical Genetics and 
Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. 
49. 
Harris MH, DuBois SG, Glade Bender JL, et al. Multicenter Feasibility Study of Tumor 
Molecular Profiling to Inform Therapeutic Decisions in Advanced Pediatric Solid Tumors: The 
Individualized Cancer Therapy (iCat) Study. JAMA Oncol. 2016. 
50. 
Mody RJ, Wu YM, Lonigro RJ, et al. Integrative Clinical Sequencing in the Management of 
Refractory or Relapsed Cancer in Youth. JAMA. 2015;314(9):913-925. 
51. 
Everett JN, Mody RJ, Stoffel EM, Chinnaiyan AM. Incorporating genetic counseling into clinical 
care for children and adolescents with cancer. Future Oncol. 2016. 
52. 
Stadler ZK, Schrader KA, Vijai J, Robson ME, Offit K. Cancer genomics and inherited risk. J 
Clin Oncol. 2014;32(7):687-698. 
53. 
Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 
mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 
2011;12(6):559-567. 
54. 
Scollon S, Bergstrom K, Kerstein RA, et al. Obtaining informed consent for clinical tumor and 
germline exome sequencing of newly diagnosed childhood cancer patients. Genome Med. 
2014;6(9):69. 
55. 
McCullough LB, Slashinski MJ, McGuire AL, et al. Is Whole-Exome Sequencing an Ethically 
Disruptive Technology? Perspectives of Pediatric Oncologists and Parents of Pediatric Patients 
With Solid Tumors. Pediatr Blood Cancer. 2016;63(3):511-515. 
56. 
Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-
stage human malignancies. Sci Transl Med. 2014;6(224):224ra224. 
57. 
Olsson E, Winter C, George A, et al. Serial monitoring of circulating tumor DNA in patients with 
primary breast cancer for detection of occult metastatic disease. EMBO molecular medicine. 
2015. 
58. 
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr. 1985;106(3):522-526. 
59. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of pediatric 
phase I trials: the rolling six design. J Clin Oncol. 2008;26(2):190-195. 
60. 
A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20(6):859-
866. 
61. 
Agresti A, Coull BA. Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician. 1998;52(2):119-126. 
62. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). European journal of cancer (Oxford, England : 1990). 
2009;45(2):228-247. 
63. 
Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2015;33(18):2106-2111. 
64. 
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. 2014;32(27):3059-3068. 
62. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 

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APPENDIX I: EXAMPLES OF PEDIATRIC MATCH AGENT CLASSES AND LINKED 
GENETIC ALTERATIONS. 
Agent class 
aMOI 
Frequency 
Most frequent tumor 
types 
Gene 
Mutation 
by panel 
Fusion 
by panel 
CNV 
(amp) 
by panel 
CNV 
(del) by 
IHC 
TRK   
inhibitor 
2-3% 
LGG, HGG, infantile 
fibrosarcoma, sarcoma 
NTRK1 
 
Yes 
 
 
 
 
 
NTRK2 
 
Yes 
 
 
 
 
 
NTRK3 
 
Yes 
 
 
FGFR 
inhibitor 
2-3% 
NB, RMS, HGG 
FGFR1 
Yes 
Yes 
 
 
 
 
 
FGFR2 
Yes 
Yes 
 
 
 
 
 
FGFR3 
Yes 
Yes 
 
 
 
 
 
FGFR4 
Yes 
 
 
 
EZH2 
inhibitor 
2-3% 
NHL 
EZH2 
Yes 
 
 
 
 
 
 
SMARCB1 
Yes 
 
 
Yes 
 
 
 
SMARCA4 
Yes 
 
 
Yes 
PI3K/mTOR 
inhibitor 
5-10% 
OS, RMS, HGG 
PIK3CA 
Yes 
 
 
 
 
 
 
PIK3R1 
Yes 
 
 
 
 
 
 
MTOR 
Yes 
 
 
 
 
 
 
PTEN 
Yes 
 
 
Yes 
 
 
 
TSC1 
Yes 
 
 
 
 
 
 
TSC2 
Yes 
 
 
 
MEK 
inhibitor 
10-20% 
NHL, LCH, RMS, 
LGG, HGG, NB, 
ARAF 
Yes 
 
 
 
 
 
 
BRAF 
Yes 
Yes 
 
 
 
 
 
KRAS 
Yes 
 
 
 

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NRAS 
Yes 
 
 
 
 
 
 
HRAS 
Yes 
 
 
 
 
 
 
NF1 
Yes 
 
 
 
 
 
 
GNAQ 
Yes 
 
 
 
 
 
 
GNA11 
Yes 
 
 
 
 
 
 
MAP2K1 
Yes 
 
 
 
ALK 
inhibitor 
2-3% 
NB, IMT, ALCL 
ALK 
Yes 
Yes 
 
 
 
 
 
ROS1 
 
Yes 
 
 
BRAF   
inhibitor 
5% 
HGG, LGG, LCH, 
PTC, CP, glioneuronal 
BRAF 
Yes 
 
 
 
PARP 
inhibitor 
1-3% 
 
BRAC1 
Yes 
 
 
 
 
 
 
BRAC2 
Yes 
 
 
 
 
 
 
ATM 
Yes 
 
 
 
 
 
 
RAD51C 
Yes 
 
 
 
 
 
 
RAD51D 
Yes 
 
 
 
CDK 4/6 
inhibitor 
2-23% 
 
CDK4 
 
 
Yes 
 
 
 
 
CDK6 
 
 
Yes 
 
 
 
 
CCND1 
 
 
Yes 
 
 
 
 
CCND2 
 
 
Yes 
 
 
 
 
CCND3 
 
 
Yes 
 
 
Abbreviations: NHL, non-Hodgkin lymphoma; LCH, Langerhans cell histiocytosis; RMS, 
rhabdomyosarcoma; LGG, low grade glioma; HGG, high grade glioma; NB, neuroblastoma; OS, 
osteosarcoma; IMT, inflammatory myofibroblastic tumor; DFP, dermatofibrosarcoma protuberans; PTC, 
papillary thyroid carcinoma. 
 
 

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APPENDIX II: APEC1621SC TARGET HISTOLOGIES FOR 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 III: LEVELS OF EVIDENCE FOR SUBPROTOCOL AGENTS AND GENE 
VARIANTS AS AMOI 
 
Levels of Evidence for Pediatric MATCH trial arms (subprotocols) 
Level 1 
The drug is FDA approved for a malignant indication and there is a molecular 
abnormality that can serve as a valid predictive marker. The sub-protocol will not 
enroll patients with conditions for which the drug is approved, or patients with 
conditions for which the drug has been shown not to have benefit. 
Level 2 
The drug is investigational, but met a clinical endpoint (PFS, response) in any 
malignancy, has evidence of target inhibition and has evidence of a predictive 
molecular marker. 
Level 3 
The drug is investigational, but has demonstrated clinical activity in any 
malignancy and evidence of target inhibition, and has evidence of a predictive 
molecular marker. 
 
Levels of Evidence for Gene Variants as aMOI. 
Level 1 
Gene variant credentialed for selection of an approved drug (e.g. BRAF V600E 
and vermurafenib) 
Level 2a 
Gene variant is an eligibility criterion for an ongoing clinical trial 
Level 2b 
Gene variant has been identified in an N of 1 response (e.g. TSC1 and everolimus) 
Level 3a 
Preclinical inferential data (in vivo and in vitro models) that provide biological 
evidence sufficient to support the use of a variant for treatment selection, e.g.: 
• 
Models with variants respond to treatment and models without variant 
do not respond to treatment 
• 
Gain of function mutations demonstrated in pre-clinical model, e.g. 
D769H variant of ERBB2 results in increased tyrosine kinase-specific 
activity and up regulates pathway signaling (clinical evidence not 
required) 
• 
Loss of function genes, tumor suppressor or pathway inhibitor (e.g. 
NF1) any variant that produces a stop codon including frameshift or 
demonstrated loss of function in pre-clinical model (does not require 
treatment evidence) 
Level 3b 
Any known fusion transcript for a targeted gene (e.g. any reported ALK 
translocation) 
Level 3c 
Any copy number amplification for a targeted gene. 

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APPENDIX V: BIOSPECIMEN FLOW DIAGRAM USED FOR STAGE 1 OF PEDIATRIC MATCH 
TRIAL AT NATIONWIDE CHILDREN’S HOSPITAL 
 
 
 

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APPENDIX VI: APEC1621SC YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621SC 
(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 that you have.  
 
4. What will happen to me on the Study? Children who take part in this study will be screened to see 
if your cancer has any specific changes that could help us decide what medicine might “match” 
best to your cancer. If we find a medicine that could “match” your tumor then we would talk to you 
about that medicine and what we know about it. If you decide to be treated with that 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 that a medicine 
you receive 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 risks to you from this study are that you may have more problems, or side 
effects, from a medicine used as part of this study. There may be risks that we don’t know about. 
 
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 and tumor tissue. We want to see if there 
are ways to tell how the cancer will respond to treatment. These samples would be taken on tumor 
and blood samples we already have, so there would be no extra procedures. 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.  
 

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INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621SC 
(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? Patients who take part in this study will be screened to see 
if your cancer has any specific changes that could help us decide what medicine might “match” 
best to your cancer. If we find a medicine that could “match” your tumor then we would talk to you 
about that medicine and what we know about it. If you decide to be treated with that medicine you 
will have some tests and check-ups done more often than if you weren’t part of this study. We will 
collect information about 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 that a medicine 
you receive 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 risks to you from this study are that you may have more problems, or side 
effects, from a medicine used as part of this study. There may be risks that we don’t know about. 
 
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 and tumor tissue. We want to see if there 
are ways to tell how the cancer will respond to treatment. These samples would be taken on tumor 
and blood samples we already have, so there would be no extra procedures. 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.  
 
 

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CTSU REGISTRATION PROCEDURES 
Permission to view and download this protocol and its supporting documents is restricted and is based on 
the person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the Cancer Trials 
Support Unit (CTSU) members’ website. 
This study is supported by the NCI CTSU.  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU members’ 
website. Permission to view and download this protocol and its supporting documents is restricted based 
on person and site roster assignment. To participate, the institution and their associated investigators and 
staff must be associated with the LPO or a Protocol Organization (PO) on the protocol. One way to search 
for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and protocol 
number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
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) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory Submission Portal 
on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the Regulatory 
section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should alert the 
CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  

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• 
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. 
 
Data Submission / Data Reporting 
Medidata Rave is the clinical data management system being used for data collection for this trial/study. 
Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments.  
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT systems; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave Read Only, 
Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus (AP) 
registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
o Rave Read Only or Rave SLA role must have at a minimum an Associates (A) registration type. 
Refer to https://dctd.cancer.gov/research/ctep-trials/for-sites/registration for registration types and 
documentation required. 
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries and 
form delinquencies, monitor data quality and timeliness, generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave Home section 
displays a table providing summary counts of Total Delinquencies and Total Queries. DQP Queries, DQP 
Delinquent Forms, DQP Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and timeliness reports. Site staff 
should review the DQP modules on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to the CTSU website. Staff 
who have Rave study access can access the Rave study data via direct links available in the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a month. These 
notifications serve as alerts that queries and/or delinquent forms require site review, providing a summary 
count of queries and delinquent forms for each Rave study that a site is participating in. Additional site staff 
can subscribe and unsubscribe to these notifications using the CTSU Report and Information Subscription 
Portal on the CTSU members’ website. 
 
To learn more about DQP use and access, click on the Help Topics button displayed on the Rave Home, 
DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports modules.