NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of LOXO-292 in Patients With Tumors Harboring RET Gene Alterations
Phase: PHASE2
Conditions: Hematopoietic and Lymphatic System Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Histiocytic and Dendritic Cell Neoplasm, Recurrent Langerhans Cell Histiocytosis, Recurrent Lymphoma, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Histiocytic and Dendritic Cell Neoplasm, Refractory Langerhans Cell Histiocytosis, Refractory Lymphoma, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory WHO Grade 2 Glioma, Wilms Tumor
Sponsor: National Cancer Institute (NCI)

  
 
 
 
i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
 
October 28, 2022 
 
 
RE: Request for Amendments with FDA requested language for Pediatric 
MATCH consents 
 
Dear 
, 
 
The study committee thanks CTEP for forwarding the Amendment Request 
dated October 17, 2022. In response to the request, please see attached 
Amendment #3 to APEC1621N. The complete list of changes can be found 
below.  
 
Please contact us if you have any further questions. 
 
Sincerely, 
 
PPD
PPD
PPD
PPD
PPD

APEC1621N 
Page 1 
Version Date: 10/28/2022 
Activated: 
Closed: 
09/14/2020 
 
Version Date: 10/28/2022 
Amendment: # 3 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
APEC1621N 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF LOXO-292 IN PATIENTS WITH TUMORS HARBORING RET 
GENE ALTERATIONS 
 
 
Open to COG Member Institutions in Australia, New Zealand, Canada, and in the USA  
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
PPD

 
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Version Date: 10/28/2022 
 
Page 2 
 
 
Contact Information 
For Regulatory Requirements 
For patient enrollments: 
For Data Submission 
Regulatory documentation must be 
submitted to the Cancer Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651- CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory Help  
Desk at 1-866-651-2878 for  
regulatory assistance.. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study will  
be done exclusively through  
Medidata Rave. Please see the 
Submission Schedule in the CRF  
packet for further instructions. 
The most current version of the study protocol must be downloaded from the protocol-specific page located on the CTSU  
members’ website (https://www.ctsu.org). Access to the CTSU members’ website is managed through the Cancer  
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires log  
in with a CTEP-IAM username and password. Permission to view and download this protocoland its supporting documents is  
restricted and is based on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be  
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 

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TABLE OF CONTENTS
SECTION
PAGE
CHILDREN’S ONCOLOGY GROUP
1
STUDY COMMITTEE
6
STUDY COMMITTEE, CONT.
7
COG OPERATIONS STAFF
7
ABSTRACT
8
EXPERIMENTAL DESIGN SCHEMA
8
1.0
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
9
Primary Aims
9
Secondary Aims 
9
Exploratory Aims 
9
2.0
BACKGROUND
9
Introduction/Rationale for Development
9
Preclinical Studies
10
Adult Studies
11
Pediatric Studies
15
Overview of Proposed Pediatric Study 
15
3.0
SCREENING AND STUDY ENROLLMENT PROCEDURES
15
Study Enrollment 
15
Informed Consent/Assent 
18
Screening Procedures 
18
Eligibility Checklist
19
Study Enrollment 
19
Institutional Pathology Report 
19
Dose Assignment
20
4.0
PATIENT ELIGIBILITY
20
Inclusion Criteria 
20
Exclusion Criteria 
23
5.0
TREATMENT PROGRAM
25
Overview of Treatment Plan
25
Criteria for Starting Subsequent Cycles 
25
Grading of Adverse Events 
25
Definition of Dose-Limiting Toxicity (DLT)
26
6.0
DOSE MODIFICATIONS FOR ADVERSE EVENTS
27
Dose Modifications for Hematological Toxicity
27
Dose Modifications for Non-Hematological Toxicity
27
Growth Plate Toxicity
27
Dose Modification for QTc Prolongation 
28
Dose Modification for Hypersensitivity 
28
7.0
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY
28
Concurrent Anticancer Therapy 
28
Investigational Agents 
28
Supportive Care 
28
Growth Factors
29

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Concomitant Medications
29
8.0
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED
29
Required Clinical, Laboratory and Disease Evaluation 
29
Monitoring for Specific Toxicities
31
Radiology Studies 
32
Circulating Tumor DNA Study (optional) 
33
9.0
AGENT INFORMATION
35
Selpercatinib                                     (12/30/2021) 
35
Obtaining the Agent
41
Agent Accountability 
41
Useful Links and Contacts
42
10.0
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
43
Criteria for Removal from Protocol Therapy
43
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
43
11.0
STATISTICAL AND ETHICAL CONSIDERATIONS
44
Sample Size and Study Duration 
44
Dosing Considerations 
44
Study Design 
44
Methods of Analysis 
45
Evaluability for Response 
45
Evaluability for Toxicity 
45
Progression free survival (PFS) 
46
Correlative Studies
46
Gender and Minority Accrual Estimates
46
12.0
EVALUATION CRITERIA
46
Common Terminology Criteria for Adverse Events (CTCAE) 
46
Progression-Free Survival
47
Response Criteria for Patients with Solid Tumors 
47
Response Criteria for Patients with Solid Tumor and Measurable Disease
50
Response Criteria for Neuroblastoma Patients
52
Response Criteria for Patients with CNS Tumors 
58
Response Criteria for Patients with Non- Hodgkin Lymphoma/Histiocytosis 
60
Best Response 
62
13.0
ADVERSE EVENT REPORTING REQUIREMENTS
63
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
63
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
64
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
66
Definition of Onset and Resolution of Adverse Events 
66
Other Recipients of Adverse Event Reports
67
Specific Examples for Expedited Reporting 
67
Reporting of Study Drug Overdose 
69
14.0
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN
69
Categories of Research Records
69
CDUS
70
CRADA/CTA/CSA
70

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Data and Safety Monitoring Plan 
72
REFERENCES
73
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES
75
APPENDIX II:  CYP3A4 SUBSTRATES INDUCERS AND INHIBITORS
76
APPENDIX III-A:  MEDICATION DIARY FOR SELPERCATINIB (LOXO-292) (CAPSULE 
FORMULATION)
79
APPENDIX III-B MEDICATION DIARY FOR SELPERCATINIB (LOXO-292) (ORAL 
SUSPENSION)
82
APPENDIX IV CORRELATIVE STUDIES
85
APPENDIX V-A: SELPERCATINIB (LOXO-292) CAPSULE DOSING NOMOGRAM
86
APPENDIX V-B: SELPERCATINIB (LOXO-292) ORAL SUSPENSION DOSING
87
APPENDIX VI: APEC1621N THERAPY DELIVERY MAP
88
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621N EXPANSION COHORTS
92
APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS FOR SUBPROTOCOL APEC1621N
93
APPENDIX IX: CTEP AND CTSU REGISTRATION PROCEDURES
96
APPENDIX X: TOXICITY-SPECIFIC GRADING
99
APPENDIX XI: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD
100
APPENDIX XII:  YOUTH INFORMATION SHEETS
103
APPENDIX XIII MEDICATIONS ASSOCIATED WITH PROLONGED QTC
105

 
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PPD PPD

 
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STUDY COMMITTEE, CONT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 8.4.4 FOR SPECIMEN SHIPPING ADDRESSES 
 
 
PPD
PPD
PPD
PPD
PPD
PPD

 
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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. 
 
ABSTRACT 
This subprotocol is a component of the Pediatric MATCH trial APEC1621. The APEC1621SC screening 
protocol details the process used to identify actionable mutations in patient tumor samples which will 
determine eligibility for this subprotocol. This is a phase 2 trial of selpercatinib (LOXO-292) in children 
with relapsed or refractory solid tumors (including lymphomas, histiocytoses and CNS) harboring RET 
genomic alterations.  Selpercatinib (LOXO-292) is a novel, highly selective, ATP-competitive small 
molecule inhibitor of the RET receptor tyrosine kinase that has shown promise in adults with RET-altered 
cancers. The selectivity and highly potent activity of selpercatinib (LOXO-292) against RET in 
combination with favorable pharmacokinetic properties (high bioavailability, predictable exposure, 
significant CNS penetration, and low potential for drug interactions) suggest it may be a promising agent 
in pediatric patients with RET-altered tumors. Selpercatinib (LOXO-292) will be given at the recommended 
phase 2 dose (RP2D) of 90 mg/m2/dose twice daily (BID) continuously for 28-day cycles. The primary 
endpoint will be objective response rate as determined by RECIST. Progression free survival (PFS) will be 
assessed as a secondary endpoint.  
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-28 
selpercatinib (LOXO-292) 
Day 28 
Evaluation 
 
Selpercatinib (LOXO-292) will be administered at a dose of 90 mg/m2/dose twice daily (max dose 160 
mg BID); a cycle will be 28 days. Evaluations will occur every other cycle x 3, then every third cycle.  
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy. Therapy may otherwise continue for up to 2 years (maximum 
of 26 cycles) provided the patient meets the criteria for starting subsequent cycles (Section 5.2) and does 
not meet any of the criteria for removal from protocol therapy criteria (Section 10.0).  
 

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1.0
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
Primary Aims 
To determine the objective response rate (ORR; complete response + partial 
response) in pediatric patients treated with selpercatinib (LOXO-292) with 
advanced solid tumors (including CNS tumors), lymphomas or histiocytic 
disorders that harbor activating genetic alterations in the RET pathway. 
Secondary Aims
To estimate the progression free survival in pediatric patients treated with 
selpercatinib (LOXO-292) with advanced solid tumors (including CNS 
tumors), lymphomas or histiocytic disorders that harbor activating genetic 
alterations in the RET pathway.
To obtain information about the tolerability of selpercatinib (LOXO-292) in 
children and adolescents with relapsed or refractory cancer. 
Exploratory Aims
To explore approaches to profiling changes in tumor genomics over time 
through evaluation of circulating tumor DNA.
2.0
BACKGROUND
Introduction/Rationale for Development 
Constitutive activation of receptors within the family of receptor tyrosine kinases (RTKs) 
is one of the most common molecular defects found in cancers. The “rearranged during 
transfection” (RET) protooncogene is one such receptor in the RTK family that is found to 
be dysregulated in many cancers. The RET receptors are transmembrane glycoproteins and 
have critical roles in the normal development of kidney and enteric nervous system 
development and in the maintenance of several tissues, including neural, neuroendocrine, 
hematopoietic and male germ cell tissues.1 Normal RET activation is initiated by a ligand 
from the glial cell line-derived neurotropic factor (GDNF) family ligands (GFLs), where 
this ligand does not bind to RET directly but instead binds to the GNDF family receptor-
alpha (GFRߙ) RET co-receptors. Ligand binding to GFRߙleads to RET dimerization and 
subsequently to RET kinase-mediated auto-phosphorylation of the tyrosine residues in the 
RET intracellular domain. Constitutive activation of RET can lead to the activation of 
several signal transduction pathways involved in cellular proliferation, motility, 
differentiation, and survival. Such downstream pathways include Mitogen-Activated 
Protein Kinase (MAPK), Phophatidylinositol-3-Kinase (PI3k), Janus Kinase-Signal 
Transducer and Activator of Transcription (JAK-STAT), Protein Kinase A (PKA) and 
Protein Kinase C (PKC). 
RET is oncogenically activated through one of two mechanisms: chromosomal 
rearrangement leading to a constitutively-activated fusion protein or through a point 
mutation leading to kinase activation.
Oncogenic RET fusions have been identified in 6% of papillary thyroid cancer (PTC) and 

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2% of lung adenocarcinoma in adults.2,3 In addition, activating RET mutations occur at 
high frequency in medullary thyroid cancer (MTC), with RET mutations present in 
>90% of MTCs in patients with multiple endocrine neoplasia type 2 (MEN2) and ~50-
60% of sporadic MTCs.4-10 Recent sequencing of tumors from 4,871 adult patients with 
diverse tumor types demonstrated that RET aberrations occurred in 1.8% of all solid 
tumors, most commonly as RET mutations (38.6%), followed by fusions (30.7%) and 
amplifications (25.0%).11 Though generally infrequent, pathogenic RET mutations 
have been described in a variety of adult cancers, including renal papillary cell 
carcinoma, low grade glioma, testicular germ cell tumor, and pheochromocytoma.12  
The incidence of RET fusions in PTC estimated to be between 24-37%, with RET 
fusions more frequently seen in pediatric PTC than PTC in adults.13-15 The presence of a 
RET fusion in pediatric PTC is associated with a more aggressive phenotype than PTCs 
without a RET fusion.16 Activating RET mutations are seen in MTC in the adolescent and 
young adult population at a similarly high frequency (93%) when compared to MTC in 
older adults.15 Lastly, RET mutations have been detected in circulating tumor DNA 
obtained from children with malignant peripheral nerve sheath tumors.17 Given the recent 
adult sequencing data demonstrating RET aberrations in 1.8% of a large variety of solid 
tumors, including sarcomas, it is likely that similar RET aberrations will be described 
in other pediatric solid tumors as well.  
Several multi-kinase inhibitors (MKIs) with some degree of anti-RET activity are 
commercially-available or are currently being studied in clinical trials, such as the Federal 
Drug Administration (FDA)-approved MKIs sorafenib, sunitinib, cabozantinib, and 
vandetanib. However, in RET-altered tumors, the efficacy of these MKIs is limited due to 
dose limitations related to off-target toxicities and/or undesirable pharmacokinetic (PK) 
properties and only modest inhibition of RET signaling. Two MKIs, cabozantinib and 
vandetanib, have received regulatory approval for advanced MTC, regardless of RET 
mutation status, with response rates of 28% and 45%, respectively, and progression-free 
survival benefit of 7.2 and 11.2 months, respectively.18,19 In both studies, subset analyses 
revealed that patients whose tumors harbored RET-activating mutations had greater benefit 
than patients whose tumors were not RET-altered.19,20
Patients with RET-altered cancers represent a population with an unmet need. Cytotoxic 
chemotherapy is often ineffective in patients with relapsed or refractory cancers, and 
targeted therapy may provide an alternative approach. Highly selective RET TKIs have not 
been developed to date. Selpercatinib (LOXO-292) is a novel, small molecule inhibitor of 
the RET receptor tyrosine kinase that has shown clinical promise in adults with RET-altered 
cancers. 
Preclinical Studies
Selpercatinib (LOXO-292) is a novel, highly selective, ATP-competitive small molecule 
inhibitor of the RET receptor tyrosine kinase. Several pre-clinical studies21 of selpercatinib
(LOXO-292) have demonstrated potent RET inhibition in both RET fusion and RET mutant 
models.21 In vitro, selpercatinib (LOXO-292) has been shown to potently inhibit the 
KIF5B-RET fusion protein and the full-length RET receptor harboring activating 
mutations (IC50 1-10 nM), with much less cytotoxicity against human cancer cell lines 
without RET alterations (IC50 100-10,000 nM). Minimal loss of inhibitory activity of 
selpercatinib (LOXO-292) was seen in the setting of potential acquired resistant mutations 
(i.e. V804L/M “gatekeeper” substitutions), which causes resistance to multi-kinase 

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inhibitors (MKIs). In xenograft models of human cancer cell lines harboring endogenous 
RET alterations, (non-small cell lung cancer CCDC6-RET and medullary thyroid cancer 
RET-C643W), and two patient-derived xenografts (PDXs) with CCDC6-RET fusions, 
selpercatinib (LOXO-292) inhibited tumor growth in a dose-dependent manner.21
Additionally, selpercatinib (LOXO-292) was more than 250-fold selective for RET than 
for 98% of 329 non-RET kinases tested in a large in vitro screen. This high degree of 
selectivity was maintained against both kinase and non-kinase off-targets when validated 
in additional enzyme, cell-based, radio-ligand binding and in vivo assays.21
Animal Toxicology
In toxicology studies of selpercatinib (LOXO-292) that were conducted in the rat and 
minipig, the primary pathologic findings for both species were noted in the tongue, 
pancreas, bone marrow and lymphoid tissues.21 Other target tissues identified in the 
minipig included the gastrointestinal (GI) tract and ovaries. In the rat, other target tissues 
identified included multi-tissue mineralization, physeal cartilage, incisor teeth, lung, and 
possibly liver. Assessment of doses associated with moribundity/death revealed a steep 
dose-response curve for both species. 
Selpercatinib (LOXO-292) was not mutagenic in the GLP bacterial mutation assay. When 
evaluated in two in vitro assays, selpercatinib (LOXO-292) was not genotoxic. 
Selpercatinib (LOXO-292) was not found to be phototoxic when evaluated in an in vitro 
neutral red uptake phototoxicity assay.21
Adult Studies
Phase 1/2 Studies
Results from a Phase 1/2 study of selpercatinib (LOXO-292) in patients t 12 years
of age (LIBRETTO-001, NCT03157128) were initially presented at the American
Society of Clinical Oncology (ASCO) annual meeting in 2018.22 As of June 2019, 
safety data were available from 531 patients who had received selpercatinib
(LOXO-292) from active ongoing Phase 1/2. In the phase 1 portion of the study, 
dose range from 20 mg QD to 240 mg BID. The median age of patients was 59 
years and ranged from 15 to 90 years.  
Selpercatinib (LOXO-292) was well-tolerated, with most treatment-emergent AEs
(TEAEs) categorized as Grade 1 in severity. A total of 271/531 (51.0%) across 
all dose levels experienced Grade 3-4 TEAEs, and considered to be related to 
study drug in 132 patients (24.9%). The most common Grade 3-4 TEAEs 
included hypertension (13.9%; 8.1% related), ALT increased (8.5%; 7.0% 
related), AST increased (6.4%; 4.5% related), hyponatremia (5.1%; 0.4% 
related), ECG QT prolonged (3.6%; 2.4% related), lymphopenia (3.4%; 1.1% 
related), thrombocytopenia and neutropenia (each 2.3%; 1.9% and 1.5% related, 
respectively), and diarrhea (2.1%; 0.8% related). Grade 4 TEAES of AST and 
ALT elevation, thrombocytopenia, and hypertension were noted in a total of 6 
patients (6/531, 1.1%), none of which were life-threatening.

 
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Patient plasma exposures were dose-dependent and linear in the dose range used 
(20 mg daily to 240 mg BID). The RP2D was determined to be a fixed dose 
of 160 mg BID (90 mg/m2/dose). A total of 3 patients (0.6%) experienced AEs 
that met criteria for TLDs, and two of these occurred at a dose of 240 mg BID. 
The only DLT observed at 160 mg BID was in one patient Grade 2 
hypersensitivity. A total of 24 patients were started at this dose during phase one 
dose escalation, and therefore the single DLT did not affect the selection of 160 
mg BID as the RP2D. The Phase 2 dose expansion portion of this study is ongoing. 
 
Efficacy in RET Fusion-positive Non-Small Cell Lung Cancer  
 
As of June 2019, clinical data were presented at the IASLC World Conference on 
Lung Cancer, with a primary analysis set of 105 patients with RET fusion-positive 
non-small cell lung cancer (NSCLC). Within this patient subset, the objective 
response rate (ORR) by investigator response assessment was 67.6% (71/105; 
95% confidence interval (CI): 58-75). The median duration of response (DOR) 
was 20.3 months (95% CI: 13.8-24.0), and the progression-free survival (PFS) 
was 18.4 months (95% CI: 12.9-24.9). ORR, DOR, and PFS were similar prior to 
prior therapy the patients had received (e.g. anti-PD-1/PD-L1, MKIs, etc). Of 
note, 11 patients in the primary analysis set had measurable CNS metastasis at 
baseline (based on investigator assessment), and the intracranial ORR in these 
patients was 90.9% (10/22; 95% CI: 59-100). Lastly, in a subset of efficacy-
evaluable patients who were treatment naïve with RET fusion-positive NSCLS, 
the ORR was 85.3% (29/34; 95% CI: 69-95), including 7 partial response (PRs) 
pending confirmation as of December 2019.  
 
Efficacy in RET-mutant and RET Fusion-positive Thyroid Cancer  
 
As presented at the 2019 European Society of Medical Oncology Congress, 226 
patients with RET-mutant medullary thyroid cancer (MTC) and 27 patients with 
RET fusion-positive thyroid cancer. The primary analysis set consisted of the first 
55 RET-mutant MTC patients who had received prior cabozantinib and/or 
vandetanib. The ORR was 56.4% (31/55; 95% CI: 42-70). The median DOR was 
not reached, with 6/29 events observed and a median follow up of 10.6 months.  
 
In a total of 88 patients with cabozantinib/vandetanib-naïve RET-mutant MTC 
treated with selpercatinib (LOXO-292), 76 were evaluable for efficacy, with an 
ORR of 59.2% (45/76; 95% CI: 47-70). The median PFS was not reached, with 
1/76 (1.3%) events observed at a median follow-up of 5.7 months.   
 
A total of 27 patients with RET fusion-positive thyroid cancer were treated with 
selpercatinib (LOXO-292), and represented 4 thyroid cancer histologies 
(papillary, poorly-differentiated, anaplastic, and Hurthle cell). Of these, 26 
patients were eligible for efficacy evaluation. The ORR was found to be 61.5% 
(16/26; 95% CI: 41-80). The median follow-up was 9.9 months with a median 
PFS not reached, with 5/26 (19.2%) events observed.   
 
Selpercatinib (LOXO-292) was granted Breakthrough Therapy Designation in 
September 2018 based on the results from LIBRETTO-001 and achieved FDA 
approval in May 2020. 
  

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RET Fusion/Mutation as biomarker
Data from this phase 1/2 study of selpercatinib (LOXO-292) suggest that neither
the specific RET fusion partner nor the specific RET point mutation altered the 
efficacy seen across the spectrum of tumor types. These data suggest that similar 
efficacy may be seen in pediatric patients with RET fusions or mutations, 
regardless of tumor type.
Pediatric Single Patient Protocols
As of 17 June 2019, Loxo Oncology has initiated 5 pediatric single patient 
protocols (SPPs), Special Access Scheme, or Temporary Authorization Use 
(ATU) cases to provide access to selpercatinib (LOXO-292) for patients with 
clinical need not meeting eligibility criteria for the ongoing clinical study. To 
date, no SAEs or TEAEs greater than Grade 3 have been attributed to study drug 
for these patients.
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
Absorption: 
Solubility and PK studies suggest that the PK exposure of selpercatinib (LOXO-
292) may be reduced by proton pump inhibitors and other antacids. Modeling data 
suggest that human exposure will be higher under fed conditions (vs. fasted) at 
higher doses of selpercatinib (LOXO-292) (t 100 mg BID). Data from the study 
LOXO-RET-17001 analyzed as of August 2018 at steady-state (Cycle 1 Day 8) 
show that selpercatinib (LOXO-292) is absorbed after oral administration with a 
median time to maximum concentration (Tmax) of approximately 2 hours. Plasma 
half-life was calculated to be approximately 20 hours (though was limited by a 
small sampling interval of 0 to 8 hours).  
The mean Cmin (pre-dose, trough concentration) is approximately 600 ng/mL in 
patients during steady-state treatment with 60 mg BID selpercatinib (LOXO-292) 
or higher, which corresponds to a mean plasma free drug concentration 
approximately equal to the IC90 for inhibition of RET.

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safety data (N=82) and preliminary efficacy data in 64 evaluable patients treated 
at doses from 20 mg QD through 240 mg BID.23
Pediatric Studies
Prior Experience in Children  
An industry-sponsored phase 1/2 study of selpercatinib (LOXO-292) in pediatric 
patients is open for enrollment as of March 2019 (NCT03899792). A small number 
of patients have been treated with selpercatinib (LOXO-292). 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
There have been no pediatric Pharmacology/Pharmacokinetic/Correlative 
Biological Studies of selpercatinib (LOXO-292).  
Overview of Proposed Pediatric Study
This is a phase 2 trial of selpercatinib (LOXO-292) monotherapy in children with recurrent 
or refractory solid tumors, CNS tumors, non-Hodgkin lymphomas and histiocytic disorders 
harboring specific activating mutations in the RET receptor tyrosine kinase. 
No MTD was reached in the adult phase 1 study and the RP2D was determined to be 160 
mg BID (90 mg/m2/dose). The dose of 90 mg/m2/dose administered BID will be used in 
this study.  
The primary aim of this trial will be to establish the objective response rate to selpercatinib
(LOXO-292). While there will not be multiple pre-determined mutation-based cohorts, 
responses will be analyzed retrospectively with respect to RET fusions versus RET-
activating mutations. 
Key secondary objectives include evaluation of the tolerability of selpercatinib (LOXO-
292) in pediatric patients. Toxicity will be assessed using the CTCAE V5.0. Imaging for 
disease evaluation will occur every other cycle x3, then every three cycles. Disease 
response will be assessed according to RECIST v1.1 for solid tumors and 2-dimensional 
measurement for CNS tumors.  
3.0
SCREENING AND STUDY ENROLLMENT PROCEDURES
Study Enrollment
Patient enrollment for this study will be facilitated using the Oncology Patient Enrollment 
Network (OPEN), a web-based registration system available on a 24/7 basis. It is integrated 
with the NCI Cancer Trials Support Unit (CTSU) Enterprise System for regulatory and 
roster data and, upon enrollment, initializes the patient position in the RAVE database. 
Access requirements for OPEN: 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). The Oncology Patient Enrollment Network (OPEN) is a web-
based registration system available on a 24/7 basis. OPEN is integrated with CTSU 
regulatory and roster data and with the Lead Protocol Organization (LPOs) 
registration/randomization systems or Theradex Interactive Web Response System 

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(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: 
x
A valid CTEP-IAM account;
x
To perform enrollments:  Be on a LPO roster, ETCTN Corresponding 
roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
x
Have an approved site registration for a protocol prior to patient 
enrollment.
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
x
Patient has met all eligibility criteria within the protocol stated 
timeframes; and 
x
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org  or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
Please see Appendix IX for detailed CTEP and CTSU Registration Procedures 
including registration in Registration and Credential Repository (RCR), 
requirements for site registration, submission of regulatory documents and how to 
check your site’s registration status.
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. For 
CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must 
be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be 

 
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Page 17 
accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
x 
Local IRB documentation; 
x 
IRB-signed CTSU IRB Certification Form; and/or 
x 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on 
the IRB/REB approval) must meet the following criteria in order for the processing 
of the IRB/REB approval record to be completed: 
 
x 
Holds an active CTEP status; 
x 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
x 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
x 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
x 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
x 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix X. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 

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CTSU General Helpdesk at: 1-888-823-5923. 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review.
Investigators and site staff will need to be registered with CTEP and have a valid 
and active Cancer Therapy Evaluation Program-Identity and Access Management 
(CTEP-IAM) account (check at < https://ctepcore.nci.nih.gov/iam/ >). This is the 
same account (user id and password) used for credentialing in the CTSU members' 
web site. To perform registrations in OPEN, the site user must have been assigned 
the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be accessed 
at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. Registrars must hold a minimum of an AP 
registration type.   
Genetic Screening Procedures for Eligibility 
Patient enrollment onto the APEC1621SC screening protocol is required. In Stage 
2 of Pediatric MATCH (effective with Amendment #4 of APEC1621SC for 
patients enrolling on screening protocol) tumor genomic testing results from a 
CAP/CLIA-certified laboratory will be reviewed by the APEC1621SC Molecular 
Review Committee after APEC1621SC screening protocol enrollment to confirm 
the identification of an actionable Mutation of Interest (aMOI) for which a 
MATCH treatment subprotocol is available. Questions regarding interpretation of 
tumor testing results for potential APEC1621N study patients (such as whether a 
specific mutation would be considered actionable for the study) should be directed 
to the APEC1621SC and APEC1621N study chairs.
The treatment assignment to MATCH to a subprotocol (if a relevant aMOI is 
detected)  will be communicated to the enrolling institution via the COG or 
MATCHBox treatment assignment mechanism at the time the results of MATCH 
are returned, upon which a reservation to APEC1621N will be secured by COG. 
Reservations should be withdrawn by the institution if at any point the patient 
indicates they do NOT intend to consent to participation or the site investigator 
indicates the patient will never be eligible for APEC1621N. 
Informed Consent/Assent 
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
Screening Procedures
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through the study-specific protocol.  Documentation of the informed consent for screening 
will be maintained in the patient’s research chart. Studies or procedures that were 

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performed for clinical indications (not exclusively to determine eligibility) may be used for 
baseline values even if the studies were done before informed consent was obtained.
Eligibility Checklist
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
Study Enrollment
Following a MATCH treatment assignment to a protocol, patients may be enrolled on the 
study once all eligibility requirements for the study have been met. Before enrolling a 
patient on study, the Study Chair or Vice Chair should be notified. Patients who give 
informed consent for the protocol in order to undergo screening for eligibility are not 
considered enrolled and should not be enrolled until the screening is completed and they 
are determined to meet all eligibility criteria. Study enrollment in Stage 2 of Pediatric 
MATCH (effective with Amendment #4 of APEC1621SC for patients enrolling on 
screening protocol) is outlined in Section 3.1.3. 
Patients must be enrolled within 2 weeks (14 days) of treatment assignment. Protocol 
therapy must start no later than 7 calendar days after the date of enrollment. Patients 
enrolling onto APEC1621N will have a COG ID obtained through their prior enrollment 
onto the screening protocol or from a prior COG study. Patients who are started on protocol 
therapy prior to study enrollment will be considered ineligible.
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated in the eligibility section below. 
Note:  No starter supplies will be provided. Drug orders of selpercatinib (LOXO-292) 
should be placed with CTEP after enrollment and treatment assignment to 
APEC1621N with consideration for timing of processing and shipping to ensure 
receipt of drug supply prior to start of protocol therapy
Reassignment Request through APEC1621SC (if unable to enroll within 8 week 
timeframe)
The treating team may email PedsMATCHOps@childrensoncologygroup.org and 
the APEC1621SC study co-chairs (dwparson@txch.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.
Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621 
master screening protocol.  

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Dose Assignment
The dose will be assigned via OPEN at the time of study enrollment.
4.0
PATIENT ELIGIBILITY
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) must be obtained within 14 days
prior to start of protocol therapy (repeat the tumor imaging if necessary).  
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived.  All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient’s medical or research record which will 
serve as the source document for verification at the time of audit.
Inclusion Criteria
APEC1621SC: Patient must have enrolled onto APEC1621SC and must 
have been given a treatment assignment to MATCH to APEC1621N based 
on the presence of an actionable mutation as defined in APEC1621SC. 
Examples of actionable mutations for APEC1621N are listed in Appendix 
VIII. 
Age: Patients must be t than 12 months and d 21 years of age at the time of 
study enrollment.
Disease Status: Patients must have radiographically measurable disease 
(See Section 12) at the time of study enrollment. Patients with 
neuroblastoma who do not have measurable disease but have MIBG+ 
evaluable disease are eligible. Measurable disease in patients with CNS 
involvement is defined as any lesion that is at minimum 10 mm in one 
dimension on standard MRI or CT.
Note:  The following do not qualify as measurable disease:  
- 
malignant fluid collections (e.g., ascites, pleural effusions)
- 
bone marrow infiltration except that detected by MIBG scan for 
neuroblastoma 
- 
lesions only detected by nuclear medicine studies (e.g., bone, gallium or 
PET scans) except as noted for neuroblastoma
- 
elevated tumor markers in plasma or CSF 

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- 
previously radiated lesions that have not demonstrated clear progression 
post radiation 
- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1.
Performance Level: Karnofsky t 50% for patients > 16 years of age and 
Lansky t 50 for patients d 16 years of age (See Appendix I).  Note:  
Neurologic deficits in patients with CNS tumors must have been relatively 
stable for at least 7 days prior to study enrollment.  Patients who are unable 
to walk because of paralysis, but who are up in a wheelchair, will be 
considered ambulatory for the purpose of assessing the performance score. 
Prior Therapy
Patients must have fully recovered from the acute toxic effects of all prior 
anti-cancer therapy and must meet the following minimum duration from 
prior anti-cancer directed therapy prior to enrollment. If after the required 
timeframe, the numerical eligibility criteria are met, e.g. blood count 
criteria, the patient is considered to have recovered adequately.
a.
Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See https://www.cogmembers.org/site/disc/devthe
rapeutics/default.aspx for commercial and Phase 1 investigational 
agent classifications. For agents not listed, the duration of this interval 
must be discussed with the study chair and the study-assigned 
Research Coordinator prior to enrollment. 
i.
GD\VDIWHUWKHODVWGRVHRIF\WRWR[LFRUmyelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
 
b.
Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts) 7 days after the 
last dose of agent. See https://www.cogmembers.org/site/disc/devthe
rapeutics/default.aspx for commercial and Phase 1 investigational 
agent classifications. For agents not listed, the duration of this interval 
must be discussed with the study chair and the study-assigned 
Research Coordinator prior to enrollment.  
c.
AntibodiesGD\VPXVWKDYHHODSVHGIURPLQIXVLRQRIODVWGRVHRI
antibody, and toxicity related to prior antibody therapy must be 
UHFRYHUHGWR*UDGH
d.
Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapyGD\VPXVWKDYHelapsed 
since last dose of corticosteroid.
e.
Hematopoietic growth factors:  14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 
growth factor. For growth factors that have known adverse events 
occurring beyond 7 days after administration, this period must be 
extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the study 

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chair and the study-assigned Research Coordinator. 
f.
Interleukins, Interferons and Cytokines (other than hematopoetic 
growth factors)   days after the completion of interleukins, 
interferon or cytokines (other than hematopoetic growth factors)
g.
Stem cell Infusions (with or without TBI): 
x
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. 
x
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   GD\V DIWHU
local XRT;  150 days after TBI, craniospinal XRT or if radiation to 
t 50% of the pelvis; 42 days if other substantial BM radiation. 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment.
j.
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG

42 
days
after 
systemically 
administered 
radiopharmaceutical therapy. 
k.
Patients must not have received prior exposure to selpercatinib
(LOXO-292) or other specific RET inhibitors. 
Organ Function Requirements 
Adequate Bone Marrow Function Defined as: 
a.
For patients with solid tumors without known bone marrow 
involvement:
- 
Peripheral absolute neutrophil count (ANC) t 1000/mm3
- 
Platelet count t 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 4.1.6.1.a
(may receive transfusions provided they are not known to be 
refractory to red cell or platelet transfusions). These patients will 
not be evaluable for hematologic toxicity.  
Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR t 70ml/min/1.73 m2 or
-
A serum creatinine based on age/gender as follows:

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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
\HDUV
1.7
1.4
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC.
Adequate Liver Function Defined as: 
-
Bilirubin (sum of conjugated + unconjugated) d 1.5 x upper limit of 
normal (ULN) for age 
-
SGPT (ALT) d 135 U/L.  (For the purpose of this study, the ULN for 
SGPT is 45 U/L.)  
-
Serum albumin t 2 g/dL.
Adequate Cardiac Function Defined As: 
-  
QTc interval d 480 milliseconds
Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when 
appropriate, will be obtained according to institutional guidelines.  
Exclusion Criteria
Pregnancy or Breast-Feeding
Pregnant or breast-feeding women will not be entered on this study due to 
risks of fetal and teratogenic adverse events as seen in animal/human studies. 
Pregnancy tests must be obtained in girls who are post-menarchal. Males or 
females of reproductive potential may not participate unless they have agreed 
to use two (2) highly effective contraceptive method for the duration of study 
treatment and for at least 2 weeks after the last dose of selpercatinib (LOXO-
292). Male study participants are to refrain from sperm donation during 
treatment and for 2 weeks after the last dose of selpercatinib (LOXO-292). 
Concomitant Medications
Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events
related to prior therapyGD\VPXVWKDYHHODSVHGVLQFHODVWGRVHRI
corticosteroid (See Section 4.1.5.1.d). 
Investigational Drugs:  Patients who are currently receiving another 
investigational drug are not eligible. 
Anti-cancer Agents:  Patients who are currently receiving other anti-cancer 

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agents are not eligible.
Anti-GVHD agents post-transplant: 
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial.
CYP3A4 Agents: Patients who are currently receiving drugs that are 
moderate or strong inducers or inhibitors of CYP3A4 are not eligible. 
Strong inducers or inhibitors of CYP3A4 should be avoided from 14 days 
prior to enrollment to the end of the study. See Appendix II for a list of 
agents. Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone 
for CNS tumors or metastases, on a stable dose, are allowed. 
Proton Pump Inhibitors (PPIs), H2 receptor antagonists and antacids: 
Concomitant use of PPIs during selpercatinib (LOXO-292) therapy should 
be avoided if feasible. If co-administration of selpercatinib and PPI is 
necessary, administer selpercatinib with a meal. If H2 receptor antagonist 
is necessary, administer selpercatinib 2 hours before or 10 hours after H2 
receptor antagonist administration. If antacid use is necessary, administer 
selpercatinib 2 or more hours before or 2 or more hours after antacid 
administration. 
Surgery: Patients who have major surgery within 14 days prior to C1D1 are 
not eligible. (Central line placement or subcutaneous port placement is not 
considered major surgery)
Patients with known clinically significant active malabsorption syndrome or 
other condition likely to affect gastrointestinal absorption of selpercatinib
(LOXO-292) are excluded. 
Patients with known hypersensitivity to any of the components of the 
investigational agent, LOXO 292 are excluded. 
Patients with uncontrolled hypertension are excluded 
Patients with uncontrolled symptomatic hyperthyroidism and hypothyroidism 
(i.e. the patient required a modification to current thyroid medication in 7 
days prior to enrollment) are excluded. 
Patients with uncontrolled symptomatic hypercalcemia and hypocalcemia 
are excluded. 
Infection:  Patients who have an uncontrolled infection are not eligible. 
Patients who have received a prior solid organ transplantation are not 
eligible.
Patients who in the opinion of the investigator may not be able to comply 
with the safety monitoring requirements of the study are not eligible.

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5.0
TREATMENT PROGRAM
Overview of Treatment Plan 
Selpercatinib (LOXO-292) Treatment Schedule 
Table
Days 1-28 
90 mg/m2/dose orally twice daily
(max dose 160 mg BID)
Day 28
Evaluation
Patients will receive selpercatinib orally twice daily, continuously for 28-day cycles (please 
see capsule dosing nomogram in Appendix V-A). Evaluations will occur at the end of every 
other cycle x 3, then every 3 cycles. A cycle may be repeated up to a total duration of 
therapy of 2 years (maximum of 26 cycles).  
Drug doses should be adjusted based on the BSA calculated from height and weight 
measured within 7 days prior to the beginning of each cycle. Selpercatinib is administered 
orally twice daily, approximately 12 hours apart. Doses may be taken without regard to food. 
Capsules are to be swallowed whole. Do not chew, crush or open capsules. Oral suspension 
may be administered orally or by naso- or gastric-feeding tube. If study subject vomits
immediately after taking a capsule dose and the capsules are still intact, the dose may be 
repeated. If study subject vomits after taking an oral suspension dose, the dose should not be 
repeated. If a dose is missed, it may be administered if there are at least 6 hours remaining 
until the next scheduled dose.
Doses of selpercatinib capsules should be rounded to the nearest 40 mg (Appendix V-A). 
Calculated dosing volumes of selpercatinib suspension formulation should be rounded to 
the QHDUHVWP/PJIRUGRVHV45 mg LQRUDOV\ULQJHVP/and 0.2 mL (4 mg) 
for doses > 45 mg LQRUDOV\ULQJHVP/for the actual deliverable dose (Appendix V-
B).  
Therapy will be discontinued if there is evidence of progressive disease or drug related 
dose-limiting toxicity that requires removal from therapy (Section 6.0). Therapy may 
otherwise continue for up to 2 years (maximum of 26 cycles) provided the patient meets 
the criteria for starting subsequent cycles (Section 5.2) and does not meet any of the criteria 
for removal from protocol therapy criteria (Section 10.0).
Selpercatinib is provided by the NCI PMB. Do not use commercial supply. 
Therapy Delivery Map
See Appendix VI for therapy delivery map for Cycle 1 and subsequent cycles.
Intra-Patient Escalation
Intrapatient dose escalation is not allowed. 
Criteria for Starting Subsequent Cycles
A cycle may be repeated every 28 days if the patient has at least stable disease and has 
again met laboratory parameters as defined in the eligibility section, Section 4.0 and 
eligible to continue agent administration per the requirements in Section 6.0
Grading of Adverse Events

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Adverse events (toxicities) will be graded according to the current version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment 
areas should have access to a copy of the current version of the CTCAEv5.0.  A copy of 
the CTCAEv5.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
Definition of Dose-Limiting Toxicity (DLT)
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. Dose limiting hematological and non-hematological 
toxicities are defined differently. 
Non-Hematological Dose-Limiting Toxicity
Grade 2 Electrocardiogram QT corrected interval prolonged (QTC > 
480ms) will be considered a non-hematological toxicity. 
Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days. See 
Appendix X for values that represent thresholds between CTCAE grades. 
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation 
x
Any Grade 2 non-hematological toxicity that persists for  7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption.
x
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity.
Hematological dose limiting toxicity 
Hematological dose limiting toxicity is defined as:
a)
In patients evaluable for hematological toxicity (see Section 4.1.6.1),   
x
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration
x
Grade 3 thrombocytopenia WKDWSHUVLVWVIRUGD\V
x
Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days within a 7-day period 
x
Grade 3 thrombocytopenia with clinically significant bleeding
x
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles (e.g. platelets <100K or ANC<1000).
Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-

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limiting toxicity. 
6.0
DOSE MODIFICATIONS FOR ADVERSE EVENTS
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
Dose Modifications for Hematological Toxicity
If a patient experiences hematological toxicity as defined in Section 5.4.2.1, 
the treatment will be held.  Counts should be checked every 3-4 days for 
thrombocytopenia and every other day for neutropenia during this time. If 
the toxicity resolves to meet eligibility parameters within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose (see 
Appendix V-A for capsule formulation dosing nomogram and Appendix V-
B for preparation of oral solution formulation). Doses reduced for toxicity 
will not be re-escalated, even if there is minimal or no toxicity with the 
reduced dose.  
If toxicity does not resolve to meet eligibility parameters within 14 days of 
drug discontinuation, the patient must be removed from protocol therapy. 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol 
therapy. 
Dose Modifications for Non-Hematological Toxicity
If a patient experiences non-hematological dose-limiting toxicity as defined 
in Section 5.4.1, the treatment will be held. When the toxicity resolves to 
meet eligibility parameters or baseline within 14 days of drug 
discontinuation, the patient may resume treatment at a reduced dose (see 
Appendix V-A for capsule formulation dosing nomogram and Appendix V-
B for oral suspension formulation). Doses reduced for toxicity will not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.
If toxicity does not resolve to meet eligibility or baseline parameters within 
14 days of drug discontinuation, the patient must be removed from protocol 
therapy. 
If dose-limiting toxicity recurs in a patient who has resumed treatment at the 
reduced dose, the patient must be removed from protocol therapy. 
Growth Plate Toxicity
Patients who are found to have radiographic evidence of an open tibial 
growth plate should follow the radiographic monitoring as outlined in 
Section 8.2.1.  

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Dose Modification for QTc Prolongation 
Adverse Reactions 
Recommended Action 
QTc interval  480-499 
x
Monitor and supplement electrolyte levels as clinically indicated, evaluation 
by a cardiologist and other necessary interventions may be considered, 
perform an additional EKG. 
x
Selpercatinib may be resumed at the dose reduction outlined in Appendix 
V-A and Appendix V-B when QTc has returned to baseline value, and with 
continued ECG monitoring as clinically indicated.
QTc interval > 500 msec.
x
Monitor and supplement electrolyte levels as clinically indicated, evaluation 
by a cardiologist and other necessary interventions may be considered, If 
any EKG demonstrates QTc > 500 msec, repeat the EKG twice (triplicate in 
total) and manually review to confirm accuracy. If QTc > 500 msec is 
confirmed on 2/3 ECGs, hold selpercatinib (LOXO-292) and assess for 
alternative causes (concomitant medications, electrolyte abnormalities).
x
Selpercatinib may be resumed at one reduced dose level when QTc has 
returned to baseline value, and with continued ECG monitoring as clinically
indicated.
QTc interval prolongation 
with signs/symptoms of life-
threatening arrhythmia
Discontinue selpercatinib permanently.
Dose Modification for Hypersensitivity
Signs and symptoms of hypersensitivity included fever, rash and 
arthralgias or myalgias with concurrent decreased platelets or transaminitis. 
If hypersensitivity occurs, withhold selpercatinib and begin corticosteroids 
at a dose of 1 mg/kg. Upon resolution of the event, resume selpercatinib at 
a reduced dose and increase the dose of selpercatinib by 1 dose level each 
week as tolerated until reaching the dose taken prior to onset of 
hypersensitivity. Continue steroids until patient reaches target dose and 
then taper. Permanently discontinue selpercatinib for recurrent 
hypersensitivity. 
7.0
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY
Concurrent Anticancer Therapy
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy.
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
Supportive Care
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 7.5 for drugs that should not be used 
concomitantly due to potential interactions with selpercatinib. 

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Growth Factors
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
Concomitant Medications 
CYP3A4 inhibitors or inducers: Strong or moderate CYP3A4 inhibitors or 
inducers are prohibited from 14 days prior to enrollment to the end of the 
study (see Appendix II for list of agents). Note: CYP3A4 inducing anti-
epileptic drugs and dexamethasone for CNS tumors or metastases, on a 
stable dose, are allowed.  
Selpercatinib is a moderate inhibitor of CYP2C8 and a weak inhibitor of 
CYP3A4. Avoid use of concomitant medications that are sensitive substrates 
of CYP2C8 or CYP3A4. 
In vitro, selpercatinib is a substrate of transport proteins P-gp and BCRP. Use 
caution when selpercatinib is co-administered with medications that are 
strong inhibitors or inducers of P-gp and BCRP. In addition, selpercatinib 
inhibits MATE1, P-gp and BCRP. Use caution when co-administered with 
medications that are sensitive substrates of MATE1, P-gp and BCRP.  
Selpercatinib is highly protein bound. Use caution when co-administered 
with other medications that are highly protein-bound. 
PPIs, H2 Receptor Antagonists and Antacids: 
Proton pump inhibitors (PPIs), H2 receptor antagonists and antacids may 
alter the pharmacokinetics of selpercatinib by reducing selpercatinib 
exposure. Avoid concomitant use of PPIs if possible. If co-administration of 
selpercatinib and PPI is necessary, administer selpercatinib with a meal. If 
H2 receptor antagonist is necessary, administer selpercatinib 2 hours before 
or 10 hours after H2 receptor antagonist administration. If antacid use is 
necessary, administer selpercatinib 2 or more hours before or 2 or more 
hours after antacid administration. 
Avoid combination with other drugs with potential to lead to prolongation 
of QTc interval, if possible (see Appendix XIII). Monitor the QT interval 
with ECGs more frequently in patients who require treatment with 
concomitant medications known to prolong the QT interval 
8.0
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory

 
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Page 30 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam  with vital signs, 
Tanner Staging, and dentition exam 
X 
Weekly 
X 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
 
CBC, differential, platelets 
X 
 Weekly 2,3 
X2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, AST, bilirubin 
X 
Weekly 
X11 
Albumin 
X 
Weekly 
 X 
Tumor Disease Evaluation4-A, 4-B, 4-C 
X 
 
Every other cycle x 3 then q 
3 cycles 4 
Plain radiograph tibial growth plate 
(bone x-ray tests)9 
X  
 
 Cycles 2 and 4, (concurrent 
with tumor disease 
evaluation),  then every 6 
months 
EKG10 
X 
 Day 1 and  Day 810 
X10 
Bone Marrow Aspirate and/or biopsy5,6 
X 
 
 
Medication Diary7 
 
Weekly 
X 
Circulating Tumor DNA (ctDNA-
optional)8 
 
 
Cycle 5, Day 1 and (for 
patients receiving 5 cycles 
only)  at end of Protocol 
Therapy OR disease 
progression  
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
3 
If patients develop Grade 3 or higher thrombocytopenia then CBCs should be checked every 3-4 days 
until recovery per section 6.1 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. If the 
institutional investigator determines that the patient has progressed based on clinical or laboratory 
evidence, he/she may opt not to confirm this finding radiographically. 
4-A     Neurological exam also required for CNS patients.  
4-B   Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8    

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4-C     Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to the start of protocol 
therapy if the patient was enrolled with or has a history of having MIBG avid tumor. Otherwise the 
patient must have either FDG-PET/CT or PET/MR prior to enrollment. For patients with neuroblastoma 
and measurable disease by CT or MRI, lesions should be measured and followed using the same modality 
(CT or MRI) in addition to MIBG or FDG-PET/CT. For patients with neuroblastoma and evaluable 
disease by MIBG scintigraphy, use the same modality (MIBG scintigraphy) to image and follow patients; 
CT/MRI are not required but may be performed as clinically indicated. Refer to Section 12.5.4 and 
Section 12.9. 
5 
Bone marrow aspirate and/or biopsy only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data.
6
Bone marrow aspirate and/or biopsy should be performed only when complete response or partial
response is identified in target disease or when progression in bone marrow is suspected.
7. 
Patient diary (see Appendix III) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE.
8.
With consent two samples will be collected on this protocol (Cycle 5 Day 1; and for patients receiving
5 cycles, at progression or end of protocol therapy) see Section 8.4 and Appendix IV for details of the
ctDNA studies. Note that a ctDNA sample is scheduled to be obtained on the APEC162SC screening 
protocol prior to the initiation of treatment on this subprotocol 
9.      Plain radiographs of at least one tibial growth plate should be obtained in all patients prior to first dose 
of protocol therapy. In patients with open growth plates, follow-up plain radiographs of the same growth 
plate(s) should be obtained according to Section 8.2.1. 
10        On Cycle 1 Day 1, Cycle 1 Day 8, and prior to subsequent cycles the morning dose of selpercatinib
(LOXO-292 should be held until the pre-dose EKG assessment can be obtained.   
11 
To be performed prior to the start of every subsequent cycle, and Day 15 of Cycle 2 and Cycle 3
Monitoring for Specific Toxicities  
Growth Plate Toxicity  
Patients will have a plain AP radiograph of a single proximal tibial growth plate 
obtained prior to the first dose of protocol therapy. 
a. If patients are found to have a closed tibial growth plate, no further 
radiographs will be required. 
b. If patients are found to have an open tibial growth plate, then repeat plain 
AP radiographs of the same tibial growth plate will be obtained prior to 
Cycles 2, 5 and every 6 months. 
• Patients with evidence of growth plate thickening or other changes 
should have a knee MRI performed to further assess the degree of 
physeal pathology and undergo more frequent x-ray follow up at 
least every 3 cycles or as clinically indicated. MRI should be 
performed without contrast.
• Patients with knee MRI changes should be managed in an 
individualized manner. Decisions regarding continuation of
selpercatinib (LOXO-292) should be made after discussion with the 
Study Chair or Study Vice-Chair and MATCH Leadership, taking 
into account the presence of any symptoms referable to the knee as 
well as the patient’s response to selpercatinib (LOXO-292). 
Consultation with an orthopedic surgeon may also be indicated. 
Plans for follow-up imaging will also be made on an individualized 
basis, taking into account the presence of symptoms at the knee or 
other joints as well as the decision to continue selpercatinib (LOXO-
292) or not.

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Radiology Studies 
Central Radiology Review for Response:  Patients who respond (CR, PR) to 
WKHUDS\RUKDYHORQJWHUPVWDEOHGLVHDVH6'F\FOHVRQSURWRFROWKHUDS\ZLOO
be centrally reviewed.  The Operations center will notify the site when a patient 
has met the criteria for review. The tumor disease evaluations to be submitted for 
review include baseline (prestudy) evaluations as well as all end of cycle tumor 
disease evaluations which occurred while the patient was on the subprotocol 
therapy study. 
Technical Details of Submission: 
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
DQG&RPPXQLFDWLRQVLQ0HGLFLQH',&20IRUPDW%03¿OHV-3*¿OHVRUKDUG
FRSLHV¿OPVDUHXQDFFHSWDEOHIRUDGHTXDWHLQWHUSUHWDWLRn of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. Submission of Diagnostic Imaging 
data in DICOM format is required. 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. 
Corresponding Radiology reports may be submitted along with the electronic 
submission sFTP or may be emailed to DataSubmission@QARC.org.  The COG 
operations center and IROC are available to assist with any queries regarding the 
corresponding radiology reports which should be included when the scans are 
submitted
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
IROC Rhode Island (formerly QARC) will facilitate the central reviews.
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low- 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created.
Sites not able to submit imaging electronically may submit imaging via CD.   CD’s 
may be sent by courier to:  

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Address for submission: IROC RI (QARC)
Building B, Suite 201 
640 George Washington Highway  
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:     (401) 753-7601 
                                       Web:    http://irocri.qarc.org
Circulating Tumor DNA Study (optional)   
Sampling Schedule   
An initial sample was previously requested at time of enrollment onto the 
APEC1621SC screening protocol. Two additional samples (optional) will be 
collected into Streck Cell-Free DNA BCT tubes at the timepoints:
 (1) Cycle 5 Day 1 
 (2) At disease progression or end of protocol therapy (for patients receiving 5 
cycles of therapy only)
  
Peripheral blood samples for circulating tumor DNA should be obtained as 
follows:  
x
For patients kg collect 20 mLs (10 mL per tube x 2 tubes)  
x
)RUSDWLHQWVkg but < 10 kg collect 10 mL (one tube) 
x
For patients < 5 kg research samples will not be collected  
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT.
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
x
Keep patient’s arm in the downward position during the collection 
procedure. 
x
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.
x
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
x
Fill tube completely.

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x
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results.
Sample Processing
Samples do not need to be processed at the collection site.
Sample Labeling
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621N), and the date and time the sample was drawn. Data should be 
recorded on the appropriate transmittal form found in RAVE, which must 
accompany the sample(s).
Sample Shipping Instructions
Specimen should be shipped at room temperature to the BPC (address below). 
Upon arrival separation, extraction, and storage of plasma and cellular DNA will 
be performed. Samples should be shipped from Monday through Friday for 
Tuesday through Saturday delivery. If blood is collected in the Streck tube on 
Friday, over the weekend or on the day before a holiday, the sample should be 
stored in a refrigerator until shipped on the next business day. Ship by FedEx 
Priority Overnight using the COG FedEx account. Blood samples should be 
shipped the same day as collection, ship blood for Saturday delivery if shipped on 
Friday. 
Ship specimens to the following address: 
 
   Biopathology Center 
Nationwide Children’s Hospital 
Protocol APEC1621N-Peds MATCH* 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org    
*Be sure to include the room number. Packages received without the room 
number may be returned to the sender. Packages must be labeled “Peds MATCH” 
in order to expedite processing at the BPC. 

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9.0
AGENT INFORMATION
Selpercatinib  
 
 
 
 
                               (12/30/2021) 
(LOXO-292, LY3527723, RETEVMO®) NSC# 812076, IND# 
 
Source and Pharmacology: 
Selpercatinib (LOXO-292) is a potent selective, small molecule inhibitor of human 
RET receptor tyrosine kinase (RTK), designed to competitively block the 
adenosine triphosphate binding sites of RET RTK in tumors with oncogenic RET 
gene fusions, RET gene alterations or increased RET activity.
Pharmacokinetics (PK)/Pharmacodynamics (PD): 
Selpercatinib is absorbed after oral administration with a median Tmax of 
approximately 2 hours. The mean absolute bioavailability of selpercatinib capsules 
is 73% (60% to 82%) in healthy subjects. The apparent volume of distribution 
(Vss/F) of selpercatinib is 191L. Protein binding of selpercatinib is 97% in vitro 
and is independent of concentration. The apparent half-life is 32 hours and steady 
state is reached in approximately 7 days. Following oral administration 69% of the 
administered dose was recovered in feces (14% unchanged) and 24% in urine (12% 
unchanged). The mean Cmin (pre-dose, trough concentration) is approximately 
600 ng/mL in patients during steady-state treatment with 60 mg BID selpercatinib
or higher, which corresponds to a mean plasma free drug concentration 
approximately equal to the IC90 for inhibition of RET. Selpercatinib exhibits 
linear PK with dose-proportionate increases in area under the curve (AUC0-24) and 
maximum concentrations (Cmax) at 20 mg to 160 mg BID dosing range. Mean 
steady-state selpercatinib CV% Cmax was 2,980 (53%) ng/ml and AUC0-24 was 
51,600 (58%) ng*h/ml.The mean plasma clearance range is 6.2-8.73 L/h within 
the above dosing range. Based on preclinical pharmacology experiments with 
human cancer cells in vitro and in murine xenograft models, meaningful inhibition 
of RET in tumors is expected to be achievable with oral dose regimens at total 
daily dosHVPJGD\7KHGRVDJHRIPJ%,'ZDVVHOHFWHGDVWKHDGXOW
recommended phase 2 dose (RP2D) based on safety data (N=82) and preliminary 
efficacy data in 64 evaluable patients treated at doses from 20 mg QD through 240 
mg BID.   
Studies in pediatric patients are ongoing. The dose of 92mg/m2 BID up to a 
maximum of 160 mg BID in pediatric patients resulted in a similar range of 
exposrure as seen in adult cancer patietns treated with 160 mg BID (AUC0-24 of 
51,600 ng*h/ml). No clinically significant differences in the PK of selpercatinib 
were observed based on mild or moderate renal impairment (creatinine clearance 
[CLcr] > 30 mL/min as estimated by Cockcroft-Gault). The effect of severe renal 
impairment (CLcr < 30mL/min) on selpercatinib PK has not been adequately 
studies. The selpercatinib AUC0-inf increased 7%, 32%, and 77% in subjects with 
mild, moderate and severe hepatic impairment, respectively.
Selpercatinib has pH-dependent solubility and its PK can be affected by agents that 
modify gastric pH such as PPIs (e.g., omeprazole). Coadministration with multiple 
daily doses of omeprazole (PPI) decreased selpercatinib AUC0-inf and Cmax by 69% 
and 
88%, 
respectively 
when 
selpercatinib was 
administered fasting. 
Coadministration with multiple daily doses of omeprazole did not significantly 

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change the selpercatinib AUC0-inf and Cmax when selpercatinib was administered 
with food.
Potential Drug Interactions 
In-vitro, selpercatinib is primarily metabolized by CYP3A4, but not by CYP1A2, 
CYP2C8, CYP2C9, or CYP2C19. Avoid use of concomitant medications that are 
moderate and strong inhibitors or inducers of CYP3A4.   
In vitro, selpercatinib showed no significant inhibition or induction of CYP1A2, 
CYP2B6, CYP2C9, CYP2C19, or CYP2D6. Selpercatinib is a moderate inhibitor 
of CYP2C8 and a weak inhibitor of CYP3A4. Avoid use of concomitant 
medications that are sensitive substrates of CYP2C8 and CYP3A4. 
In vitro, selpercatinib is a substrate of transport proteins P-gp and BCRP, but is not a 
substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or 
MATE2-K. Use caution when co-administered with medications that are strong 
inhibitors or inducers of P-gp and BCRP. 
In vitro, selpercatinib inhibits MATE1, P-gp and BCRP. Selpercatinib did not 
inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE2-K or 
BSEP. Use caution when co-administered with medications that are sensitive 
substrates of MATE1, P-gp and BCRP.
Proton pump inhibitors (PPIs), H2 receptor antagonists and antacids may alter the 
pharmacokinetics of selpercatinib by reducing selpercatinib exposure. Avoid 
concomitant use of PPIs if possible. If co-administration of selpercatinib and PPI 
is necessary, administer selpercatinib with a meal. If H2 receptor antagonist is 
necessary, administer selpercatinib 2 hours before or 10 hours after H2 receptor 
antagonist administration. If antacid use is necessary, administer selpercatinib 2 or 
more hours before or 2 or more hours after antacid administration. 
Selpercatinib is 97% protein-bound in human plasma. Use caution when co-
administered with other medications that are highly protein-bound. 
Selpercatinib can cause concentration-dependent QT prolongation. Monitor the 
QT interval more frequently when concomitantly administered with strong and 
moderate CYP3A4 inhibitors and drugs known to prolong QT interval and in 
patients at significant risk of developing QT prolongation.  
Patient Care Implications: 
Selpercatinib must not be administered to pregnant or nursing females. Women 
study participants of reproductive potential and fertile men study participants and 
their partners must abstain or use effective contraception (including barrier 
method) while receiving study treatment and for at least 2 weeks after the last dose 
of selpercatinib. Discontinue breastfeeding during treatment and for at least 2 
weeks after the last dose of selpercatinib. Male study participants are to refrain 
from sperm donation during treatment and for 2 weeks after the last dose of 
selpercatinib. 
Impaired wound healing can occur in patients taking selpercatinib. Withhold 
selpercatinib for at least 7 days prior to elective surgery. Do not administer for at 

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Selpercatinib will be provided as 40 mg and 80 mg capsules formulation, as well as 
1.4 gram powder for oral suspension
x
40 mg capsules are opaque grey, size 2, hard gelatin capsules. The capsule shell 
is composed of gelatin, titanium dioxide, ferric oxide black and is imprinted 
with “Lilly”, “3977” and “40 mg” in black ink. Each capsule contains 40 mg of 
selpercatinib (30% by weight) and the following inactive ingredients: 
microcrystalline cellulose (92 mg) and silicon dioxide (1.3 mg). Capsules are 
supplied in 60-count HDPE bottles with induction seals and child-resistant 
plastic caps.
x
80 mg capsules are opaque light blue, size 0, hard gelatin capsules. The capsule 
shell is composed of gelatin, titanium dioxide, FD&C blue #1 and is imprinted 
with “Lilly”, “2980”, and “80 mg” in black ink. Each capsule contains 80 mg 
of selpercatinib (30% by weight) and the following inactive ingredients: 
microcrystalline cellulose (183.4 mg) and silicon dioxide (2.7 mg). Capsules 
are supplied in 120-count HDPE bottles with induction seals and child-resistant 
plastic caps. 
x
1.4 gram powder for oral suspension is supplied in amber glass bottles, PP28 
neck, with a 28 mm child resistant cap. The white to off-white powder for 
oral suspension bottles contains no excipients.  
-
Site-supplied Ora-Sweet® SF and Ora-Plus® are required for oral 
suspension preparation and site-supplied 28 mm LDPE (e.g., Comar® 
product number 22-0198) press-in bottle adapters are required for use 
with an oral syringe for dosing purposes.  
Oral Suspension Preparation: 
1.4 gm Powder for oral suspension: Add 35 mL of Ora-Plus® and 35 mL of 
Ora-Sweet® SF (70 mL total volume) to each 1.4 gm bottle to yield a 
suspension of 20 mg/mL. Shake well.  
1. Remove the cap from the amber glass bottle containing 1.4 g of 
selpercatinib.  
2. To the amber glass bottle containing powder add 35 mL of Ora-Plus®, 
cap the bottle and shake by hand. Then add 35 mL of Ora-Sweet® SF 
to make a total volume of 70 mL (final suspension concentration = 20 
mg/mL). 
3. Cap the bottle tightly and then shake by hand until no solids are
observed on the bottom of the bottle. A vortex can be used if available.  
4. Insert adapter into bottle via the ribbed end. This will require some 
minimum force to insert all the way. 
5.  Replace the cap 
6. Prior to measuring out each dose, shake the bottle by hand to ensure a 
smooth suspension of the liquid. Try to avoid the formation of 
bubbles. 
7. The dosing syringe should be filled with an equal volume of water 
after each dose administration to be sure all residue of the suspension 
is ingested. A new syringe should be used for each dose. 

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Storage 
Store capsules at controlled room temperature between 20°C to 25°C (66°F 
to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F). Store 
intact powder for oral suspension bottles at controlled room temperature 
between 20°C to 25°C (66°F to 77°F). Excursions permitted between 15°C 
to 30°C (59°F to 86°F).  Store prepared oral suspension bottles refrigerated 
at 2°C to 8°C. Do not freeze the suspension.
If a storage temperature excursion is identified, promptly return 
selpercatinib capsules and intact powder for oral suspension bottles to 
controlled room temperature, or prepared oral suspension bottles to 
refrigerated temperature and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability.
Stability
Stability studies of the intact bottles (capsules and powder for oral 
suspension) are ongoing. It is recommended that selpercatinib capsules be 
dispensed in the original manufacturer’s container. If capsules must be 
repackaged, they are to be repackaged from the manufacturer-supplied 
white HDPE bottle into a pharmacy-supplied white HDPE bottle for 
dispensing purposes. When repackaged into the pharmacy HDPE bottles 
there is no difference in expiration from the source material.
Selpercatinib powder for oral suspension is to be dispensed in the 
manufacturer’s container. Oral suspension must be used within 42 days 
following preparation under refrigerated storage conditions.
Guidelines for Administration: 
Refer to treatment (Section 5.0) and dose modification (Section 6.0) sections of 

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the protocol. Capsules are administered orally. Oral suspension may be administered 
orally or by naso- or gastric-feeding tube. In the case of enteral administration, the 
tube must be flushed appropriate amount of water (up to 30 mL) post 
administration of each dose.
Selpercatinib is administered twice daily, approximately 12 hours apart. Doses may 
be taken without regard to food. Capsules are to be swallowed whole. Do not chew, 
crush or open capsules. If study subject vomits immediately after taking a capsule 
dose and the capsules are intact, dose may be repeated. If study subject vomits after 
taking an oral suspension dose, the dose should not be repeated. If a dose is missed, 
it may be administered if there are at least 6 hours remaining until the next scheduled 
dose. Instruct patients to shake oral suspension bottles well prior to dosing.
Supplier:  
Selpercatinib is supplied by Eli Lilly and distributed by the Pharmaceutical 
Management Branch, CTEP, DCTD, NCI. Do not use commercial supply.
Obtaining the Agent
Agent Ordering and Agent Accountability
NCI-supplied agents may be requested by eligible participating investigators (or 
their authorized designee) at each participating institution. The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational 
agents.  The eligible participating investigators at each participating institution 
must be registered with CTEP, DCTD through an annual submission of FDA Form 
1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and 
Financial Disclosure Form (FDF).  If there are several participating investigators 
at one institution, CTEP-supplied investigational agents for the study should be 
ordered under the name of one lead participating investigator at that institution.
Note: No starter supplies will be provided. Drug orders of selpercatinib
should be placed with CTEP after enrollment and treatment assignment to 
APEC1621N with consideration for timing of processing and shipping to 
ensure receipt of drug supply prior to start of protocol therapy. If expedited 
shipment is required, sites should provide an express courier account through the 
Online Agent Order Processing (OAOP) application. Provide the patient ID 
number in the comment box when submitting an order request.
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status and a “current” password and active person registration status. For questions 
about drug orders, transfers, returns, or accountability call or email PMB anytime. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.  
Agent Accountability  
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all 

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agents received from the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP forms page.  Store 
and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP IAM 
account and the maintenance of an “active” account status, a “current” password, 
and active person registration status. Questions about IB access may be directed to 
the PMB IB coordinator via email.
Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
x NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov    
x PMB policies and guidelines: 
 
 
http://ctep.cancer.gov/branches/pmb/agent_management.htm     
x PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP  
CTEP Identity and Access Management (IAM) account: 
   
  https://ctepcore.nci.nih.gov/iam/  
x
   
x
  
x
  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
x
  
x Registration and Credential Repository (RCR): 
https://ctepcore.nci.nih.gov/rcr/    
PPD
PPD
PPD
PPD

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10.0
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
Criteria for Removal from Protocol Therapy 
a)
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12).
b)
Adverse Events requiring removal from protocol therapy (See Section 6).
c)
Refusal of protocol therapy by patient/parent/guardian 
d)
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e)
Completion of 26 cycles of therapy. 
f)
Physician determines it is not in the patient’s best interest.
g)
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1).
h)
Study is terminated by Sponsor.
i)
Pregnancy
j)
Patient did not receive protocol treatment after study enrollment
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
Follow-Up Data Submission and APEC1621SC Off Study Criteria
Patients who are off subprotocol therapy will initially be followed on the therapeutic 
subprotocol for a 30-day period. During follow-up on the therapeutic subprotocol ongoing 
adverse events, or adverse events that emerge after the patient is removed from protocol 
therapy, but within 30 days of the last dose of investigational agent, must be followed and 
reported via RAVE and CTEP-AERS (if applicable). Upon completion of subprotocol 
follow-up period, the patient will continue to be followed on the APEC1621SC screening 
protocol. Follow-up data submission will occur until one of the APEC1621SC Off Study 
Criteria is met (See Section 10 of APEC1621SC for details); consent is withdrawn or the 
patient dies or is lost to follow-up. 

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5%, if the treatment is ineffective, to 25% if the targeted therapy is sufficiently 
effective to warrant further study. If there are at least 3 responses out of 20 in the 
primary cohort, the biomarker/therapy match will be deemed a success. 
Histology-Specific Biomarker Positive Expansion Cohorts: 
,I   SDWLHQWV LQ WKH primary cohort with the same histology show signs of 
objective response (CR/PR according to the response criteria  in Section 12.3), a 
histology-specific biomarker positive expansion cohort will open after the primary 
cohort is completed to up to 7 evaluable patients for a total sample size of 10 
evaluable biomarker positive patients with that histology. This will allow us to 
estimate more precisely the activity in biomarker positive patients of that 
histology. See Appendix VII for a list of target tumor histologies. 
We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 KLVWRORJLHVKDYHUHVSRQVHVZHZLOORSHQDWRWDORIH[SDQVLRQFRKRUWVDV
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts.
Methods of Analysis
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.25 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.   
Evaluability for Response
Any eligible patient who is enrolled and receives at least one dose of protocol therapy will 
be considered evaluable for response. Any patient who receives non-protocol anti-cancer 
therapy during the response evaluation period will be considered a non-responder for the 
purposes of the statistical rule, unless they show an objective response prior to receiving 
the non-protocol anti-cancer therapy (in which case they will be considered a responder). 
Patients who demonstrate a complete or partial response confirmed by central review will 
be considered to have experienced a response. All other patients will be considered non-
responders. Patients who are not evaluable for response evaluation may be replaced for the 
purposes of the statistical rule. All patients considered to have a response (CR or PR) must 
have imaging studies reviewed centrally at the COG. Centers will be notified by the COG 
about requests for scans of patients with stable disease. Preliminary assessment of activity 
using institutionally provided tumor measurements will be entered into CDUS quarterly. 
The central review by COG will be provided as the final reviewed assessment of response 
when such becomes available.
Evaluability for Toxicity
All eligible patients who receive at least one dose of protocol therapy will be considered in 
the evaluation of toxicity

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Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence.
Response Criteria for Patients with Solid Tumors 
See the table in Section 8.0 for the schedule of tumor evaluations. In addition to the 
scheduled scans, a confirmatory scan should be obtained on the next consecutive cycle
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) 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) [Eur J Ca 45:228-
247, 2009].  Key points are that 5 target lesions are identified and that changes in the largest
diameter (unidimensional measurement) of the tumor lesions but the shortest diameter of 
malignant lymph nodes are used in the RECIST v 1.1 criteria. 
Definitions
12.3.1.1 Evaluable for objective response: 
Eligible patients who receive at least one dose of protocol therapy will 
be considered evaluable for response. Evaluable patients who 
demonstrate a complete or partial response confirmed by central review 
before receiving non-protocol anti-cancer therapy will be considered a 
responder. All other evaluable patients will be considered non-
responders 
12.3.1.2 Evaluable Non-Target Disease Response: 
Eligible patients who have lesions present at baseline that are evaluable
but do not meet the definitions of measurable disease and have received 
at least one dose of protocol therapy will be considered evaluable for
non-target disease response. The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
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).

 
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Page 48 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
12.3.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
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 
ZLWK   WR  15 mm short axis), are considered non-measurable 
disease. 
 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 
 
12.3.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion that can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the 
disease. 
 
12.3.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 

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noted throughout follow-up.  
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. 
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 t 10 mm diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
12.3.3.2 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable. 
12.3.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. 
12.3.3.4 PET-CT:  At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements.  However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
12.3.3.5 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
12.3.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 

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Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease.
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.26
Response Criteria for Patients with Solid Tumor and Measurable Disease
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target and non-target lesions.  
Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 
mm. If immunocytology is available, no disease 
must 
be 
detected 
by 
that 
methodology.  
Normalization of tumor markers if elevated at 
study enrollment (for patients with neuroblastoma). 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD):
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 

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increase of at least 5 mm.  (Note:  the appearance of 
one or more new lesions is also considered 
progressions). Note: in presence of SD or PR in target 
disease but unequivocal progression in non-target or 
non-measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-target 
disease such that the overall tumor burden 
has increased sufficiently to merit discontinuation 
of 
therapy. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study. 
Evaluation of Non-Target Lesions
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis). 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits. 
Progressive Disease (PD):
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, 
not a single lesion increase.    
Overall Response Assessment
Table 1: For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response 
when Confirmation is 
Required*
CR
CR
No
CR
 28 days Confirmation
CR
Non-
CR/Non-PD
No
PR
 28 days Confirmation
CR
Not evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
No
PR

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evaluated
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
documented at least once 
28 days from baseline
PD
Any
Yes or No
PD
no prior SD, PR or CR
Any
PD**
Yes or No
PD
Any
Any
Yes
PD
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression.
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment.
Table 2: For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised
Table 3: Overall Response for Patients with Neuroblastoma and Measurable Disease
CT/MRI
MIBG
Bone Marrow
Overall
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Any
PD
Any
Any
PD
PD
SD
CR/PR/SD
Non-PD
SD
PR
CR/PR
Non-PD
PR
CR/PR
PR
Non-PD
PR
CR
CR
Non-PD
PR
CR
CR
CR
CR
Overall Best Response Assessment
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9  from a sequence of overall response assessments.
Response Criteria for Neuroblastoma Patients 
This study will use the revised International Neuroblastoma Response Criteria for disease 
assessment. 27The updated response criteria incorporate current approaches to imaging of 
neuroblastoma, including functional imaging. Furthermore, a standardized approach to assessment 
of bone marrow involvement is included.  The current INRC do not include methods of disease 
assessment that are less sensitive and/or specific for neuroblastoma (99Tc bone scan and 
catecholamine levels). 

 
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Page 53 
 
Key sites and terms 
3ULPDU\VLWH7KHSULPDU\VLWHZLOOEHLGHQWLILHGDVDPHDVXUDEOHOHVLRQ 10 mm in diameter as 
assessed by cross sectional imaging (CT or MRI scan). Primary site measurements must be 
recorded in millimeters (or decimal fractions of centimeters). The longest diameter of the primary 
tumor will be recorded at baseline. Serial measurements of the primary tumor will include 
assessment of tumor size in the same orthogonal plane at the time of each evaluation.28 In patients 
with bilateral adrenal lesions, response will be based on the sum of the longest dimensions of both 
adrenal 
lesions 
unless 
biopsy 
proves 
one 
to 
be 
ganglioneuroma 
rather 
than 
neuroblastoma/ganglioneuroblastoma. In patients with multi-focal non-adrenal disease, the largest 
tumor will be considered the primary tumor. Response in additional lesions will be assessed as 
described below for metastatic lesions. 
  
Tracer avidity (123I-MIBG or FDG-PET) in the primary site will be recorded at baseline. The scan 
appropriate for serial disease assessments should be used at each disease re-evaluation timepoint 
(e.g. 123I-MIBG avid primary lesions should be followed using 123I-MIBG scans during therapy). 
  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a metastatic 
O\PSKQRGHPXVWEH 15 mm in short axis when assessed by CT or MRI scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short 
axis of a discreet lymph node will be measured and followed as per RECIST criteria. Patients with 
neuroblastoma may have conglomerate masses of non-discrete lymph nodes (i.e. multiple 
contiguous retroperitoneal nodes). When a short axis of a discreet node cannot be identified, a 
lymph node conglomerate can be measured using the longest diameter of the composite lesion. 
Tracer avidity of metastatic nodes will be recorded at baseline and during disease evaluations. 
 
For the purposes of response assessment, target lesions are disease sites that are measurable (non-
QRGDOVRIWWLVVXHPDVV PPLQORQJHVWGLPHQVLRQRUO\PSKQRGH 15 mm in short axis) and 
tracer avid OR are biopsy positive for neuroblastoma or ganglioneuroblastoma. The sum of 
diameters of target lesions is defined as the sum of the short axis of discrete lymph nodes (i.e., 
cervical, axillary nodes) added to the sum of the longest diameters of non-lymph node soft tissue 
metastases.   
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 PPRUSDWKRORJLFDOO\PSKQRGHVZLWK 10 to < 15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions are considered non-measurable. 
 
Bone lesions: Osteomedullary disease will be assessed using 123I-MIBG scans or FDG-PET scans. 
Technetium bone scans are no longer used as part of the revised INRC and are not included as part 
of disease reassessments during this trial. The extent of tracer avid disease will be evaluated using 
the Curie scoring system (see Curie Scoring System). SPECT may be used to confirm the presence 
or absence of lesions in a given segment of the body. The absolute Curie score should be reported 
at baseline. A relative score (Curie score at the time of disease assessment divided by baseline Curie 
score) should be recorded at the time of each disease evaluation. 
 
Bone marrow disease: Bilateral bone marrow aspirates and trephine biopsies are required at disease 
assessment timepoints. The extent of marrow involvement in all four samples should be recorded. 
Use of immunohistochemical staining for evaluation of trephine biopsies is strongly encouraged. 
The percentage of tumor infiltration of bone marrow space assessed by histologic evaluation of 
trephine/biopsies or counting the number of tumor cells in aspirates by cytology or 

 
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Page 54 
immunocytology (recommended 
if 
available) 
divided 
by 
the 
number 
of 
hematopoietic/mononuclear cells evaluated to obtain a percentage involvement (methodology 
described by Burchill et al.).29 The bone marrow sample with the highest percentage of tumor 
infiltration is used for response assessment. If >  WR  5% tumor infiltration is the highest 
percentage seen among samples obtained, the result should be recorded as minimal marrow disease. 
 
Response Criteria 
 
PRIMARY (SOFT TISSUE) TUMOR RESPONSE1  
RESPONSE 
ANATOMICAL IMAGING + MIBG 
(FDG-PET2) IMAGING 
Complete 
Response 
(CR) 
• 
< 10 mm residual soft tissue at primary site, 
AND 
• 
complete resolution of MIBG or FDG-PET 
uptake (for MIBG non-avid tumors) at 
primary site 
Partial 
Response 
(PR) 
• 
30% decrease in longest diameter (LD) of 
primary site 
• 
MIBG or FDG-PET uptake at primary site 
stable, improved or resolved 
Progressive 
Disease (PD) 
• 
> 20% increase in longest diameter taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study), AND  
• 
a minimum absolute increase of 5 mm in 
longest dimension3  
Stable 
Disease (SD) 
Neither sufficient shrinkage for PR nor 
sufficient increase for PD at the primary site 
1Not for use in assessment of metastatic sites 
2 For 123I-MIBG non-avid tumors 
3 A mass that has not met PD measurement criteria but has fluctuating 123I-MIBG avidity will not 
be considered progressive disease. 
 
 
RESPONSE AT METASTATIC SOFT TISSUE AND BONE SITES 
RESPONSE 
ANATOMICAL IMAGING + MIBG (FDG-PET1) IMAGING 
Complete 
Response (CR) 
• 
Resolution of all sites of disease defined as: 

 
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Page 55 
• 
Non-primary target and non-target lesions measure < 10 mm AND 
• 
Lymph nodes identified as target lesions decrease to a short axis < 15 
mm, AND  
• 
MIBG uptake or FDG-PET uptake (for MIBG non-avid tumors) of non-
primary lesions resolves completely 
Partial 
Response (PR) 
• 
30% decrease in sum of diameters2 of non-primary target lesions compared to 
baseline, AND all of the following: 
• 
Non-target lesions may be stable or smaller in size AND 
• 
No new lesions AND 
• 
50% reduction in MIBG absolute bone score (Relative MIBG bone 
score WRRU 50% reduction in number of FDG-PET avid 
bone lesions3,4 
Progressive 
Disease (PD) 
Any of the following5: 
• 
Any new soft tissue lesion detected by CT or MRI that is also MIBG avid or 
FDG-PET avid; 
• 
Any new soft tissue lesion seen on anatomic imaging that is biopsied and 
confirmed to be a neuroblastoma or ganglioneuroblastoma; 
• 
Any new bone site that is MIBG avid;   
• 
A new bone site that is FDG-PET avid (for MIBG non-avid tumors) AND has 
CT or MRI findings consistent with tumor OR has been confirmed 
histologically to be neuroblastoma or ganglioneuroblastoma; 
• 
> 20% increase in longest diameter taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study), AND a 
minimum absolute increase of 5 mm in sum of diameters of target soft tissue 
lesions; 
• 
Relative MIBG score 1.24 
Stable Disease 
(SD) 
Neither sufficient shrinkage for PR nor sufficient increase for PD of non-primary lesions 
1 Used for MIBG non-avid tumors 
2Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (i.e., cervical, axillary 
nodes) added to the sum of the longest diameters of non-lymph node soft tissue metastases.  Masses of 
conglomerate non-discrete lymph nodes will be measured using longest diameter. 
3 For patients with soft tissue metastatic disease, resolution of MIBG and/or FDG-PET uptake at the soft 
tissue sites is not required; all size reduction criteria must be fulfilled. 
4Relative Curie score is the absolute score for bone lesions at time of response assessment divided by 
the absolute score for bone lesions at entry onto a clinical trial. MIBG-SPECT or MIBG-SPECT/CT 
may be used for scoring purposes but the same imaging methodology should be used for all evaluations. 
5The post-infusion MIBG scan is not considered a diagnostic study for the purposes of response 
assessment. Progressive disease should NOT be designated on the basis of this scan. 
 
 
BONE MARROW RESPONSE 
RESPONSE 
BONE MARROW STATUS1 

 
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Page 56 
Complete response 
(CR) 
Bone marrow with no tumor infiltration upon reassessment, independent of 
baseline tumor involvement  
Progressive disease 
(PD) 
Any of the following: 
• 
Bone marrow without tumor infiltration that becomes > 5% tumor 
infiltration upon reassessment; or 
• Bone marrow with tumor infiltration that increases by > 2 fold and has 
> 20% tumor infiltration upon reassessment. 
Minimal disease 
(MD) 
Any of the following: 
• 
%RQHPDUURZZLWKWXPRULQILOWUDWLRQDQGUHPDLQV!-
tumor infiltration upon reassessment; or 
• %RQHPDUURZZLWKQRWXPRULQILOWUDWLRQWKDWEHFRPHVWXPRU
infiltration upon reassessment; or 
• Bone marrow with >20% tumor infiltration that has > 0-WXPRU
infiltration upon reassessment. 
Stable disease (SD) 
Bone marrow with tumor infiltration that remains positive with > 5% tumor 
infiltration upon reassessment but does not meet CR, MD or PD criteria 
1Immunohistochemistry strongly encouraged 
 
DETERMINATION OF OVERALL RESPONSE 
RESPONSE 
CRITERIA 
Complete Response (CR) 
All components meet criteria for CR 
Partial Response (PR) 
PR in at least one component and all other 
components are either CR, MD (Bone 
marrow), PR (Soft tissue or Bone) or Not 
involved (NI); no component with PD.   
Minor Response (MR) 
PR or CR in at least one component but at least 
one other component with SD; no component 
with PD. 
Stable Disease (SD) 
SD in one component with no better than SD or 
NI in any other component; no component with 
PD. 
Progressive Disease (PD) 
Any component with PD 
NI = Not involved, site not involved at study entry and remains not involved; MD = Minimal Disease, for 
bone marrow assessment only. 
 
 
 
 
 

 
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Page 57 
 
 
 
 
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 12.8 from a sequence of overall response 
assessments. 
 
Primary Tumor 
Soft Tissue and Bone Metastatic Disease 
(MIBG or FDG-PET or PET/MR) 
Bone Marrow Metastatic Disease  
Overall 
CR 
CR 
CR 
CR 
CR for one response component with either CR or NI for other components 
CR 
CR 
CR 
MD 
PR 
CR 
PR 
CR 
PR 
CR 
PR 
MD 
PR 
CR 
PR 
NI 
PR 
CR 
NI 
MD 
PR 
PR 
CR 
CR 
PR 
PR 
CR 
NI 
PR 
PR 
CR 
MD 
PR 
PR 
PR 
CR 
PR 
PR 
PR 
NI 
PR 
PR 
PR 
MD 
PR 
PR 
NI 
CR 
PR 
PR 
NI 
NI 
PR 
PR 
NI 
MD 
PR 
NI 
CR 
MD 
PR 
NI 
PR 
CR 
PR 
NI 
PR 
MD 
PR 
CR 
CR 
SD 
MR 
CR 
PR 
SD 
MR 
CR 
SD 
CR 
MR 
CR 
SD 
MD 
MR 
CR 
SD 
SD 
MR 
CR 
SD 
NI 
MR 
CR 
NI 
SD 
MR 
PR 
CR 
SD 
MR 
PR 
PR 
SD 
MR 
PR 
SD 
CR 
MR 
PR 
SD 
MD 
MR 
PR 
SD 
SD 
MR 
PR 
SD 
NI 
MR 
PR 
NI 
SD 
MR 
SD 
CR 
CR 
MR 
SD 
CR 
MD 
MR 
SD 
CR 
SD 
MR 
SD 
CR 
NI 
MR 
SD 
PR 
CR 
MR 
SD 
PR 
MD 
MR 
SD 
PR 
SD 
MR 
SD 
PR 
NI 
MR 
SD 
SD 
CR 
MR 
SD 
NI 
CR 
MR 
NI 
CR 
SD 
MR 
NI 
PR 
SD 
MR 
NI 
SD 
CR 
MR 
SD 
SD 
MD 
SD 
NI 
SD 
MD 
SD 
SD 
NI 
MD 
SD 
NI 
NI 
MD 
SD 
SD 
SD 
SD 
SD 
SD 
NI 
SD 
SD 
NI 
SD 
SD 
SD 
NI 
SD 
NI 
SD 
NI 
NI 
SD 
SD 

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nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures.
Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice).
Any change in size of non-target lesions should be noted, though does not need to be 
measured.
Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions:
x
Complete Response (CR): Disappearance of all target lesions. Off all steroids 
with stable or improving neurologic examination.
x
Partial response (PR): GHFUHDVHLQWKHVXPRIWKHSURGXFWVRIWKHWZR
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. 
x
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.
x
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions.
Increasing doses of corticosteroids required to maintain stable neurological status 
should be strongly considered as a sign of clinical progression unless in the context 
of recent wean or transient neurologic change due e.g. to radiation effects. 
Response Criteria for Non-Target Lesions:
x
Complete Response (CR): Disappearance of all non-target lesions.
x
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions.

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x
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.
Response criteria for tumor markers (if available):
Tumor markers will be classified simply as being at normal levels or at 
abnormally high levels.
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 
12.8 from a sequence of overall response assessments.
Response Criteria for Patients with Non- Hodgkin Lymphoma/Histiocytosis
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria26, with modification from the Lugano classification.30
Disease Parameters
Measurable disease: A measurable node must have an LDi (longest 
diameter) greater than 1.5 cm. A measurable extranodal lesion should have 
an LDi greater than 1.0 cm. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Non-measured disease: All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
Target lesions: For patients staged with CT, up to six of the largest target 
nodes, nodal masses, or other lymphomatous lesions that are measurable 

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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.
Evaluation of Measurable Disease
Complete Response (CR)
Disappearance of all disease. CT or MRI should be free of residual mass or 
evidence of new disease. FDG-PET should be negative. 
Complete Response Unconfirmed (CRu)
Residual mass is negative by FDG-PET; no new lesions by imaging examination; 
no new and/or progressive disease elsewhere
Partial Response (PR)
50% decrease in SPD (the sum of the products of the largest diameter and the 
perpendicular diameter for a tumor mass) on CT or MRI; FDG-PET may be 
positive (Deauville score or 4 or 5 with reduced lesional uptake compared with 
baseline); no new and/or PD; morphologic evidence of disease may be present in 
BM if present at diagnosis; however, there should be 50% reduction in percentage 
of lymphoma cells. 
No Response (Stable Disease)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study.
Progressive disease
For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on 
FDG-PET with increase in lesional uptake from baseline, or development of new 
morphologic evidence of disease in BM
Evaluation of Non-measured Lesions (CT-based response, PET/CT based 
response not applicable)30
Complete Response (CR):
Absent non-measured lesions. 
Partial response (PR):
Absent/normal, regressed, lesions, but no increase.
Stable Disease (SD): 
No increase consistent with progression 
Progressive Disease (PD): New 
or 
clear 
progression 
of 
preexisting 
non-measured lesions.
Evaluation of organ enlargement30  
Complete Response (CR): 
Regress to normal  
Partial response (PR):
Spleen must have regressed by >50% in length 
beyond normal 

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Stable Disease (SD): 
No increase consistent with progression
Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline. 
New or recurrent splenomegaly
Best Response
Two objective status determinations of disease status, obtained on two consecutive 
determinations, separated by at least a 3 week time period, are required to determine the 
patient’s overall best response. Two objective status determinations of CR before 
progression are required for best response of CR. Two determinations of PR or better 
before progression, but not qualifying for a CR, are required for a best response of PR. 
Two determinations of stable/no response or better before progression, but not qualifying 
as CR or PR, are required for a best response of stable/no response; if the first objective 
status is unknown, only one such determination is required. Patients with an objective 
status of progression on or before the second evaluations (the first evaluation is the first 
radiographic evaluation after treatment has been administered) will have a best response of 
progressive disease. Best response is unknown if the patient does not qualify for a best 
response of progressive disease and if all objective statuses after the first determination and 
before progression are unknown.
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
Table 5.  Sequences of overall response assessments with corresponding best 
response.
1st Assessment
2nd Assessment
Best Response
Progression
Progressive disease
Stable, PR, CR
Progression
Progressive disease
Stable
Stable
Stable
Stable
PR, CR
Stable
Stable
Not done
Not RECIST classifiable
PR
PR
PR
PR
CR
PR
PR, CR
Not done
Not RECIST classifiable
CR
CR
CR
Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).

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The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements. 
13.0
ADVERSE EVENT REPORTING REQUIREMENTS
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the Case Report Forms
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting.
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
Expedited Reporting Requirements – Serious Adverse Events (SAEs)
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
1) Death.
2) A life-threatening adverse drug experience.
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
KRVSLWDOL]DWLRQIRU 24 hours). This does not include hospitalizations that are part 
of routine medical practice.
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.
5) A congenital anomaly/birth defect.
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.

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Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair 
have the primary responsibility for AE identification, documentation, grading, and 
assignment of attribution to the investigational agent/intervention. It is the 
responsibility of the treating physician to supply the medical documentation 
needed to support the expedited AE reports in a timely manner. 
Any medical documentation supporting an expedited report (eg, H & P, 
admission and/or notes, consultations, ECG results, etc.) MUST be faxed 
within 48-72 hours to the NCI. NOTE: English is required for supporting 
documentation submitted to the numbers listed below in order for the NCI to 
meet the regulatory reporting timelines. 
Fax supporting documentation for AEs related to investigational agents 
supplied under a CTEP IND to: 
  
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 
(310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator).  
x
ALWAYS include the ticket number on all faxed documents.
x
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports.
CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page  
https://eapps-ctep.nci.nih.gov/ctepaers. 
Send supporting documentation to the NCI by fax (fax# 301-640-9193)                           
and 
by 
email to both COGCAdEERS@childrensoncologygroup.org , 
the
APEC1621N 
COG 
Study 
Assigned 
Research 
Coordinator, 
and 
COGAERS@childrensoncologygroup.org; Attention: COG AERS Coordinator.  
ALWAYS include the ticket number on all faxed and emailed documents. 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner
Step 1: Identify the type of adverse event using the current version of the NCI CTCAEv5.0.  
The descriptions and grading scales found in the current version of the CTCAEv5.0 
will be used for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAEv5.0.  A copy of the CTCAEv5.0 can be downloaded from 
the CTEP website (http://ctep.cancer.gov).
Step 2:  Grade the adverse event using the NCI CTCAEv5.0. 
Step 3:  Review Table A in this section to determine if:
x
the adverse event is considered serious;
x
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or
x
there are any protocol-specific exceptions to the reporting requirements.  
PPD

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x
If an adverse event occurs more than once in a course (cycle) of therapy only 
the most severe grade of the event should be reported. 
x
If an adverse event progresses through several grades during one course of 
therapy, only the most severe grade should be reported.
x
The duration of the AE is defined as the duration of the highest (most severe) 
grade of the Adverse Effects. 
x
The resolution date of the AE is defined as the date at which the AE returns 
to baseline or less than or equal to Grade 1, whichever level is higher (note 
that the resolution date may therefore be different from the date at which the 
grade of the AE decreased from its highest grade).  If the AE does not return 
to baseline the resolution date should be recorded as "ongoing."   
x
An adverse event that persists from one course to another should only be 
reported once unless the grade becomes more severe in a subsequent course. 
An adverse event which resolves and then recurs during a different course, 
must be reported each course it recurs. 
Other Recipients of Adverse Event Reports
Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the 
CRF packet (See Section 14.1).
Adverse events determined to be reportable must also be reported according 
to the local policy and procedures to the Institutional Review Board 
responsible for oversight of the patient. 
Specific Examples for Expedited Reporting
Reportable Categories of Death
x Death attributable to a CTCAE v5.0 term. 
x Death Neonatal: A disorder characterized by “Newborn deaths occurring during 
the first 28 days after birth.”  
x Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE v5.0 term associated with Grade 5. 
x Death NOS: A cessation of life that cannot be attributed to a CTCAE v5.0 term 
associated with Grade 5. 
x Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease) should be
submitted.  

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x Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
x Any death that occurs more than 30 days after the last dose of treatment with 
an investigational agent which can be attributed (possibly, probably, or 
definitely) to the agent and is not clearly due to progressive disease must be 
reported via CTEP-AERS per the timelines outlined in the table above.
Reporting Secondary Malignancy 
Secondary Malignancy: 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, 
radiation 
or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event: 
1) Leukemia secondary to oncology chemotherapy
(e.g., acute 
myelocytic leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy.  
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
Second Malignancy: 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy).  Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or 
“Death 
Neonatal”, 
the 
Pregnancy 
Information 
Form, 
available
at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to 301-897-7404. The potential risk of exposure of the fetus 
to the investigational agent should be documented in the “Description of Event” 
section of the CTEP-AERS report.
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in 
an expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 

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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 https
://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregnancy
ReportForm.pdf.  If the baby is born with a birth defect or anomaly, then a second 
CTEP-AERS report is required.
Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE v5.0 as “Death in utero.” 
Any pregnancy loss needs to be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the “Pregnancy, puerperium and perinatal conditions” SOC. Do 
NOT report a pregnancy loss as a Grade 5 event since CTEP-AERS recognizes 
any Grade 5 event as a patient death.
Death Neonatal
Neonatal death, defined in 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.
Reporting of Study Drug Overdose  
Study drug overdose refers to the uses of the study drug outside of that specified by the 
protocol.  
x
Overdose: Accidental or intentional use of the study drug in an amount 
higher than the protocol defined dose.  
Any study drug overdose should be reported on the Reporting Period-Dosing CRF. All 
AEs associated with an overdose should be entered both on the Reporting Period CRF and 
reported expeditiously using the CTEP-AERS.
14.0
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN
Categories of Research Records 
Research records for this study can be divided into three categories
1.
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
2.
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center.

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3.
Computerized Information Electronically Submitted:  All other data will be 
entered in RAVE with the aid of schedules and worksheets (essentially paper 
copies of the OPEN and RAVE screens) provided in the case report form (CRF) 
packet. 
See separate CRF Packet, which includes submission schedule.
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
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.   
CRADA/CTA/CSA
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement.
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the provisions in the “Intellectual Property Option to Collaborator” (http://ctep.cancer.go
v/industryCollaborations2/intellectual_property.htm) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 
Agent(s) may not be used for any purpose outside the scope of this 
protocol, nor can Agent(s) be transferred or licensed to any party not 
participating in the clinical study.  Collaborator(s) data for Agent(s) are 
confidential and proprietary to Collaborator(s) and shall be maintained as 
such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be 
shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient or patient’s family member participating 
on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of 
different collaborative agreements , the access to and use of data by each 
Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as “Multi-Party Data”):
a.
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 

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proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industr
yCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and 
Results and Raw Data will be collected , used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
Email: ncicteppubs@mail.nih.gov    
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
 
 

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Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 
Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the developmental therapy 
scientific committee; and a member from the NCI. The DSMC meets at least every 
6 months to review current study results, as well as data available to the DSMC 
from other related studies. Approximately 6 weeks before each meeting of the 
Phase 1 and 2 DSMC, study chairs will be responsible for working with the study 
statistician to prepare study reports for review by the DSMC. The DSMC will 
provide recommendations to the COG Developmental Therapeutics Chair and the 
Group Chair for each study reviewed to change the study or to continue the study 
unchanged. Data and Safety Committee reports for institutional review boards can 
be prepared using the public data monitoring report as posted on the COG Web 
site.
Monitoring by the Study Chair and MATCH Leadership 
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the 
MATCH Chair, Vice Chair and Statistician on a weekly conference call.

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REFERENCES 
1. 
Mulligan LM: RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 14:173-86, 2014 
2. 
Integrated genomic characterization of papillary thyroid carcinoma. Cell 159:676-90, 2014 
3. 
Fusco A, Grieco M, Santoro M, et al: A new oncogene in human thyroid papillary carcinomas and 
their lymph-nodal metastases. Nature 328:170-2, 1987 
4. 
Agrawal N, Jiao Y, Sausen M, et al: Exomic sequencing of medullary thyroid cancer reveals 
dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 
98:E364-9, 2013 
5. 
Carlson KM, Dou S, Chi D, et al: Single missense mutation in the tyrosine kinase catalytic domain 
of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad 
Sci U S A 91:1579-83, 1994 
6. 
Donis-Keller H, Dou S, Chi D, et al: Mutations in the RET proto-oncogene are associated with 
MEN 2A and FMTC. Hum Mol Genet 2:851-6, 1993 
7. 
Eng C, Smith DP, Mulligan LM, et al: Point mutation within the tyrosine kinase domain of the RET 
proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol 
Genet 3:237-41, 1994 
8. 
Hofstra RM, Landsvater RM, Ceccherini I, et al: A mutation in the RET proto-oncogene associated 
with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 
367:375-6, 1994 
9. 
Ji JH, Oh YL, Hong M, et al: Identification of Driving ALK Fusion Genes and Genomic Landscape 
of Medullary Thyroid Cancer. PLoS Genet 11:e1005467, 2015 
10. 
Mulligan LM, Kwok JB, Healey CS, et al: Germ-line mutations of the RET proto-oncogene in 
multiple endocrine neoplasia type 2A. Nature 363:458-60, 1993 
11. 
Kato S, Subbiah V, Marchlik E, et al: RET Aberrations in Diverse Cancers: Next-Generation 
Sequencing of 4,871 Patients. Clin Cancer Res 23:1988-1997, 2017 
12. 
Huang KL, Mashl RJ, Wu Y, et al: Pathogenic Germline Variants in 10,389 Adult Cancers. Cell 
173:355-370.e14, 2018 
13. 
Ballester LY, Sarabia SF, Sayeed H, et al: Integrating Molecular Testing in the Diagnosis and 
Management of Children with Thyroid Lesions. Pediatr Dev Pathol 19:94-100, 2016 
14. 
Cordioli MI, Moraes L, Bastos AU, et al: Fusion Oncogenes Are the Main Genetic Events Found 
in Sporadic Papillary Thyroid Carcinomas from Children. Thyroid 27:182-188, 2017 
15. 
Vanden Borre P, Schrock AB, Anderson PM, et al: Pediatric, Adolescent, and Young Adult Thyroid 
Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase 
Fusions. Oncologist 22:255-263, 2017 
16. 
Mostoufi-Moab S, Labourier E, Sullivan L, et al: Molecular Testing for Oncogenic Gene 
Alterations in Pediatric Thyroid Lesions. Thyroid 28:60-67, 2018 
17. 
Kurihara S, Ueda Y, Onitake Y, et al: Circulating free DNA as non-invasive diagnostic biomarker 
for childhood solid tumors. J Pediatr Surg 50:2094-7, 2015 
18. 
Elisei R, Schlumberger MJ, Müller SP, et al: Cabozantinib in progressive medullary thyroid cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
31:3639-3646, 2013 
19. 
Wells SA, Jr., Robinson BG, Gagel RF, et al: Vandetanib in patients with locally advanced or 
metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 30:134-141, 2012 
20. 
Schlumberger M, Elisei R, Müller S, et al: Overall survival analysis of EXAM, a phase III trial of 
cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Annals of 
oncology : official journal of the European Society for Medical Oncology 28:2813-2819, 2017 
21. 
Prior IA, Lewis PD, Mattos C: A comprehensive survey of Ras mutations in cancer. Cancer Res 
72:2457-67, 2012 
22. 
Drilon AE, Subbiah V, Oxnard GR, et al: A phase 1 study of LOXO-292, a potent and highly 
selective RET inhibitor, in patients with RET-altered cancers. Journal of Clinical Oncology 36:102-

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102, 2018 
23. 
Drilon A, Rekhtman N, Arcila M, et al: Cabozantinib in patients with advanced RET-rearranged 
non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 
17:1653-1660, 2016 
24. 
A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-66, 2001 
25. 
Agresti A, Coull BA: Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician 52:119-126, 1998 
26. 
Sandlund JT, Guillerman RP, Perkins SL, et al: International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol 33:2106-11, 2015 
27. 
Park JR, Bagatell R, Cohn SL, et al: Revisions to the International Neuroblastoma Response 
Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning 
Meeting. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 35:2580-2587, 2017 
28. 
Bagatell R, McHugh K, Naranjo A, et al: Assessment of Primary Site Response in Children With 
High-Risk Neuroblastoma: An International Multicenter Study. J Clin Oncol 34:740-6, 2016 
29. 
Burchill SA, Beiske K, Shimada H, et al: Recommendations for the standardization of bone marrow 
disease assessment and reporting in children with neuroblastoma; on behalf of the International 
Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer, 2016 
30. 
Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32:3059-68, 2014 
 
 

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

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

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teniposide 
tetracycline 
ticagrelor5 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.2.2.1 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (GUXJVWKDWGHPRQVWUDWHDQLQFUHDVHLQ$8&RI-fold with strong inhibitors) 

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APPENDIX V-B: SELPERCATINIB (LOXO-292) ORAL SUSPENSION DOSING 
 
Drug doses should be adjusted based on the BSA calculated from height and weight measured within 7 
days prior to the beginning of each cycle.   
 
Patients with BSA < 0.84 m2 must receive the oral suspension formulation.  
 
Patients with BSA  0.84 m2 may take either the capsule or suspension formulation (See Appendix 
V-A for dosing nomogram for selpercatinib capsule formulation).  
 
Patients receiving the liquid formulation who experience dose-limiting toxicity should have their dose 
reduced by 25% so that patients receive 75% of the original prescribed dose. 
Selpercatinib white to off-white powder for oral suspension is provided to the pharmacy in 1.4 gm amber 
glass bottles where it is compounded into a 20 mg/mL suspension with the addition of 1:1 Ora-Plus® and 
Ora-Sweet® SF. A site-supplied 28 mm press-in bottle adapter is required for use with an oral syringe 
for dosing purpose.  
 
Selpercatinib will be given at 90 mg/m2/dose BID (maximum of 160 mg BID). &DOFXODWHGGRVHV
mg should be prepared in oral syringes d 3 mL with dosing volumes of selpercatinib suspension 
formulation rounded to the nearest 0.1 mL (2 mg). Calculated doses > 45 mg should be prepared in oral 
V\ULQJHVP/ZLWKGRVLQJYROXPHVRIselpercatinib suspension formulation rounded to the nearest 0.2 
mL (4 mg). It is recommended that oral dosing syringes should be only filled up to 75% of the maximum 
volume.  
 
To calculate dosing volumes for each patient based on BSA, the following formula should be used: 
 
Dosing Volume (mL) = Prescribed Dose (mg/m2) x BSA (m2) 
       
 
 
 
 
 
 
 20 (mg/mL) 
 
Round dosing volumes according to the above rules. 
Examples: 
x 
Patient BSA 0.44 m2, Dose Level 1 (90 mg/m2/dose) Æ Calculated Dose = 39.6 mg BID 
         
Calculated Volume (mL) = (90 mg/m2/dose x 0.44 m2) / (20 mg/mL) = 1.98 mL  
Final 'RVLQJ9ROXPHP/ P/URXQGHGWRQHDUHVWP/IRUGRVHVPJ 
Final Dose to be administered = 2 mL x 20 mg/mL = 40 mg BID 
x 
Patient BSA 0.87 m2, Dose Level 1 (90 mg/m2/dose) Æ Calculated Dose = 78.3 mg BID 
 
             Calculated Volume (mL) = (90 mg/m2/dose x 0.87 m2) / (20 mg/mL) =3.915 mL  
Final Dosing Volume (mL) = 4 mL (rounded to the nearest 0.2 mL for dose > 45 mg) 
Final Dose to be administered = 4 mL x 20 mg/mL = 80 mg BID 
 
 
 
 
 
 

  
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                                                                                                                                                        Page 2 of 2   
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Page 89 
Cycle 1  
 
Required Observations in Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. For information related to prestudy observations please refer to Section 8.1  
 
*Please refer to section 8.1 for the specific timing of these observations. For information related to 
prestudy observations please refer to Section 8.1 Studies on Day 28/1 may be obtained within 72 hours 
prior to the start of the subsequent cycle. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This 
listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN OTHER 
STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
Treatment Details: Cycle 1 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are met 
(whichever occurs later). 
 
 
 
a. 
History/Physical Exam (including VS, Tanner Staging, and routine dentition examination 
per local SOC). 
 
b. 
CBC/differential/platelets- If patients have Grade 4 neutropenia then CBCs should be 
checked at least every other day until recovery to Grade 3 or until meeting the criteria for 
dose limiting toxicity. If patients develop Grade 3 or higher thrombocytopenia then 
CBCs should be checked every 3-4 days until recovery 
c. 
Electrolytes including Ca++, PO4, Mg++ 
d. 
Creatinine, ALT,AST, bilirubin 
e. 
Albumin  
f. 
Ht/Wt/BSA 
g. 
Medication Diary (see Appendix III-A and Appendix III-B) should be reviewed after 
completion of each treatment cycle and uploaded into RAVE. The medication diary should be 
collected weekly.  
h. 
 Plain radiograph tibial growth plate (bone x-ray tests) prior to cycles 2 and 5, then every 6 
months. 
i. 
EKG- Collected on Cycle 1 Day 1 and Cycle Day 8.  On Cycle 1 Day 1 and Cycle 1 
Day 8 the morning dose of  selpercatinib (LOXO-292) should be held until the Pre-
dose EKG assessment can be obtained. Please refer to Section 8.1 for more 
information. 

  
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                                                                                                                                                        Page 2 of 2   
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Page 91 
Subsequent Cycles 
 
* Please refer to section 8.1 for the specific timing of these observations. Studies on Day 28/1 may be 
obtained within 72 hours prior to the start of the subsequent cycle.
Required Observations in All Subsequent Cycles 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
Treatment Details: Subsequent Cycles 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later) 
a. 
History/Physical Exam (including VS, Tanner Staging, and routine dentition examination per local 
SOC) 
b. 
Ht/Wt/BSA 
c. 
CBC/differential/platelets If patients develop Grade 4 neutropenia then CBCs should be checked every 
3 to 4 days until recovery to Grade 3 or until meeting the criteria for dose limiting toxicity. If patients 
develop Grade 3 or higher thrombocytopenia then CBCs should be checked every 3-4 days until 
recovery 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, AST, bilirubin (required prior to the start of the next cycle, and on Day 15 of Cycles 
2 and 3) 
f. 
Albumin 
g. 
Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. Tumor Disease Evaluation should 
be obtained on the next consecutive cycle after initial documentation of either a PR or CR.  
Subsequent scans may restart 2 cycles after the confirmatory scan. If the institutional investigator 
determines that the patient has progressed based on clinical or laboratory evidence, he/she may opt 
not to confirm this finding radiographically. Neurological exam also required for CNS patients. Non- 
Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior to 
start of therapy and should also be followed with PET scans if positive at diagnosis. 
h. 
Bone Marrow Aspirate and/or biopsy- Every other cycle x 3 then q 3 cycles. Only required in patients 
suspected of having bone marrow metastasis on the basis of history, symptoms, laboratory evaluation 
or other clinical data. Should only be performed on patients with known bone marrow involvement 
at baseline. Bone marrow aspirate and/or biopsy should be performed only when complete response 
or partial response is identified in target disease or when progression in bone marrow is suspected. 
i. 
Medication Diary- (see Appendix III-A and Appendix III-B) should be reviewed after completion of 
each treatment cycle and uploaded into RAVE. 
j. 
Circulating Tumor DNA (ctDNA-optional)- With consent,  two samples will be collected on this 
SURWRFRO&\FOH'D\DQGIRUSDWLHQWVUHFHLYLQJF\FOHVDWSURJUHVVLRQRUHQGRISURWRFRO
therapy) see Section 8.4 for details of the ctDNA studies.  
k. 
Plain radiograph tibial growth plate (bone x-ray tests) prior to cycles 2 and 5, then every 6 months. 
l. 
EKG- Prior the start of subsequent cycles, the morning dose of  selpercatinib (LOXO-292) 
should be held until the Pre-dose EKG assessment can be obtained. Please refer to Section 
8.1 for more information.  

  
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Page 92 
 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621N EXPANSION COHORTS 
Target tumor types considered for biomarker-positive expansion cohorts in the event of agent activity 
in a specific tumor type. 
 
 
 
 
 
Tumor type 
1. Ependymoma 
2. Ewing Sarcoma/Peripheral PNET 
3. Hepatoblastoma 
4. Glioma, high grade 
5. Glioma, low grade 
6. Langerhans Cell Histiocytosis 
7. Malignant Germ Cell Tumor 
8. Medulloblastoma  
9. Neuroblastoma 
10. Non-Hodgkin Lymphoma 
11. Non-RMS Soft Tissue Sarcoma 
12. Osteosarcoma 
13. Rhabdoid Malignancy 
14. Rhabdomyosarcoma 
15. Wilms Tumor 
16. Other Histology (based on COG/NCI-CTEP approval) 

  
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Page 93 
APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS FOR SUBPROTOCOL 
APEC1621N 
INCLUSION 
VARIANTS 
  
  
  
Hotspots 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
RET 
COSM29803 
SNV 
p.C618R 
3 
RET 
COSM980 
SNV 
p.C618Y 
3 
RET 
COSM29804 
SVN 
p.C620R 
3 
RET 
COSM29805 
SNV 
p.C620S 
3 
RET 
COSM968 
DEL 
p.E632_L633del 
2 
RET 
COSM1048 
INDEL 
p.E632_T636delinsSS 
2 
RET 
COSM982 
DEL 
p.E632_L633del 
2 
RET 
COSM973 
DEL 
p.E632_C634del 
2 
RET 
COSM1049 
INDEL 
p.E632_A640delinsVRP 
2 
RET 
COSM1237919 
SNV 
p.C634F 
3 
RET 
COSM1738369 
SNV 
p.C634G 
3 
RET 
COSM966 
SNV 
p.C634R 
3 
RET 
COSM1237918 
SNV 
p.C634S 
3 
RET 
COSM975 
SNV 
p.C634W 
3 
RET 
COSM974 
SNV 
p.C634Y 
3 
RET 
COSM1716312 
SNV 
p.E768Q 
3 
RET 
COSM1347811 
SNV 
p.E768G 
3 
RET 
COSM21338 
SNV 
p.E768D 
3 
RET 
rs79658334 
SNV 
p.V804M 
2 
RET 
COSM977 
MNV 
p.A883F  
2 
RET 
COSM981 
MNV 
p.A883F 
2 
RET 
COSM133167 
SNV 
p.A883S 
3 
RET 
COSM3415038 
SNV 
p.R912W 
3 
RET 
COSM188545 
SNV 
p.R912L 
3 
RET 
COSM3437793 
SNV 
p.R912Q 
3 
RET 
COSM965 
SNV 
p.M918T  
2 
RET 
COSM1347818 
SNV 
p.M918V 
3 
 
 
 
 
 
 
 
 
 
 
Fusions 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
aMOI 
LOE 
RET 
ACBD5-RET.A11R12 
Fusion 
RET Fusion 
2 
RET 
AFAP1-RET.A3R12 
Fusion 
RET Fusion 
2 
RET 
AKAP13-RET.A35R12 
Fusion 
RET Fusion 
2 
RET 
AKAP13-RET.A36R12 
Fusion 
RET Fusion 
2 

  
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RET 
CCDC6-RET.C1R11 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C1R11.1 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C1R12 
Fusion 
RET Fusion 
2 
RET 
CCDC6-
RET.C1R12.COSF1271 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C1R13 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C1R9 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C2R11 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C2R12.1 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C5ins16R11 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C8R11 
Fusion 
RET Fusion 
2 
RET 
CCDC6-
RET.C8R11.COSF1518 
Fusion 
RET Fusion 
2 
RET 
CCDC6-RET.C8R12 
Fusion 
RET Fusion 
2 
RET 
CUX1-RET.C10R12 
Fusion 
RET Fusion 
2 
RET 
ERC1-
RET.E11R12.COSF1507 
Fusion 
RET Fusion 
2 
RET 
ERC1-RET.E12R12 
Fusion 
RET Fusion 
2 
RET 
ERC1-RET.E17R12 
Fusion 
RET Fusion 
2 
RET 
ERC1-RET.E7R12 
Fusion 
RET Fusion 
2 
RET 
FKBP15-RET.F25R12 
Fusion 
RET Fusion 
2 
RET 
GOLGA5-
RET.G7R12.COSF1503 
Fusion 
RET Fusion 
2 
RET 
HOOK3-
RET.H11R12.COSF1509 
Fusion 
RET Fusion 
2 
RET 
KIAA1468-RET.K10R12 
Fusion 
RET Fusion 
2 
RET 
KIF5B-
RET.K15R11.COSF1255.1 
Fusion 
RET Fusion 
2 
RET 
KIF5B-
RET.K15R12.COSF1232 
Fusion 
RET Fusion 
2 
RET 
KIF5B-
RET.K16R12.COSF1230 
Fusion 
RET Fusion 
2 
RET 
KIF5B-RET.K18R12 
Fusion 
RET Fusion 
2 
RET 
KIF5B-
RET.K22R12.COSF1253 
Fusion 
RET Fusion 
2 
RET 
KIF5B-
RET.K23R12.COSF1234 
Fusion 
RET Fusion 
2 
RET 
KIF5B-
RET.K24R11.COSF1262 
Fusion 
RET Fusion 
2 
RET 
KIF5B-RET.K24R8.COSF1236 
Fusion 
RET Fusion 
2 
RET 
KTN1-
RET.K29R12.COSF1513 
Fusion 
RET Fusion 
2 
RET 
MYH13-RET.M35R12 
Fusion 
RET Fusion 
2 
RET 
NCOA4-
RET.N6R12.COSF1340 
Fusion 
RET Fusion 
2 

  
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Page 95 
RET 
NCOA4-
RET.N7R12.COSF1491 
Fusion 
RET Fusion 
2 
RET 
PCM1-
RET.P29R12.COSF1481 
Fusion 
RET Fusion 
2 
RET 
PRKAR1A-
RET.P7R12.COSF1511 
Fusion 
RET Fusion 
2 
RET 
RUFY2-RET.R9R12 
Fusion 
RET Fusion 
2 
RET 
SPECC1L-RET.S10R11.NGS.1 
Fusion 
RET Fusion 
2 
RET 
SPECC1L-RET.S10R12 
Fusion 
RET Fusion 
2 
RET 
TBL1XR1-RET.T9R11.NGS.1 
Fusion 
RET Fusion 
2 
RET 
TBL1XR1-RET.T9R12 
Fusion 
RET Fusion 
2 
RET 
TRIM24-
RET.T9R12.COSF1521 
Fusion 
RET Fusion 
2 
RET 
TRIM27-
RET.T3R12.COSF1519 
Fusion 
RET Fusion 
2 
RET 
TRIM33-RET.T11R12 
Fusion 
RET Fusion 
2 
RET 
TRIM33-RET.T15R12 
Fusion 
RET Fusion 
2 
RET 
TRIM33-
RET.T16R12.COSF1525 
Fusion 
RET Fusion 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Page 97 
Protocol-Specific Requirements For Site Registration: 
x 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
x 
Click on Regulatory  at the top of the screen; 
x 
Click on Site Registration; and  
x 
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 a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
 
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 

  
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Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and click 
on the accept link in the upper right-corner of the iMedidata page. Site staff will not be able to 
access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be accessed 
by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning is required 
and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata 
instead of the Rave EDC link; once the successful completion of the eLearning has been recorded, 
access to the study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the Data 
Management section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on the 
DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead Protocol 
Organization for delinquent form details and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding questions about Rave Calendaring 
functionality.   
 
 

  
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Page 99 
 
 
APPENDIX X: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
> ULN- d 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3.0 x ULN 
Grade 3: 
> 3.0 x ULN -10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
Grade 1: 
> 45 U/L - d 135 U/L 
Grade 2: 
136 U/L - 225 U/L 
Grade 3: 
226 U/L - 900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for AST is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - d 150 U/L 
Grade 2: 
151 U/L -250 U/L 
Grade 3: 
251 U/L -1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN - 5.0 x ULN 
Grade 3: 
> 5.0 x ULN -20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Page 100 
 
APPENDIX XI: PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions 
with Other Drugs and Herbal Supplements  
 
Patient 
Name: 
      
Diagnosis:        
Trial #: 
      
Study 
Doctor: 
      
Study 
Doctor 
Phone #:  
      
Study 
Drug(s): 
Selpercatinib 
(LOXO-292) 
 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, 
pharmacists), and tell them you are taking part in a clinical trial sponsored by the National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
 
Selpercatinib interacts with certain specific liver enzymes and certain transport proteins that help move 
drugs in and out of cells. Selpercatinib can also interact with certain stomach acid-reducing medications, 
medications that are considered highly protein-bound or medications that can affect your heart’s electrical 
activity. 
 
 
Explanation 
CYP 
Isoenzymes  
The enzymes in question are CYP3A4 and CYP2C8. Selpercatinib is broken down by 
CYP3A4 and may be affected by other drugs that moderately or strongly inhibit or induce 
this enzyme. Selpercatinib weakly inhibits CYP3A4 and moderately inhibits CYP2C8 
and may affect other drugs that are broken by these enzymes. 
Protein 
Transporters  
The proteins in question are P-gp, BCRP and MATE1. Selpercatinib is moved in and out 
of cells/organs by P-gp and BCRP and may be affected by other drugs that strongly inhibit 
or induce these transport proteins. Selpercatinib inhibits P-gp, BCRP and MATE1 and 
may affect other drugs that require these transport proteins to move in and out of 
cells/organs. 
Heart’s 
electrical 
activities 
 
Acid-
reducing 
medications 
The heart’s electrical activity may be affected by selpercatinib. The study doctor may be 
concerned about QTc prolongation and any other medicine that is associated with greater 
risk for having QTc prolongation.  
 
Antacids and medications called proton-pump inhibitors and H2 receptor antagonists can 
change how Selpercatinib is broken down and distributed throughout your body and may 
reduce its effectiveness. 
Protein-
Binding 
 
Selpercatinib binds to a high percentage of proteins in your blood and may affect the activity 
of other drugs that also bind highly to these proteins or the other drugs may affect the activity 
of selpercatinib.  
 
These are the things that you need to know: 
 
The study drug selpercatinib, may interact with other drugs which can cause side effects. For this reason, it 
is very important to tell your doctors about all your medicines, including: (a) medicines you are taking 

  
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before this clinical trial, (b) medicines you start or stop taking during this clinical trial, (c) medicines you 
buy without a prescription (over-the-counter remedy), (d) herbals or supplements (e.g., St. John’s Wort). It 
is helpful to bring your medication bottles or an updated medication list with you.  
 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered “moderate” or “strong” 
inducers/inhibitors of CYP3A4 and “strong” inducers/inhibitors of transport proteins P-gp and BCRP; any 
medicines that are considered substrates of CYP2C8, CYP3A4, P-gp, BCRP and MATE1; certain 
medicines that can affect your heart’s electrical activity; certain medicines used to reduce stomach acid; 
and, medicines considered highly protein-bound. 
 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
o Avoid ingesting grapefruit juice, grapefruit and Seville oranges while taking selpercatinib. 
o Avoid using herbal supplements, such as St. John’s wort while taking selpercatinib. 
o Over-the-counter antacids or stomach acid reducing medicines called proton pump 
inhibitors or H2 antagonists may be used if necessary, but your study doctor will inform 
you how to take these medicines with selpercatinib. Examples of proton pump inhibitors 
include Prilosec (omeprazole), Prevacid (lansoprazole) and Nexium (esomeprazole). 
Examples of H2 receptor antagonists include Zantac (ranitidine), Pepcid (famotidine), and 
Tagamet (cimetidine).    
x Make sure your doctor knows to avoid certain prescription medicines.  
o Avoid any medicines considered “moderate” or “strong” inducers/inhibitors of CYP3A4 
and “strong” inducers/inhibitors of transport proteins P-gp and BCRP. 
o Avoid any medicines considered sensitive substrates of CYP2C8 and CYP3A4.  
o Use caution with any medicines considered substrates of MATE1, P-gp or BCRP. 
o Prescription and over-the-counter antacids and stomach acid reducing medicines such as 
proton pump inhibitors and H2 receptor antagonists may be used if necessary, but your 
study doctor will inform you how to take these medications with selpercatinib.  
x Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine.   
 
 
 
Version: OCT2021 
 
(Next page: Patient Drug Interaction Wallet Card) 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

                                                      THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621N 
Version Date: 10/28/2022 
 
Page 103 
APPENDIX XII:  YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621N 
(For Children from 7 through 13 Years of Age) 
 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) in 
children with a cancer that has come back after treatment or is difficult to treat 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is being 
done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because other treatments 
did not get rid of the cancer. A research study is when doctors work together to try out new ways to 
help people who are sick. In this study, we are trying to learn more about how to treat the kind of 
cancer you have.  
 
4. What will happen to me in the study? Children who are part of this study have been “matched” to a 
medicine. We think that this medicine will help you and other kids that have the same kind of cancer 
as you have. If you decide to be treated with this medicine, you will have some tests and check-ups 
done more often than if you weren’t part of this study. We will follow your health after you finish the 
study treatment. 
 
Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is for your cancer to stop 
growing, or even shrink, but we don’t know for sure if there is any benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you may have more problems, or side effects, 
from a medicine used in this study. There may be risks that we don’t know about yet. 
 
5. Do I have to be in the study? You and your family can choose to be part of this study or not. You and 
your family can also decide to stop being in this study at any time once you start. There may be other 
treatments for your illness that your doctor can tell you about. If you have any questions or don’t like 
what is happening, please tell your parent, the doctor or nurse. 
 
6. We are asking your permission to collect additional 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 samples that 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. You do not have to participate if you do 
not want to. 
 

                                                      THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621N 
Version Date: 10/28/2022 
 
Page 104 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621N 
(For Teens from 14 through 17 Years of Age) 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) in 
children with a cancer that has come back after treatment or is difficult to treat 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is being 
done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because other treatments 
did not get rid of the cancer. A research study is when doctors work together to try out new ways to 
help people who are sick. In this study, we are trying to learn more about how to treat the kind of cancer 
that you have.  
 
4.  What will happen to me on the study? Your tumor has a mutation that matches selpercatinib (LOXO-
292), and so you have been assigned to selpercatinib (LOXO-292). The doctors want to see if 
selpercatinib (LOXO-292) will make children with your type of cancer get better. We don’t know if 
selpercatinib (LOXO-292) will work well to get rid of your cancer. That is why we are doing the study. 
       
Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that selpercatinib may 
cause your cancer to stop growing or to shrink for a period of time but we don’t know for sure if there 
is any benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The primary risk to you from this study is that you may have side effects, from 
selpercatinib. Your doctor will talk to you about the risks we know about from selpercatinib. There 
may be other risks from selpercatinib that we don’t know about yet.  
 
5. Will I be paid to be in this study? You will not be paid for being in this study. 
 
6. Do I have to be in the study? You and your family can choose to be part of this study or not. You and 
your family can also decide to stop being in this study at any time once you start. There may be other 
treatments for your illness that your doctor can tell you about. If you have any questions or don’t like 
what is happening, please tell your parent, the doctor or nurse. 
 
8. We are asking your permission to collect additional 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 blood samples that 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. You do not have to participate if you do 
not want to. 
 
 
 

                                                      THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621N 
Version Date: 10/28/2022 
 
Page 105 
APPENDIX XIII MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
The use of the following medications should be avoided during protocol therapy if reasonable 
alternatives exist. This is not an inclusive list. Because the lists of these agents are constantly 
changing, it is important to regularly consult frequently updated medical references. For the most 
current list of medications, please refer to the following reference: Woosley, RL and Romero, KA, 
www.Crediblemeds.org, QTdrugs List, Accession Date December 19th, 2019, AZCERT, Inc. 1822 
Innovation Park Dr., Oro Valley, AZ  85755 
 
 
Medications with known risk of Torsades de Pointes (TdP) 
Amiodarone 
Fluconazole 
Anagrelide 
Haloperidol 
Arsenic trioxide 
Hydroxychloroquine 
Azithromycin 
Ibutilide  
Chloroquine 
Levofloxacin 
Chlorpromazine 
Methadone  
Cilostazol  
Moxifloxacin  
Ciprofloxacin  
Ondansetron 
Citalopram 
Oxaliplatin 
Clarithromycin 
Papaverine HCL (intra-coronary) 
Disopyramide 
Pentamidine 
Dofetilide 
Pimozide 
Domperidone 
Procainamide 
Donepezil 
Propofol 
Droperidol 
Quinidine  
Dronedarone 
Sevoflurane 
Erythromycin 
Sotalol 
Escitalopram 
Thioridazine  
Flecainide  
Vandetanib  
 
 
 
Medications with possible risk of Torsades de Pointes (TdP) 
Alfuzosin 
Lofexidine 
Apalutamide 
Lopinavir/Ritonavir 
Apomorphine 
Maprotilin 
Aripiprazole 
Memantine 
Artemeter/Lumefantrine  
Midostaurin 
Asenapine  
Mifepristone 
Atomoxetine  
Mirabegron 
Bedaquiline  
Mirtazapine 
Bendamustine  
Moexipril/Hydrochlorothiazide 
Betrixaban  
Necitumumab 
Bortezomib 
Nicardipine  
Bosutinib 
Nilotinib  
Buprenorphine 
Nortriptyline 
Cabozantinib 
Nusinersen 
Capecitabine 
Ofloxacin 

                                                      THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY. 
APEC1621N 
Version Date: 10/28/2022 
 
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Ceritinib 
Osimertinib 
Clomipramine 
Oxytocin 
Clozapine 
Paliperidone 
Cobimetinib 
Palonosetron 
Crizotinib 
Panobinostat 
Dabrafenib 
Pasireotide 
Dasatinib 
Pazopanib  
Degarelix 
Perflutren lipid microspheres 
Desipramine 
Perphenazine 
Deutetrabenazine 
Pimavanserin 
Dexmedetomidine 
Pitolisant (Tiprolisant) 
Dextromethorphan/Quinidine 
Pretomanid 
Dolasetron 
Primaquine phosphate 
Efavirenz 
Promethazine  
Eliglustat 
Ribociclib 
Encorafenib 
Rilpivirine 
Entrectinib 
Romidepsin 
Epirubicin 
Saquinavir 
Eribulin mesylate 
Siponimod 
Ezogabine (Retigabine) 
Sorafenib 
Felbamate 
Sunitinib  
Fingolimod 
Tacrolimus 
Fluorouracil (5-FU) 
Tamoxifen 
Gemifloxacin  
Telavancin 
Gilteritinib  
Telithromycin 
Glasdegib 
Tetrabenazine 
Granisetron 
Tipiracil/Trifluridine 
Hydrocodone-ER 
Tizanidine 
Iloperidone 
Tolterodine 
Imipramine (Melipramine) 
Toremifene 
Inotuzumab ozogamicin 
Tramadol 
Isradipine 
Trimipramine 
Ivosidenib 
Valbenazine 
Lapatinib 
Vardenafil  
Lefamulin 
Vemurafenib  
Lenvatinib 
Venlafaxine 
Leuprolide (Leuprorelin) 
Vorinostat 
Lithium