NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of LOXO-101 (Larotrectinib) in Patients With Tumors Harboring Actionable NTRK Fusions
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Kidney Wilms Tumor, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma
Sponsor: National Cancer Institute (NCI)

  
 
 
 
i 
 
G Douglas S. Hawkins, MD 
Seattle Children's Research  
Institute 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
Children's Hospital Colorado 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Executive Director of Clinical  
Research Operations 
Mary Beth Sullivan, MPH 
msullivan@childrensoncology 
group.org  
 
Executive Director of 
Data Operations 
Thalia Beeles, MPH 
tbeeles@childrensoncology 
group.org 
 
Executive Director of 
Administration and Finance 
Lee Ann DeRita, MBA, CMA,  
CFE 
lderita@childrensoncology 
group.org 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
1333 S. Mayflower Avenue 
Suite 260 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A National Cancer Institute- 
funded group member of the  
National Clinical Trials Network 
 
 
October 28, 2022 
 
 
Martha Kruhm, M.S., RAC 
Protocol and Information Office (PIO) Head 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
RE: Request for Amendments with FDA requested language for Pediatric 
MATCH consents 
 
Dear Ms. Kruhm, 
 
The study committee thanks CTEP for forwarding the Amendment Request 
dated October 17, 2022. In response to the request, please see attached 
Amendment #7 to APEC1621A. The complete list of changes can be found 
below.  
 
Please contact us if you have any further questions. 
 
Sincerely, 
 
Emma Archuleta, B.S., Protocol Coordinator (for) 
Katherine  Janeway, M.D., APEC1621A Study Chair, and 
Douglas S. Hawkins, M.D., Group Chair, Children’s Oncology Group 
 

 
                        
APEC1621A 
 
                                                                                                                      
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Page 1 
 
Activated: July 24th, 2017  
 
Version Date: 10/28/2022 
 
Closed: 
 
Amendment # 7 
 
 
 
 
 
 
 
 
 
 
 
 
     CHILDREN’S ONCOLOGY GROUP 
 
 
APEC1621A 
 
NCI-COG PEDIATRIC MATCH 
(MOLECULAR ANALYSIS FOR THERAPY CHOICE)- 
PHASE 2 SUBPROTOCOL OF LOXO-101 (LAROTRECTINIB) IN PATIENTS WITH TUMORS 
HARBORING ACTIONABLE NTRK FUSIONS 
 
 
Open to COG Member Institutions in the USA  
 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED 
OR USED FOR ANY OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN 
THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY 
ANY PERSON OR ENTITY.  RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH 
DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO 
GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY 
SUBJECT.  THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL 
ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE 
THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT 
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL 
HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
STUDY CHAIR 
Katie Janeway, MD 
Dana-Farber/Harvard Cancer Center 
Pediatric Oncology 
450 Brookline Ave Street, Dana 3 
Boston, MA 02215 
Phone:  (617) 632-4994 
Email: katherine_janeway@dfci.harvard.edu 
 
 
 

 
                        
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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- CTSU (2878) 
for regulatory assistance. 
Please refer to the patient enrollment section 
of the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://open.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or email:  
1-888-823-5923, or  ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively 
through Medidata Rave. Please 
see the Data Submission 
Schedule in the CRF packet for 
further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded from the protocol-
specific page located on the CTSU members’ website (https://www.ctsu.org). Access to the CTSU members’ website is 
managed through the Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) 
registration system and requires log in with a CTEP-IAM username and password. Permission to view and download 
this protocol and its supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU Regulatory Support System (RSS). 
For clinical questions (ie, patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (ie, unrelated to patient eligibility, treatment, or clinical data submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence will be 
triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
 

 
                                            
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TABLE OF CONTENTS 
SECTION 
PAGE 
CHILDREN’S ONCOLOGY GROUP 
1 
STUDY COMMITTEE 
5 
STUDY COMMITTEE, CONT. 
6 
COG OPERATIONS STAFF 
6 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
 
Primary Aims 
8 
 
Secondary Aims 
8 
 
Exploratory Aims 
8 
2.0 
BACKGROUND 
9 
 
Introduction/Rationale for Development 
9 
 
Preclinical Studies 
10 
 
Adult Studies 
13 
 
Larotrectinib Activity in NTRK Fusion Positive Malignancies 
14 
 
Pediatric Studies 
15 
 
Overview of Proposed Pediatric Study 
15 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
16 
 
Study Enrollment 
16 
 
Informed Consent/Assent 
19 
 
Screening Procedures 
19 
 
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 
26 
 
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 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
28 
 
Concurrent Anticancer Therapy 
28 
 
Investigational Agents 
28 
 
Supportive Care 
28 
 
Growth Factors 
28 
 
Concomitant Medications 
28 

 
                                            
APEC1621A 
 
                                                                                                                      
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
29 
 
Required Clinical, Laboratory and Disease Evaluation 
29 
 
Radiology Studies 
31 
 
Pharmacology (optional) 
32 
 
Circulating Tumor DNA Study (optional) 
34 
9.0 
AGENT INFORMATION 
36 
 
Larotrectinib          09/28/22 
36 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
42 
 
Criteria for Removal from Protocol Therapy 
42 
 
Follow-Up Data Submission and APEC1621SC Off Study Criteria 
42 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
43 
 
Sample Size and Study Duration 
43 
 
Dosing Considerations 
43 
 
Study Design 
43 
 
Methods of Analysis 
44 
 
Evaluability for Response 
44 
 
Evaluability for Toxicity 
44 
 
Progression free survival (PFS) 
44 
 
Pharmacokinetic and Correlative Studies 
45 
 
Gender and Minority Accrual Estimates 
45 
12.0 
EVALUATION CRITERIA 
45 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
45 
 
Progression-Free Survival 
46 
 
Response Criteria for Patients with Solid Tumors 
46 
 
Response Criteria for Patients with Solid Tumor and Measurable Disease 
50 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
52 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
54 
 
Response Criteria for Patients with CNS Tumors 
55 
 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
57 
 
Best Response 
58 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
60 
 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
60 
 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
61 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements:
 
63 
 
Definition of Onset and Resolution of Adverse Events 
63 
 
Other Recipients of Adverse Event Reports 
64 
 
Specific Examples for Expedited Reporting 
64 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
66 
 
Categories of Research Records 
66 
 
CDUS 
66 
 
CRADA/CTA/CSA 
66 
 
Data and Safety Monitoring Plan 
68 
REFERENCES 
69 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
70 

 
                                            
APEC1621A 
 
                                                                                                                      
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APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
71 
APPENDIX III-A:  MEDICATION DIARY FOR LOXO-101 (LAROTRECTINIB) (CAPSULE 
FORMULATION) 
74 
APPENDIX III-B:  MEDICATION DIARY FOR LOXO-101 (LAROTRECTINIB) (LIQUID 
FORMULATION) 
77 
APPENDIX III-C:  LOXO-101 (LAROTRECTINIB) PATIENT CLINICAL TRIAL WALLET CARD 80 
APPENDIX IV-A: LOXO-101 (LAROTRECTINIB) DOSING NOMOGRAM (CAPSULE 
FORMULATION) 
81 
APPENDIX IV-B: LOXO-101 (LAROTRECTINIB) DOSING PREPARATION (LIQUID 
FORMULATION) 
82 
APPENDIX V CORRELATIVE STUDIES 
83 
APPENDIX VI: APEC1621A THERAPY DELIVERY MAP 
84 
APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621A EXPANSION COHORTS 
88 
APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS FOR SUB-PROTOCOL 
APEC1621A 
89 
APPENDIX IX:  YOUTH INFORMATION SHEETS 
92 
APPENDIX X: CTEP AND CTSU REGISTRATION PROCEDURES 
94 
APPENDIX XI: TOXICITY-SPECIFIC GRADING 
98 
 
 
 
 

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STUDY COMMITTEE 
STUDY CHAIR 
Nita Seibel, MD 
Katie Janeway, MD 
National Cancer Institute 
Target and Agent Prioritization 
9609 Medical Center Drive, MSC 9739 
Dana-Farber/Boston Children’s 
Rockville, MD 20892 
Pediatric Oncology 
Phone:  (240) 276-6560 
450 Brookline Ave, Dana 3-130 
Fax:  (240) 276-7892 
Boston, MA 02115 
Email: seibelnl@mail.nih.gov  
Phone:   (617) 632-4994 
 
Email: katherine_janeway@dfci.harvard.edu 
STUDY VICE CHAIR 
 
Steven G. Dubois, MD 
Will Parsons, MD, PhD 
Dana-Farber/Boston Children’s 
Baylor College of Medicine 
450 Brookline Ave, Dana 3-141F 
1102 Bates, Suite 1030.15 
Boston, MA 02115 
Houston, TX 77030 
Phone: (617) 632-5460 
Phone: (832) 824-4643 
Email: steven_dubois@dfci.harvard.edu 
Email: dwparson@txch.org 
 
 
Douglas Hawkins, MD,PhD 
Brian Crompton, MD 
COG Group Chair 
Dana-Farber/Boston Children’s 
Seattle Children’s Hospital  
450 Brookline Ave. 
1909 9th Ave 
Boston, MA 02115 
Seattle, WA 98101 
Email: brian_crompton@dfci.harvard.edu 
Phone:  (206) 884-1107 
 
Email: doug.hawkins@seattlechildrens.org 
Todd Alonzo, PhD 
 
Study Statistician  
Stacey Berg, MD 
COG Statistics and Data Center- Monrovia 
Study Design and Logistics 
Monrovia, CA 91016 
Baylor College of Medicine 
Phone: (626) 241-1522 
Pediatric Oncology  
Fax: (626) 445-4334 
6621 Fannin Street 
Email: talonzo@childrensoncologygroup.org 
MC3-3320 
 
Houston, TX 77030 
 
Phone: (832) 824-4588 
Joel Reid, PhD. 
Fax:  (832) 825-4039 
Study Pharmacologist 
Email: sberg@txch.org 
Mayo Clinic  
 
Guggenheim 17-37 
Elizabeth Fox, MD 
200 First St SW 
Study Design and Logistics 
Rochester, MN 55905 
Saint Jude Children's Research Hospital 
Phone: (507) 284-0822 
Cancer Center; Clinical Trials Administration 
Fax: (507) 284-3906 
262 Danny Thomas Place, MS 281 
Email: reid.joel@mayo.edu  
Memphis, TN 38105 
  
Phone: (901) 595-3300 
Jin Piao, PhD 
Fax:  (901) 595-7031 
Study Statistician 
Email: elizabeth.fox@stjude.org 
COG Statistics and Data Center- Monrovia 
 
Phone: (626) 241-1572 
 
Email: jpiao@childrensoncologygroup.org 
 
 
 
 
 
 
 

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STUDY COMMITTEE, CONT. 
 
 
Alvin Russell Ongoco, BS 
Study CRA 
Jane Chen, PharmD 
Study Pharmacist  
Seattle Children’s Hospital 
Children’s Healthcare of Atlanta 
1900 9th Ave 
1405 Clifton Rd NE 
Seattle, WA 98101 
Atlanta, GA  30322 
Phone (206) 884-1214 
Phone: (404) 785-0342 
Email: alvinrussell.ongoco@seattlechildrens.org 
Email: jane.chen@choa.org 
 
 
COG OPERATIONS STAFF 
Vanessa Fierro, BS 
Lauren Saguilig, MS 
Research Coordinator 
Children’s Oncology Group – Operations Center 
Monrovia, CA  91016 
Master Statistician  
Children’s Oncology Group – Operations Center 
Monrovia, CA 91016 
Phone (626) 241-1615 
Phone: (626) 241-1547 
Email: vafierro@childrensoncologygroup.org 
Email: lsaguilig@childrensoncologygroup.org 
 
 
Emma Archuleta, B.S. 
Scientific Writer/Protocol Coordinator 
 
Children’s Oncology Group – Operations Center 
Monrovia, CA  91016 
 
Phone: (626) 241-1645 
 
Email: earchuleta@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Group Operations (GOC) and 
 
Statistics & Data Center (SDC) contacts see: 
 
https://members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
NCI-Supplied Agents 
LOXO-101(larotrectinib) 
 
(NSC #788607,IND# 
) 
 
 
 
IND Sponsor: DCTD, NCI 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Version Date: 10/28/2022                                                    
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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 NCI-COG Pediatric MATCH trial APEC1621. The APEC1621SC 
screening protocol details the process used to identify actionable mutations in patient tumor samples which 
will determine eligibility for this subprotocol. Here we will conduct a phase 2 trial of LOXO-101 
(larotrectinib) in children with recurrent or refractory solid tumors (including non-Hodgkin lymphomas, 
histiocytoses and CNS tumors) harboring NTRK gene fusion proteins. 
 
LOXO-101 (larotrectinib) has shown tumor regression in non-clinical cancer models and in patients with 
tumors harboring NTRK gene fusion proteins. This is a Phase 2 study of LOXO-101 (larotrectinib) an orally 
bioavailable, potent, ATP-competitive, selective inhibitor of TRKA, TRKB, and TRKC in patients enrolled 
in APEC1621 who are determined to have NTRK 1, 2 or 3 translocations. LOXO-101 (larotrectinib) will 
be given orally or through NG- or G- tube at a dose of 100 mg/m2/dose BID (capped at 100 mg per dose). 
The primary endpoint will be objective response rate as determined by RECIST. Progression free survival 
(PFS) will be assessed as a secondary endpoint. In addition, toxicity will be assessed, the pharmacokinetics 
of LOXO-101 (larotrectinib) in children will be evaluated and the ability to detect NTRK fusions in 
circulating cell-free tumor DNA in plasma will be evaluated. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
Treatment Schedule Table 
Days 1-28 
LOXO-101 (larotrectinib) orally 
or via NG- or G-tube  twice 
daily 
Day 28 
Evaluation 
 
Drug will be administered orally or via NG- or G- tube twice daily with no break; a cycle will be 28 days. 
Evaluations will occur at the end of every other cycle x 3, then every 3 cycles. 
 
Therapy will be discontinued if there is evidence of progressive disease or drug related dose-limiting 
toxicity that requires removal from therapy (Section 6.0). Therapy may otherwise continue for up to 2 years 
provided the patient meets the criteria for starting subsequent cycles (Section 5.2) and does not meet any 
of the criteria for removal from protocol therapy criteria (Section 10.0).  
 

 
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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 LOXO-101 (larotrectinib) with 
advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or 
histiocytic disorders harboring NTRK 1/2/3 fusions. 
 
 
Secondary Aims 
 
 
To estimate the progression free survival in pediatric patients treated with LOXO-
101 (larotrectinib) with advanced solid tumors (including CNS tumors), non-
Hodgkin lymphomas or histiocytic disorders with NTRK 1/2/3 fusions. 
 
 
To obtain additional information about the tolerability of LOXO-101 
(larotrectinib) in children with relapsed or refractory cancer. 
 
 
To provide preliminary estimates of the pharmacokinetics of LOXO-101 
(larotrectinib) in children with relapsed or refractory cancer. 
 
 
Exploratory Aims 
 
 
To explore approaches to profiling changes in tumor genomics over time through 
evaluation of circulating tumor DNA.  
 
 

 
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2.0 
BACKGROUND 
 
 
Introduction/Rationale for Development 
The TRK family are receptor tyrosine kinases involved in nervous system development. 
NTRK1, NTRK2 and NTRK3 encode TRKA, TRKB and TRKC respectively. TRK 
receptors are expressed in the nervous system and diseases resulting from loss of function 
mutations in NTRK genes reveal important roles for TRK in pain sensation, appetite 
control, memory and balance. Gene fusions involving each of the NTRK genes have been 
identified in a wide range of malignancies including the following seen in pediatric 
patients: gliomas, mesoblastic nephroma, and infantile fibrosarcoma.1  
 
The reported TRK fusions occurring in cancer have the 3’ region of TRK including the 
kinase domain fused to the 5’ sequence from another gene. For example, the ETV6-NTRK3 
fusion identified in mesoblastic nephroma, infantile fibrosarcoma and other malignancies 
has a varying breakpoints but always contains the kinase domain of TRKC and the SAM 
dimerization domain of ETV6. It has been thought that the ETV6-NTRK3 fusion was 
pathognomonic for infantile fibrosarcoma.2 However, a recent case in which a novel 
EML4-NTRK3 fusion was identified in a case with histology and clinical presentation 
consistent with a more aggressive manifestation of infantile fibrosarcoma raises the 
possibility that other TRK fusions may be identified in this disease.3 Infantile fibrosarcoma 
is rare, often treatable with surgery or chemotherapy and infrequently metastatic or 
recurrent. However, locally aggressive cases do occur and medical management is 
considered in these cases. Likewise, mesoblastic nephroma has an excellent prognosis with 
surgery alone. Thus, these pediatric diseases in which NTRK fusions are common are less 
likely to need therapy on a phase 2 trial such as the pediatric MATCH study. In diffuse 
intrinsic pontine glioma (DIPG) and other pediatric high grade gliomas NTRK fusions were 
identified in 8 of 112 cases sequenced.4 These pediatric malignancies, particularly DIPG 
have a poor prognosis.  
 
It is not possible to precisely determine the frequency of NTRK 1/2/3 fusions in childhood 
malignancies eligible for this arm of the pediatric MATCH protocol using available 
databases. Detection of fusion events requires whole genome sequencing, RNA sequencing 
or specific fusion detection, methods that have not been utilized on a sufficient number of 
samples from recurrent childhood solid tumors and lymphomas with data in these databases 
for an accurate prediction of frequency of fusions. In the iCat study in which 100 patients 
with high risk, recurrent or refractory solid tumors had aCGH performed and targeted 
sequencing with only NTRK1 assayed for fusions, one patient with an undifferentiated 
sarcoma was found to have a novel EML4-NTRK3 fusion event based on a distinct aCGH 
pattern.5 In an unpublished institutional tumor sequencing study utilizing a targeted next 
generation sequencing assay capturing intronic sequences of only NTRK1 for translocation 
detection, 1 of approximately 100 solid tumors sequenced (a sarcoma secondary to 
radiation) was found to have an NTRK1 translocation (Janeway, personal communication).  
 
LOXO-101 is an orally bioavailable, potent, ATP-competitive, selective inhibitor of 
TRKA, TRKB, and TRKC. LOXO-101 has shown tumor regression in non-clinical cancer 
models and in adult patients with tumors harboring NTRK gene fusion proteins. A phase 1 
of LOXO-101 in adult patients with advanced solid tumors is ongoing (discussed further 
below). LOXO-101 dosing in this trial is flat dose. The maximum tolerated dose (MTD) 
has not been reached. At all doses administered in the Phase 1 trial, the peak concentrations 
are sufficient for 98% inhibition of TRKA/B/C and partial responses to LOXO-101 all 3 

 
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treated patients with NTRK fusions have been seen. 6 A pediatric liquid formulation has 
been developed and tested in animals.  
 
 
Preclinical Studies 
 
 
Antitumor Activity 
LOXO-101 has potent inhibition of cell growth and proliferation driven by 
alteration in the TRK family of proteins versus control (non-TRK driven) cell 
lines with IC50 ranging from 1 to 59 nM (Table 1). 
 
Table 1. Potency of LOXO-101 in TRK driven and non-TRK driven cell lines 
 
 
LOXO-101 displays tumor growth inhibition in xenografts of TRK fusion models (Figure 1) 
 
Figure 1. Effect of LOXO-101 on TRK fusion xenografts 
 
 

 
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Animal Toxicology 
LOXO-101 has been evaluated in 2 in vitro studies that explored possible cardiac 
electrophysiological effects using the human ether-à-go-go (hERG) assay, and in 
12 in vivo safety pharmacology studies of the cardiovascular, gastrointestinal, 
CNS, and respiratory system in rats, dogs, and monkeys. LOXO-101 displayed a 
concentration-dependent inhibition of the hERG channel at concentrations from 
10–300 μM, with an IC50 of 147 µM.  No changes were detected in 
electrocardiogram (ECG) parameters, including the QT interval corrected for heart 
rate (QTc), in any of the cardiovascular studies. In the monkey, decreases in 
arterial blood pressure (diastolic and systolic) and heart rate changes (both 
decreases and increases) were noted at LOXO-101 doses of 100 and 200 mg/kg. 
Dose-dependent increases in gastric motility were observed in rats given single 
doses, as well as increases in gastric secretion at a dose of 100 mg/kg.  No gastric 
irritation was detected at any dose.  No neurobehavioral effects were seen in rats 
given single doses of LOXO-101 or multiple doses of 30 mg/kg BID; however, a 
worsening of Rotorod performance (measuring coordination and neuromuscular 
coordination) was observed in rats at multiple doses of 100 mg/kg BID. 
 
The toxicological evaluation of LOXO-101 has included a single-dose oral study 
in rats, 3 repeat-dose BID studies in rats, and 3 repeat-dose once daily (QD) studies 
in cynomolgus monkeys.  Exposures have extended out to 42 days and daily doses 
have ranged from 100 to 600 mg/kg in the single-dose study and from 20 to               
300 mg/kg/day in the repeat-dose studies.  The liver appeared to be the body 
system most consistently affected by LOXO-101.  Dose-related increases in liver 
weights were observed; microscopically this appeared to be due to hepatocellular 
hypertrophy.  Additional findings included increases in alanine aminotransferase 
(ALT) (both species) and aspartate aminotransferase (AST) (monkey).  Decreases 
in serum albumin and increases in blood urea nitrogen (BUN) occurred in both 
species.  The liver effects in both species were fully reversible.   In both rats and 
monkeys, changes in multiple hematologic parameters were seen with no 
corresponding microscopic changes in bone marrow.  Decreases in red blood cell 
(RBC) mass indices (RBC count, hematocrit, and hemoglobin) were sometimes 
accompanied by compensatory increases in reticulocytes and/or splenic 
extramedullary hematopoiesis with or without increase in spleen weight.  Increases 
in monocytes were seen.  Prolonged prothrombin time (PT) (rat, monkey), 
increased fibrinogen (rat) and shortened partial thromboplastin time (PTT) (rat) 
were observed but with no apparent coagulation disorders.  
 
Overall, the rat was considered to be the most sensitive species.  Body weight gains 
and increases in food consumption (rats only) were sometimes associated with 
increases in serum cholesterol.  Heart weights were increased in the rat but with 
no associated histologic findings.  Skin lesions were observed consistently and 
hypersalivation occasionally in rats.  Decreases in uterine weights were attributed 
to uterine atrophy.  Increased thyroid weights in female rats correlated with 
hypertrophy of thyroid follicular epithelia.  
 
Little or no effects on neuromuscular function or cardiac electrophysiology were 
seen.  LOXO-101 was not genotoxic in any of the tests conducted.   Based on 
studies in which the no-observable-adverse-effect-level (NOAEL) was calculable, 
LOXO-101 had a single-dose NOAEL of 600 mg/kg (rats) and repeat-dose values 
of 10 mg/kg/day (monkeys) and 20 mg/kg/day (rats). 

 
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Preclinical Pharmacokinetic Studies 
LOXO-101 has low nanomolar potency against all three TRK family members in 
enzyme and cellular assays, with 100 to 1,000-fold selectivity relative to other 
kinases.  LOXO-101 binds to the human TRKA receptor in vitro with an IC50 
of 11.5 nM. In cellular assays, it inhibits TRKA and constitutively-active 
TRKA with IC50 values of 9.8 and 6.4 nM, respectively. LOXO-101 reduces 
TRKA phosphorylation in clinically-relevant NTRK1 gene fusion proteins and 
in cell lines derived from subjects. As LOXO-101 is a specific inhibitor of the 
TRK family of kinases, it had no anti-proliferative effect in tumor cell lines 
that do not express constitutively-active TRKA. LOXO-101 inhibits TRKB and 
TRKC with potencies approximately equal to its potency against TRKA (IC50 = 
5.3 nM and 6.4 nM, respectively). It inhibits no other kinase significantly at 
concentrations up to 1000 nM. 
 
In NIH-3T3 immunocompromised mice implanted with cells that express a 
constitutively active TRKA that was created by deletion of its second 
immunoglobulin domain (termed TRKA), single, oral doses of LOXO-101 at 
30 and 100 mg/kg suppressed TRKA phosphorylation in tumors for up to 12 hours, 
while twice-daily oral doses of 100 mg/kg caused significant inhibition of tumor 
growth.   
 
Pharmacokinetic (PK) investigations of LOXO-101 have been conducted in mice, 
rats, dogs, and monkeys.  Studies demonstrated oral bioavailability of 
approximately 30% to 100% across all species tested.   
 
In a 2-way cross-over study in dogs that compared the PK of a single 100-mg adult 
PIC formulation to 5 mL of a 20-mg/kg pediatric solution formulation, maximum 
drug concentration (Cmax) and area under the concentration versus time curve 
(AUC) of LOXO-101 were equal and the plasma concentration-versus-time 
profiles were superimposable (Figure 2).  These data suggest, coupled with the 
animal PK data and interim clinical PK data, suggest that the PK of the 
hydroxypropyl--cyclodextrin (HP--CD) solution formulation will be similar to 
those of the current capsule formulation in humans. 
 
 

 
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fatigue (42%), dizziness (29%) and anemia (21%). Two patients have had grade 
3 AEs leading to dose cohort expansions: elevated AST, grade 3 (Dose Level        
150 mg BID) and delirium, grade 3 (Dose Level 100 mg BID). Each case was 
subsequently deemed unrelated to study drug by the treating investigator, and the 
pts remained on study at reduced doses without recurrence. All three pts with 
NTRK-fusions enrolled have achieved a PR: an undifferentiated sarcoma with an 
LMNA-NTRK1 fusion (59% decrease; 7 cycles+), a c-kit-negative GI Stromal 
Tumor (GIST) with an ETV6-NTRK3 fusion (30% decrease; 2 cycles+), and a 
mammary analogue secretory carcinoma of the salivary glands with an ETV6-
NTRK3 fusion (64% decrease; 2 cycles+). These patients were treated at either 
100 or 150 mg BID. 7 The adult recommended phase II dose (RP2D) is                            
100 mg BID. 
 
 
Phase 2 Studies 
A Phase 2 study titled ‘A Phase II Basket Study of the Oral TRK Inhibitor 
LOXO-101 in Subjects with NTRK Fusion-Positive Tumors’ (Study LOXO-
TRK-15002) has been initiated. This Phase 2 study is a multi-center, open-label 
study of subjects with advanced cancer harboring a fusion of NTRK1, NTRK2, 
or NTRK3. The study will include 8 cohorts of subjects with tumors bearing 
NTRK fusions, including non-small cell lung cancer, thyroid cancer, sarcoma, 
colorectal cancer, salivary gland cancer, biliary cancer, and primary CNS 
tumors, as well as a cohort that will enroll subjects not included in the 
histologies listed above. 
 
 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
In the Phase 1, first-in-human clinical study for LOXO-101 (Study LOXO-TRK-
14001) PK analysis showed maximum plasma concentrations of LOXO-101 were 
reached 30-60 minutes following dosing. The unbound drug concentrations of 
LOXO-101 appear sufficient for approximately 98% inhibition of TRKA/B/C at 
peak concentrations at all dose levels (50 mg QD, 100 mg QD, 200 mg QD,                    
100 mg BID, and 150 mg BID). 
 
 
Larotrectinib Activity in NTRK Fusion Positive Malignancies 
 
As of a November 10, 2016 data cutoff, 59 patients with refractory solid tumors 
had been enrolled and treated with single agent LOXO-101, including eight 
patients with cancers harboring NTRK fusions. Seven patients with NTRK fusion 
cancers were on study sufficiently long for an efficacy assessment, while an eighth 
NTRK fusion patient had been recently enrolled and was not yet evaluated for 
response. Six of the seven efficacy evaluable patients achieved a confirmed partial 
response, as defined by standard RECIST criteria. The seventh patient, as 
previously reported, demonstrated clear radiographic tumor regressions, including 
in the central nervous system, and remains on study, but had not met the threshold 
required for a RECIST response. All responders remained in response, with one 
patient in cycle 22, one patient in cycle 19, one patient in cycle 18, two patients in 
cycle 15 and one patient in cycle 11. Each cycle is 28 days, or approximately one 
month. 
 
 

 
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Pediatric Studies 
 
 
Prior Experience in Children  
A pediatric phase 1 study of LOXO-101 (NCT02637687) enrolled its first patient 
in December 2015. On this study LOXO-101 is administered PO BID. A 
physiologically-based PK approach (SimCyp®) was used to determine the 
starting dose (in mg/m2) for pediatric patients that is needed to match the exposure 
(AUC) to a dose (currently 100 mg PO BID) that has been previously tested in 
adults, has not met dose limiting toxicity (DLT) criteria, and results in sufficient 
unbound drug concentrations to produce 98% inhibition of TRKA/B/C. A total of 
25 patients have been treated as of 4/13/17 (ages ranging from 1 month to 18 
years): 4 patients on Cohort 1, 11 patients on Cohort 2, and 10 patients on Cohort 
3. The most recent patient was enrolled on 4/12/17 and 24 patients are evaluable 
for DLT. 10 patients have been treated at 100 mg/m2/dose (max 100 mg) BID 
dosing (7 patients from Cohort 3; 3 patients from Cohorts 1 or 2 and dose 
escalated). Thus far no DLTs have been seen to date at any dose.                            
At 100 mg/m2/dose BID (n=10), the following grade 3/4 adverse events have been 
reported: neutropenia (n=2), nausea (n=1), increased ALT (n=1), weight increase 
(n=1). The pediatric RP2D has been called as 100 mg/m2 (capped at 100 mg) 
BID. 
 
For this trial, LOXO-101 will be administered at the starting dose of the pediatric 
phase 1 trial, 100 mg/m2/dose BID with a maximum of 100 mg BID. In the 
pediatric phase 1 trial, radiographic responses have been seen in patients with 
NTRK fusions treated at the 100 mg/m2 dose.  
 
 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
Pediatric-specific pharmacology and PK are not yet available.  
 
 
Overview of Proposed Pediatric Study 
This Phase 2 study will assess the clinical effects of LOXO-101 (larotrectinib) 
administered orally twice daily of a 28-day cycle to pediatric and adolescent patients. 
LOXO-101 (larotrectinib) will be given at a dose of 100 mg/m2/dose BID (capped at                  
100 mg per dose) which corresponds to the RP2D from the pediatric phase I trial.  
 
Disease status will be evaluated by CT or MRI after every other cycle x 3 then every 3 
cycles. Radiographic response will be assessed using RECIST criteria. Toxicity will be 
graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0.  
 
In addition to optional pharmacokinetic studies, we propose to collect plasma samples from 
patients to evaluate the detection of NTRK fusions in ctDNA in solid tumors. 
 
 
 

 
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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 
(IWRS) for retrieval of patient registration/randomization assignment. OPEN will 
populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
 
Requirements for OPEN access:  
• 
A valid CTEP-IAM account; 
• 
To perform enrollments:  Be on a LPO roster, ETCTN Corresponding 
roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient 
enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Access OPEN at https://open.ctsu.org  or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
Please see Appendix X for detailed CTEP and CTSU Registration Procedures 

 
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including: registration in Registration and Credential Repository (RCR), 
requirements for site registration, submission of regulatory documents and how to 
check your site’s registration status. 
 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. For 
CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must 
be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue 
to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the 
CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on 
the IRB/REB approval) must meet the following criteria in order for the processing 
of the IRB/REB approval record to be completed: 
 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 

 
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Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix X. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. 
 
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 APEC1621A study patients (such as whether a 
specific mutation would be considered actionable for the study) should be directed 
to the APEC1621SC and APEC1621A study chairs. 
 
The treatment assignment to a MATCH to a subprotocol (if a relevant aMOI is 
detected) will be communicated to the enrolling institution via the COG treatment 
assignment mechanism, upon which a reservation to APEC1621A 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 APEC1621A. 
 
 

 
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Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent.  This can be accomplished 
through the study-specific protocol.  Documentation of the informed consent for screening 
will be maintained in the patient’s research chart. Studies or procedures that were 
performed for clinical indications (not exclusively to determine eligibility) may be used for 
baseline values even if the studies were done before informed consent was obtained. 
 
 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist.  A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
 
Study Enrollment 
 
Following a MATCH treatment assignment to a protocol, patients may be enrolled on the 
study once all eligibility requirements for the study have been met. Before enrolling a 
patient on study, the Study Chair or Vice Chair should be notified. Patients who give 
informed consent for the protocol in order to undergo screening for eligibility are not 
considered enrolled and should not be enrolled until the screening is completed and they 
are determined to meet all eligibility criteria. Study enrollment 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. The date 
protocol therapy is projected to start must be no later than seven (7) calendar days after the 
date of study enrollment. Patients enrolling onto APEC1621A will have a COG ID 
obtained through their prior enrollment onto the master 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 LOXO-101 (larotrectinib) 
should be placed with CTEP after enrollment and treatment assignment to 
APEC1621A with consideration for timing of processing and shipping to ensure 
receipt of drug supply prior to start of protocol therapy. 
 
 
Institutional Pathology Report 
The institutional pathology report from the tumor specimen submitted for sequencing will 
have been uploaded into RAVE immediately following enrollment on the APEC1621SC 
screening protocol.  
 

 
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Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy.  Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility.  If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum creatinine.  If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies, bone marrow biopsy and/or aspirate (when applicable) must be obtained within 14 days 
prior to start of protocol therapy (repeat the tumor imaging if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th.   
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived.  All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient’s medical or research record which will 
serve as the source document for verification at the time of audit. 
 
 
Inclusion Criteria 
 
 
APEC1621SC: Patient must have enrolled onto APEC1621SC and must have been 
given a treatment assignment to MATCH to APEC1621A based on the presence 
of an actionable mutation as defined in APEC1621SC. Examples of actionable 
mutations for APEC1621A are listed in Appendix VIII. 
  
 
Age:  Patients must be ≥ than 12 months and  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  
- 
previously radiated lesions that have not demonstrated clear progression 
post radiation  

 
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- 
leptomeningeal lesions that do not meet the measurement requirements for 
RECIST 1.1. 
 
 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I).  Note:  Neurologic deficits in 
patients with CNS tumors must have been relatively stable for at least 7 days prior 
to study enrollment.  Patients who are unable to walk because of paralysis, but who 
are up in a wheelchair, will be considered ambulatory for the purpose of assessing 
the performance score. 
 
 
Prior Therapy 
 
 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/devtherapeutics/default.a
spx for commercial and Phase 1 investigational agent classifications. 
For agents not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research Coordinator 
prior to enrollment. 
 
i. ≥ 21 days after the last dose of cytotoxic or myelosuppressive 
chemotherapy (42 days if prior nitrosourea).  
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days after the 
last dose of agent.  
 
See https://www.cogmembers.org/site/disc/devtherapeutics/default.a
spx for commercial and Phase 1 investigational agent classifications. 
For agents not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research Coordinator 
prior to enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Corticosteroids: See Section 4.2.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. 
 
e. Hematopoietic growth factors: ≥ 14 days after the last dose of a long-
acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting 
growth factor. For growth factors that have known adverse events 
occurring beyond 7 days after administration, this period must be 

 
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extended beyond the time during which adverse events are known to 
occur.  The duration of this interval must be discussed with the study 
chair and the study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than hematopoietic 
growth factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than hematopoietic growth factors) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g. modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
Note: Radiation may not be delivered to “measurable disease” tumor 
site(s) being used to follow response to subprotocol treatment. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-
MIBG): 
≥ 
42 
days 
after 
systemically 
administered 
radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to other NTRK 
inhibitors including but not limited to LOXO-101 (larotrectinib), 
entrectinib (RXDX-101), DS6051, PLX7486. 
 
 
Organ Function Requirements 
 
 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors without known bone marrow 
involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
 
b. Patients with known bone marrow metastatic disease will be eligible 
for study provided they meet the blood counts in 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.  
 

 
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 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR utilizing child length and stature data published 
by the CDC.8 
 
 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT)  135 U/L.  (For the purpose of this study, the ULN 
for SGPT is 45 U/L). 
- 
Serum albumin  2 g/dL. 
 
 Adequate Neurologic Function Defined as: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Nervous system disorders (CTCAE v5.0) resulting from prior 
therapy must be  Grade 2, with the exception of decreased tendon 
reflex (DTR). Any grade of DTR is eligible. 
 
 
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 an effective contraceptive method for the duration of study treatment. 
 
 
Concomitant Medications 
 
 Corticosteroids:  Patients receiving corticosteroids who have not been on 
a stable or decreasing dose of corticosteroid for at least 7 days prior to 
enrollment are not eligible. If used to modify immune adverse events 
related to prior therapy, ≥ 14 days must have elapsed since last dose of 

 
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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 
agents are not eligible. 
 
 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease (GVHD) post bone marrow transplant 
are not eligible for this trial. 
 
 
CYP3A4 Agents: Patients who are currently receiving drugs that are 
strong inducers or inhibitors of CYP3A4 are not eligible. Strong inducers 
or inhibitors of CYP3A4 should be avoided from 14 days prior to 
enrollment to the end of the study. See Appendix II for a list of agents.  
Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS 
tumors or metastases, on a stable dose, are allowed. 
 
 
Patients who have received prior therapy with a specific inhibitor of TRK 
(including but not limited to entrectinib (RXDX-101), DS-6051b, and PLX7486) 
are not eligible. 
 
 
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 
 
Treatment Schedule Table 
Days 1-28 
LOXO-101 (larotrectinib) 100 mg/m2/dose   
orally or via NG- or G- tube twice daily 
 (maximum 100 mg per dose) 
Day 28 
Evaluation 
 
LOXO-101 (larotrectinib) will be given at 100 mg/m2/dose PO or via NG- or G- tube BID 
with a maximum of 100 mg per dose. LOXO-101 (larotrectinib) capsules should not be 
opened and must be swallowed whole. If vomiting occurs following dosing, doses should 
NOT be repeated and the next dose should be administered at the regularly scheduled time. 
If a dose is missed, it may be administered if there is at least 8 hours remaining until the 
next scheduled dose. Liquid formulation is also available and may be administered orally 
or via NG- or G- tube.  
 
A cycle of therapy is considered to be 28 days.  A cycle may be repeated up to a total 
duration of therapy of approximately 2 years (max 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, and according to the dosing 
nomogram (see Appendix IV).  Doses of LOXO-101 (larotrectinib) capsules should be 
rounded to the nearest 25 mg (Appendix IV-A). Calculated dosing volumes of LOXO-101 
(larotrectinib) liquid formulation should be rounded to the nearest 0.1 mL (2 mg) for doses 
≤ 45 mg (in oral syringes ≤ 3.0 mL) and 0.2 mL (4 mg) for doses > 45 mg (in oral syringes 
≥ 5.0 mL) for the actual deliverable dose (Appendix IV-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). Patients who 
require dose reduction for toxicity will be administered 75% of the starting dose (see 
Appendix IV-A & IV-B for dosing details).  Therapy may otherwise continue for up to 2 
years provided the patient meets the criteria for starting subsequent cycles (Section 5.2) 
and does not meet any of the criteria for removal from protocol therapy criteria (Section 
10.0).  
 
Larotrectinib is supplied by Bayer and distributed by the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI. Do not use commercial supply. 
 
 
Therapy Delivery Map 
See Appendix VI for APEC1621A Therapy Delivery Map  
 
 
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.  
 
 

 
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Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the current version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).  All appropriate treatment 
areas should have access to a copy of the current version of the CTCAE v5.0.  A copy of 
the CTCAE v5.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. Dose limiting hematological and non-hematological 
toxicities are defined differently.   
 
 
Non-Hematological Dose-Limiting Toxicity 
 
 Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns 
to levels that meet initial eligibility criteria or baseline within 7 days. 
See Appendix XI for values that represent thresholds between CTCAE 
grades. 
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L 
regardless of baseline. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation 
 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
 
Hematological dose limiting toxicity  
 
 Hematological dose limiting toxicity is defined as: 
 
a) In patients evaluable for hematological toxicity (see Section 6.1),   
• 
Grade 4 thrombocytopenia or neutropenia, not due to malignant 
infiltration 
• 
Grade 3 thrombocytopenia that persists for ≥ 7 days 
• 
Grade 3 thrombocytopenia requiring a platelet transfusion on two 
separate days within a 7-day period 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Neutropenia or thrombocytopenia that causes a delay of > 14 days 
between treatment cycles" (e.g. platelets <100K or ANC<1000). 
 

 
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 Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity.  
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth 
factor. 
 
 
Dose Modifications for Hematological Toxicity 
 
 
If a patient experiences hematological dose-limiting 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 
IV-A for capsule formulation dosing nomogram and Appendix IV-B for 
preparation of liquid 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 IV-A for capsule 
formulation dosing nomogram and Appendix IV-B for preparation of liquid 
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 a dose-limiting toxicity recurs in a patient who has resumed treatment at the 
reduced dose, the patient must be removed from protocol therapy. 
 
 

 
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered the patient will be removed from protocol therapy. 
 
 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Please see COG Supportive Care guidelines at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. See Section 
7.5 for drugs that should not be used concomitantly due to potential interactions with LOXO-
101 (larotrectinib). 
 
 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study Chair 
should be notified before growth factors are initiated. 
 
 
Concomitant Medications 
 
7.5.1 
CYP3A4/5 inhibitors or inducers: Strong CYP3A4/5 inhibitors or inducers are 
prohibited from 14 days prior to enrollment to the end of the study (See Appendix 
II for list of agents). Avoid grapefruit or grapefruit juice as these may also increase 
plasma concentrations of larotrectinib.  
 
Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors 
or metastases, on a stable dose, are allowed. Use caution in patients who are taking 
concomitant medications that are substrates of CYP3A4.  
 
7.5.2 
If feasible, avoid concomitant treatment with strong p-glycoprotein (P-gp) or 
breast cancer resistance protein (BCRP) inhibitors and strong P-gp inducers.  
 
 
Use with caution in patients who are taking concomitant medications that are 
sensitive or narrow therapeutic range substrates of CYP3A4 (see Appendix II). 
 
 

 
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8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, bone 
marrow aspirate and/or biopsy, must be obtained within 14 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Neurologic Exam 
X 
 
 
 
Height, weight, BSA 
X 
 
X 
Performance Status 
X 
 
 
Pregnancy Test1 
X 
 
 
CBC, differential, platelets 
X 
Twice Weekly 
(every 3 to 4 days)2,3 
Weekly2,3 
Urinalysis 
X 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
 
X 
Tumor Disease Evaluation4-A, 4-B, 4-C 
X 
 
Every other cycle x 3 
then q 3 cycles 4 
Bone Marrow Aspirate and/or biopsy5,6 
X6 
 
 
Medication Diary7 
 
Weekly 
X 
Pharmacokinetics (optional)8 
X 
X 
 
Circulating Tumor DNA (ctDNA-
optional)9 
 
 
Cycle 5, Day 1 and 
(for patients receiving 
≥ 5 cycles only) at 
end of Protocol 
Therapy OR disease 
progression 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control.  Abstinence is an acceptable method of 
birth control. 
2 
If patients have Grade 4 neutropenia then CBCs should be checked at least every other day until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
3 
If patients develop Grade 4 thrombocytopenia then CBCs should be checked every 3 to 4 days until 
recovery, per Section 6.1. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. If the 
institutional investigator determines that the patient has progressed based on clinical or laboratory 

 
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evidence, he/she may opt not to confirm this finding radiographically. 
4-A    Neurological exam also required for CNS patients.     
4-B  Non- Hodgkin Lymphoma/ Histiocytosis patients are required to have PET scans within 2 weeks prior 
to start of therapy and should also be followed with PET scans if positive at diagnosis. Refer to Section 
12.8   
4-C    Patients with neuroblastoma must have both CT/MRI and MIBG scintigraphy prior to enrollment if the 
patient was enrolled with or has a history of having MIBG avid tumor. Otherwise the patient must have 
both CT/MRI and bone scan prior to enrollment. For patients with neuroblastoma and measurable disease 
by CT or MRI, lesions should be measured and followed using the same modality (CT or MRI) in 
addition to MIBG or bone scan. For patients with neuroblastoma and evaluable disease by MIBG 
scintigraphy or bone scan, use the same modality (MIBG scintigraphy or bone scan) to image and follow 
patients; CT/MRI are not required but may be performed as clinically indicated. Refer to Section 12.5.4 
and Section 12.9. 
5 
Bone marrow aspirate and/or biopsy only required in patients suspected of having bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data. Should only 
be performed on patients with known bone marrow involvement at baseline.   
6 
Bone marrow aspirate and/or biopsy should be performed only when complete response or partial 
response is identified in target disease or when progression in bone marrow is suspected. 
7  
Medication diary (see Appendix III) should be reviewed weekly during cycle 1, after completion of 
each treatment cycle, and uploaded into RAVE. 
8 
See Section 8.3 for details of PK studies. 
9       With consent, two samples will be collected on this protocol (Cycle 5 Day 1; and for patients receiving 
≥ 5 cycles at progression or end of protocol therapy), see Section 8.4 for details of the ctDNA studies. 
Note that a ctDNA sample is scheduled to be obtained on the APEC1621SC screening protocol prior to 
the initiation of treatment on this subprotocol. 
 
 

 
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Radiology Studies 
 
 
Central Radiology Review for Response:  Patients who respond (CR, PR) to 
therapy or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy will 
be centrally reviewed.  The Operations center will notify the site when a patient 
has met the criteria for review. The tumor disease evaluations to be submitted for 
review include baseline (pre-study) evaluations as well as all end of cycle tumor 
disease evaluations which occurred while the patient was on the subprotocol 
therapy study. 
 
 
Technical Details of Submission:  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI (QARC) must be submitted in Digital Imaging 
and Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 
contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
 
Submission of Diagnostic Imaging data in DICOM format is required.  
Submission of the digital files and reports via TRIAD is preferred.  Instructions for 
TRIAD set up are below. 
 
Alternatively, the images and reports may be submitted via sFTP to IROC Rhode 
Island. Digital data submission instructions including instructions for obtaining a 
sFTP account, can be found at http://irocri.qarc.org. Follow the link labeled digital 
data.  Sites using the Dicommunicator software to submit imaging may continue 
to use that application. 
 
Corresponding Radiology reports may be submitted along with the electronic 
submission via TRIAD or sFTP or may be emailed to DataSubmission@QARC.o
rg.  The COG operations center and IROC are available to assist with any queries 
regarding the corresponding radiology reports which should be included when the 
scans are submitted 
 
Questions may be directed to DataSubmission@QARC.org or 401.753.7600. 
  
Digital RT Data Submission Using TRIAD (if TRIAD is available at your site): 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure method 
to transmit DICOM and DICOM RT files and other digital objects, such as reports. 
TRIAD de-identifies and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
Site physics staff who will submit images through TRIAD will need to be 
registered with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP Identity and Access Management (IAM) account.  Please refer to 
CTEP Registration Procedures of the protocol for instructions on how to request a 
CTEP-IAM account. 

 
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To submit images, the site TRIAD user must be on the site roster and be assigned 
the 'TRIAD site user' role on the CTSU roster.  Users should contact the site’s 
CTSU Administrator or Data Administrator to request assignment of the TRIAD 
site user role.   
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with the proper user role, he/she 
will need to have the TRIAD application installed on his/her workstation to be able 
to submit images. TRIAD installation documentation can be found by following 
this link https://triadinstall.acr.org/triadclient/   
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password. 
 
If you have any questions regarding this information, please send an e-mail to the 
TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
IROC Rhode Island (formerly QARC) will facilitate the central reviews. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low- 
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created. 
 
Sites not able to submit imaging electronically may submit imaging via CD.   CD’s 
may be sent by courier to:  
 
Address for submission: IROC RI (QARC) 
Building B, Suite 201 
640 George Washington Highway  
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:     (401) 753-7601 
Web:    http://irocri.qarc.org 
 
 
Pharmacology (optional) 
 
 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of LOXO-101 
(larotrectinib) in children. Pharmacokinetic analysis will be conducted at a 
centralized laboratory using validated assays. 
 
 

 
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             Fax: (208) 882-9246 
 
Email: jzimmer@alturasanalytics.com 
 
A notification email should be sent to Jennifer Zimmer with courier name, airway 
bill number, expected delivery date/time and shipment contact. 
 
 
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:  
• 
For patients ≥ 10 kg collect 20 mLs (10 mL per tube x 2 tubes)  
• 
For patients ≥ 5 kg but < 10 kg collect 10 mL (one tube)  
• 
For patients < 5 kg research samples will not be collected  
 
In all cases, blood draw volumes should strictly adhere to institutional limitations, 
taking other blood draws into consideration. However, if a reduction in volume is 
required, samples should be collected in 10 mL increments (ie. 0, 10, or 20 mL 
should be collected such that each Streck Cell-Free DNA BCT is completely 
filled). 
 
Established institutional guidelines should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. If therapeutic heparin dosing contamination is a possibility, 
venipuncture is recommended as a first choice collection method. If a Streck Cell-
Free DNA BCT tube immediately follows a heparin tube in the draw order, we 
recommend collecting an EDTA tube as a waste tube prior to collection in the 
Streck Cell-Free DNA BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
• 
Keep patient’s arm in the downward position during the collection 
procedure. 
• 
Hold the tube with the stopper in the uppermost position so that the tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
• 
Release tourniquet once blood starts to flow in the tube, or within 2 
minutes of application. 
• 
Fill tube completely. 

 
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• 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results.  
• 
Store blood in Streck tube at room temperature until shipment 
 
 
Sample Processing 
Samples do not need to be processed at the collection site. 
 
 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D (APEC1621A), 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 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 APEC1621A– Peds MATCH* 
 
 
700 Children’s Drive, WA1340 
 
 
Columbus, OH 43205 
 
 
Phone: (614) 722-2865 
 
 
Fax: (614) 722-2897 
Email:BPCBank@nationwidechildrens.org 
 
*Labeling is extremely important for this project. Packages must be labeled “Peds 
MATCH” in order to expedite processing at the BPC. Be sure to include the room 
number. Packages received without the room number may be returned to the 
sender. 
 
 

 
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9.0 
AGENT INFORMATION 
 
 
Larotrectinib   
 
 
 
 
 
 
 09/28/22 
(larotrectinib sulfate, Vitrakvi®, LOXO-101, BAY 2757556) NSC# 788607,  
    
IND# 
 
  
 
Structure and molecular weight  
Larotrectinib sulfate is a small molecule with an empirical formula of 
C21H24F2N6O6S and a molecular weight of 526.52 (hydrogen sulfate salt), 428.4 
(free base). The chemical name is (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-
1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide 
hydrogen sulfate. 
 
Larotrectinib is an ATP-competitive, selective inhibitor of the tropomyosin-related 
kinase (TRK) family of neurotrophin receptors, demonstrating inhibition of all three 
known TRK receptors (TRKA, TRKB and TRKC). In normal tissue, activated TRK 
receptor signaling may stimulate cellular growth, survival and differentiation. TRK 
receptors are encoded by NTRK genes; NTRK1, NTRK2, and NTRK3. NTRK gene 
fusions appear to be oncogenic and inhibition of TRK receptors may provide benefit 
to patients with malignancies due to oncogenic alterations in the NTRK genes. 
 
 
Supplied by:  
Bayer AG and distributed by the Pharmaceutical Management Branch, CTEP, 
DCTD, NCI. Do not use commercial supply 
 
 
Formulation 
• 
25 mg capsules are opaque white, size 2, hard gelatin capsules containing 25 mg 
of Larotrectinib sulfate. The capsules contain no excipients. Capsules are 
supplied in 60-count, 72-count or 100-count HDPE bottles with induction seals 
and child-resistant plastic caps. 
• 
100 mg capsules are opaque white, size 0, hard gelatin capsules containing                
100 mg of Larotrectinib sulfate. The capsules contain no excipients. Capsules are 
supplied in 60-count, 72-count or 100-count HDPE bottles with induction seals 
and child-resistant plastic caps. 
• 
50 mL or 100 mL liquid oral solution containing 20 mg/mL of larotrectinib 
sulfate filled into 60 mL (ORA-SWEET free) or 100 mL. Kylix, amber type III 
glass bottles, PP28 neck, with a 28 mm child resistant cap and tamper evident 
closure with Triseal liner. 
o The 50 mL bottle of oral solution is a colorless to yellow or orange or 
brownish liquid containing the following inactive ingredients: purified 
water, USP; Kleptose HPB Parenteral Grade, USP; Citric Acid, 
anhydrous, USP; Flavor strawberry, specification; Sodium benzoate, 
NF; Sodium citrate, USP; Sucralose, USP/NF 
o The 100 mL bottle of oral solution is a colorless to clear yellow to orange 
liquid containing the following inactive ingredients: purified water, 
USP; Kleptose HPB Parenteral Grade, USP; ORA-SWEET®; Sodium 
Citrate, Dihydrate, Granular, USP; 231a12 Natural Masking Type 
Flavor (Abelei); 231a39 Natural Bitterness Masking Type Flavor 
(Abelei); Bitterness Masking Flavor, Nat (FONA - Liquid); 
FONATECH® Taste Modifier Flavor, Nat 

 
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o A site-supplied 28 mm LDPE (e.g., Comar® product number 22-
0198; B Braun Exadoral®) or polypropylene press-in bottle 
adapter is required for use with an oral syringe for dosing 
purposes.  
 
 
Storage 
Store capsules at room temperature below 30° (86°F). Store liquid oral solution 
refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze 
 
If a storage temperature excursion is identified, promptly return larotrectinib 
capsules to controlled room temperature and larotrectinib liquid oral solution 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 
Bottle labels contain an expiration date. Larotrectinib sulfate capsules for a cycle 
may be counted out and repackaged from the manufacturer-supplied HDPE bottle 
into a pharmacy-supplied HDPE bottle for dispensing purposes. Instruct patients to 
store the prescription container away from areas of high heat and humidity.  
 
Larotrectinib sulfate liquid oral solution is to be dispensed in the manufacturer’s 
container as a whole bottle. After opening, store capsules below 30°C (86°F) and oral 
solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 30 days. 
 
 
 
Administration 
See Section 6.0 for dose modifications and Section 5.0 Treatment section of the 
protocol for dosing and administration details. Larotrectinib is administered orally or 
via NG- or G-tube and may be taken without regard to food. Larotrectinib sulfate may 
be taken without regard to food. Capsules are to be swallowed whole. Do not chew, 
crush or open capsules. Please note the maximum dose of 100 mg per dose BID. 
 
 
Potential Drug Interactions 
Larotrectinib is a substrate of cytochrome P450 (CYP) 3A, P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP). Co-administration of larotrectinib 
with strong CYP3A inhibitors, P-gp and BCRP inhibitors increases larotrectinib 
plasma concentrations. Co-administration of larotrectinib with strong CYP3A and 
P-gp inducers decreases larotrectinib plasma concentrations. Avoid concomitant 
use of strong CYP3A inhibitors or inducers for 14 days prior to enrollment through 
the end of protocol therapy Appendix II). Avoid grapefruit or grapefruit juice as 
these may also increase plasma concentrations of larotrectinib.  
 
If feasible, avoid concomitant administration with strong P-gp or BCRP 
inhibitors and strong P-gp inducers.  
 
Larotrectinib inhibits CYP3A weakly both in vitro and in vivo. Exercise caution 
with concomitant use of CYP3A substrates with narrow therapeutic range (e.g. 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, or tacrolimus; Appendix II) in patients taking larotrectinib. 
If concomitant use of these CYP3A substrates with narrow therapeutic range is 

 
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Generalized muscle weakness; Joint range of motion decreased; Musculoskeletal and connective tissue disorder - 
Other (muscle twitching); Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); 
Musculoskeletal and connective tissue disorder - Other (pain in jaw); Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (acute myeloid leukemia); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (bile duct adenocarcinoma); Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (glioma, glioblastoma multiforme); Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (malignant neoplasm progression, neoplasm progression); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (metastases to central nervous system) 
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dysarthria; Dysesthesia; 
Dysgeusia; Edema cerebral; Extrapyramidal disorder; Headache; Memory impairment; Nervous system disorders - 
Other (motor dysfunction); Peripheral sensory neuropathy; Somnolence; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Confusion; Delirium; Personality change; Restlessness 
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Nasal congestion; 
Oropharyngeal pain; Pleural effusion; Productive cough; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (hypoventilation); Sneezing; Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Larotrectinib sulfate (BAY 2757556, LOXO-101) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 

 
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 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 responsible investigator 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 larotrectinib should 
be placed with CTEP after enrollment and treatment assignment to 
APEC1621A with consideration for timing of processing and shipping to 
ensure receipt of drug supply prior to start of protocol therapy. If expedited 
shipment is required, sites should provide an express courier account through the 
Online Agent Order Processing (OAOP) application. Provide the patient ID 
number in the comment box when submitting an order request. 
 
 Clinical Drug Request  
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,  “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 Inventory Records 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP forms page.  Store 
and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
 
9.1.12 Investigator Brochure Availability 
The current versions of the IB(s) for the agents will also be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP IAM 
account and the maintenance of an “active” account status, a “current” password, 
and active person registration status. Questions about IB access may be directed to 
the PMB IB coordinator via email. 
 
 Useful Links and Contacts  
• CTEP Forms, Templates, Documents:   
http://ctep.cancer.gov/forms/ 
• NCI CTEP Registration: 
RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 

 
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http://ctep.cancer.gov/branches/pmb/agent_management.htm    
• PMB Online Agent Order Processing (OAOP) application:  
 
 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account:  
     https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: 
 
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  
• PMBAfterHours@mail.nih.gov 
• IB Coordinator:  
• IBcoordinator@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575  
Monday through Friday between 8:30 am and 4:30 pm (ET) 
 
10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12). 
b) 
Adverse Events requiring removal from protocol therapy (See Section 6). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Completion of 26 cycles of therapy. 
f) 
Physician determines it is not in the patient’s best interest. 
g) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of protocol therapy (See Section 8.1). 
h) 
Study is terminated by Sponsor. 
i) 
Pregnancy 
j) 
Patient did not receive protocol treatment after study enrollment. 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent from the APEC1621SC screening protocol. Patients who are removed from 
protocol therapy in subsequent cycles should have the necessary observations to 
ensure adequate clinical care.  
 
 
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 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 

 
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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 VIII for a list of target tumor histologies. 
 
We will open up to 3 such expansion cohorts for biomarker positive patients (i.e., 
if 3 histologies have ≥ 3 responses, we will open a total of 3 expansion cohorts as 
described above). Note that this can only happen if the response rate in the primary 
cohort is at least 45% (9/20) and there cannot be more than 21 additional evaluable 
patients in total for these expansion cohorts. 
 
 
Methods of Analysis 
Response criteria are described in Section 12. A responder is defined as a patient who 
achieves a best response of PR or CR on the study. Response rates will be calculated as the 
percent of evaluable patients who are responders, and confidence intervals will be 
constructed using the Wilson score interval method.10 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. When opening expansion cohorts, the 
evaluation period for determination of best response will be 6 treatment cycles. All other 
patients will be considered non-responders. Patients who are not evaluable for response 
evaluation may be replaced for the purposes of the statistical rule. All patients considered 
to have a response (CR or PR) must have imaging studies reviewed centrally at the COG. 
Centers will be notified by the COG about requests for scans of patients with stable disease. 
Preliminary assessment of activity using institutionally provided tumor measurements will 
be entered into CDUS quarterly. The central review by COG will be provided as the final 
reviewed assessment of response when such becomes available. 
  
 
Evaluability for Toxicity 
All eligible patients who receive at least one dose of protocol therapy (will be considered 
in the evaluation of toxicity. 
 
 
Progression free survival (PFS) 
Progression free survival will be defined as time from the initiation of protocol treatment 
to the occurrence of any of the following events: disease progression or disease recurrence 
or death from any cause. All patients surviving at the time of analyses without events will 
be censored at their last follow-up date. 

 
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(http://ctep.cancer.gov). 
 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of subprotocol 
treatment to time of progression or death, whichever occurs first. 
 
Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g., when multiple lesions 
show opposite responses, the progressive disease takes precedence. 
 
 
Response Criteria for Patients with Solid Tumors  
See the table in Section 8.0 for the schedule of tumor evaluations. Eligible patients must 
have measurable disease present at baseline and have had their disease re-evaluated after 
at least one dose of protocol therapy. In addition to the scheduled scans, a confirmatory 
scan should be obtained on the next consecutive cycle following initial documentation of 
objective response. 
 
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor (non-CNS) and measurable disease (Section 12.4); b) 
neuroblastoma with MIBG positive lesions (Section 12.5); c) CNS tumor (Section 12.7); 
and d) non-Hodgkin lymphoma/hystiocytosis (Section 12.8). Note: Neuroblastoma patients 
who do not have MIBG positive lesions should be assessed for response as solid tumor 
patients with measurable disease. 
 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).11  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. 
 
 

 
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 Definitions 
 
 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.  
 
 Evaluable Non-Target Disease Response:  
Eligible patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease and have received at 
least one dose of protocol therapy will be considered evaluable for non-
target disease. The response assessment is based on the presence, absence, 
or unequivocal progression of the lesions.  
 
 Disease Parameters 
 
 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 
mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area 
might or might not be considered measurable. If the investigator 
thinks it appropriate to include them, the conditions under which 
such lesions should be considered must be defined in the 
protocol. 
 
 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes with 
≥ 10 to < 15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent 
cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions. 

 
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 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the 
next largest lesion that can be measured reproducibly should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
 
 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
 Clinical lesions:  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and  
10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case 
of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
 Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans). Ideally, 
the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  
 

 
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 PET-CT:  At present, the low dose or attenuation correction CT portion of 
a combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements.  However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST or International Pediatric non-Hodgkin 
Lymphoma Response Criteria measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
 Tumor markers: Tumor markers alone cannot be used to assess response.  
If markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.  
 
 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare cases 
(e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
 FDG-PET: While FDG-PET response assessments need additional study, 
it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly 
possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-
up is a sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is 
not confirmed as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds 
to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
 Note: A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
For patients with a positive PET scan at diagnosis, PET can be used to 
follow response in addition to a CT scan using the International 
Pediatric non-Hodgkin Lymphoma Response Criteria.12 
 

 
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Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the 
baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions 
is also considered progressions). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study 
 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis) 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
patient to be considered in complete clinical 
response. 
 

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

 
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Table 3: Overall Response for Patients with Neuroblastoma and Measurable Disease 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.9  from a sequence of overall response assessments. 
 
 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  

 
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1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
 Overall Response Assessment 
 
Table 4: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
 

 
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MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
 
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement 
 
 Bone Marrow Involvement  
Note: patients with bone marrow as the ONLY site of disease are not eligible for 
this study. Response criteria in this section are intended to be used when 
assessing marrow involvement as a component of overall response.  
 
Histologic analysis at the local institution of marrow tumor cell involvement is 
required for patients with a history of marrow involvement. Marrow aspirate and 
biopsy should be evaluated at baseline and every 2 cycles thereafter. Note: If 
progressive disease is documented by RECIST criteria using tumor measurements 
or by MIBG scan, then a repeat BM is not needed to confirm PD.  
 
Complete Response:  
No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies 
performed at least 21 days apart. Normalization of urinary 
catecholamines or other tumor markers if elevated at 
study enrollment. 
 
Progressive Disease:  
In patients who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there 
is a doubling in the amount of tumor in the marrow AND 
a minimum of 25% tumor in bone marrow by 
morphology. (For example, a patient entering with 5% 
tumor in marrow by morphology must increase to ≥ 25% 
tumor to have progressive disease; a patient entering with 
30% tumor must increase to > 60%). 
 
In patients who enroll without evidence of neuroblastoma 
in bone marrow will be defined as progressive disease if 
tumor is detected in 2 consecutive bone marrow biopsies 
or aspirations done at least 21 days apart. 

 
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Stable Disease: 
Persistence of tumor in bone marrow that does not meet 
the criteria for either complete response or progressive 
disease. 
 
 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined from the sequence of the 
overall response assessments as described in Section 12.9. 
 
 
Response Criteria for Patients with CNS Tumors 
 
 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 
• 
Complete Response (CR): Disappearance of all target lesions. Off all steroids 
with stable or improving neurologic examination. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements; on a stable or decreasing dose of steroids with 
a stable or improving neurologic examination. 
 

 
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• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD; on a stable or 
decreasing dose of steroids with a stable or improving neurologic examination. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
Increasing doses of corticosteroids required to maintain stable neurological 
status should be strongly considered as a sign of clinical progression unless in 
the context of recent wean or transient neurologic change due e.g. to radiation 
effects.  
 
 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
 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 
 
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analysis of treatment effect.  Best response is determined as outlined in Section 
12.9 from a sequence of overall response assessments. 
 
 
 
Response Criteria for Patients with non-Hodgkin Lymphoma/Histiocytosis 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric non-Hodgkin 
Lymphoma Criteria, with modification from the Lugano classification.13,14 
 
 Disease Parameters 
 
 Measurable disease: A measurable node must have an LDi (longest 
diameter) greater than 1.5 cm. A measurable extranodal lesion should have 
an LDi greater than 1.0 cm. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
   Non-measured disease: All other lesions (including nodal, extranodal, 
and assessable disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
 
 Target lesions: For patients staged with CT, up to six of the largest target 
nodes, nodal masses, or other lymphomatous lesions that are measurable 
in two diameters (longest diameter [LDi] and shortest diameter) should be 
identified from different body regions representative of the patient’s 
overall disease burden and include mediastinal and retroperitoneal disease, 
if involved. 
 
 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 

 
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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)14 
 
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 enlargement14  
 
Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by >50% in length 
beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic length 
must increase by 50% of the extent of its prior 
increase beyond baseline. If no prior splenomegaly, 
must increase by at least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
 
Best Response 
Two objective status determinations of disease status, obtained on two consecutive 
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 

 
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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). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 

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

 
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documentation submitted to the numbers listed below in order for the NCI to 
meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents 
supplied under a CTEP IND to: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax# 
(310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 CTEP-AERS Expedited Reporting Methods  
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
https://ctepcore.nci.nih.gov/ctepaers/pages/task 
 
Send supporting documentation to the NCI by fax (fax# 301-640-9193) and by 
email to the APEC1621A 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 NCI CTCAE v5.0.  The descriptions 
and grading scales found in the revised CTCAE v5.0 will be used for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE v5.0.  
A copy of the CTCAE v5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov). 
 
Step 2:  Grade the adverse event using the NCI CTCAE v5.0. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• 
there are any protocol-specific exceptions to the reporting requirements.  
 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless 
of attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 

 
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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 
• Death attributable to a CTCAE v5.0 term.  
 
• Death Neonatal: A disorder characterized by “Newborn deaths occurring during 
the first 28 days after birth.”  
• Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE v5.0 term associated with Grade 5.  
 
• Death NOS: A cessation of life that cannot be attributed to a CTCAE v5.0 term 
associated with Grade 5.  
 
• Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease) should be 
submitted.  
 
• Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
• Any death that occurs more than 30 days after the last dose of treatment with 
an investigational agent which can be attributed (possibly, probably, or 
definitely) to the agent and is not clearly due to progressive disease must be 
reported via CTEP-AERS per the timelines outlined in the table above. 
 
 Reporting Secondary Malignancy 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, 
radiation 
or 
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 

 
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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 
“Neonatal 
loss”, 
the 
Pregnancy 
Information 
Form, 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to 301-897-7404. The potential risk of exposure of the fetus 
to the investigational agent should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the fetus to 
agents that may be teratogenic. For this reason, pregnancy needs to be reported in 
an expedited manner via CTEP-AERS as Grade 3 “Pregnancy, puerperium and 
perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 
 
Pregnancy needs to be followed until the outcome of the pregnancy is known at 
intervals deemed appropriate by her physicians. The “Pregnancy Information 
Form” should be used for all necessary follow-ups. This form is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregn
ancyReportForm.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 

 
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a neonatal death resulting from a patient pregnancy or pregnancy in partners of 
men on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death. 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data:  These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted:  All other data will be 
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:  This study has been assigned to CDUS-Complete reporting; all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS 
reporting guidelines must be reported via the monitoring method identified above.   
 
 
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.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 

 
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information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order as described in the IP Option to Collaborator (http://ctep.cancer.gov
/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical 
Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
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 

 
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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. 
 
 
 
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. 
Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. 
Cancer Discov. 2015;5(1):25-34. 
2. 
Loh ML, Ahn P, Perez-Atayde AR, Gebhardt MC, Shamberger RC, Grier HE. Treatment of 
infantile fibrosarcoma with chemotherapy and surgery: results from the Dana-Farber Cancer 
Institute and Children's Hospital, Boston. J Pediatr Hematol Oncol. 2002;24(9):722-726. 
3. 
Tannenbaum-Dvir S, Glade Bender JL, Church AJ, et al. Characterization of a novel fusion gene 
EML4-NTRK3 in a case of recurrent congenital fibrosarcoma. Cold Spring Harb Mol Case Stud. 
2015;1: a000471. 
4. 
Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and 
pediatric non-brainstem high-grade glioma. Nat Genet. 2014;46(5):444-450. 
5. 
Harris MH, DuBois SG, Glade Bender J, et al. Multicenter feasibility study of tumor 
molecular profiling to inform therapeutic decisions in advanced pediatric solid tumors. 
JAMA Oncology. 
6. 
Doebele RC, Davis LE, Vaishnavi A, et al. An Oncogenic NTRK Fusion in a Patient with Soft-
Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer 
Discov. 2015. 
7. 
Hong DS BM, Doebele RC, et al. . Clinical safety and activity from a phase 1 study of LOXO-101, 
a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions AACR-NCI-
EORTC Molecular Targets and Cancer Therapeutics Annual Meeting 2015(abstract: PR13). 2015. 
8. 
Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr. 1985;106(3):522-526. 
9. 
A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20(6):859-
866. 
10. 
Agresti A, Coull BA. Approximate Is Better than "Exact" for Interval Estimation of Binomial 
Proportions. The American Statistician. 1998;52(2):119-126. 
11. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
12. 
Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma 
Response Criteria. J Clin Oncol. 2015;33(18):2106-2111. 
13. 
Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-dependent 
transcriptional elongation. Cell. 2009;138(1):129-145. 
14. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol. 2014;32(27):3059-3068. 
 
 

 
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APPENDIX II:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is not an inclusive list. Because the lists of these agents are constantly changing, it is important to 
regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alfentanil4,5  
alprazolam5 
amiodarone4 
amlodapine 
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 
elivitegravir/ritonavir 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir/ritonavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
ombitasvi +/- dasabuvir 
nefazodone 
nelfinavir 
paritaprevir/ritonavir 
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 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
pimozide5 
quetiapine5 
quinidine4  
regorafenib 
rilpivirine5 
rivaroxaban5 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
tadalafil5 
telaprevir 
temsirolimus 
teniposide 

 
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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 7.5 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥ 5-fold with strong inhibitors)  

 
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APPENDIX IV-B: LOXO-101 (LAROTRECTINIB) DOSING PREPARATION (LIQUID 
FORMULATION) 
 
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 < 0.66 m2 must receive the liquid formulation.  
 
Patients with BSA ≥ 0.66 m2 may take either the capsule or liquid formulation. (See Appendix IV-A 
for dosing nomogram for LOXO-101 (larotrectinib) 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. 
 
The concentration of LOXO-101 (larotrectinib) liquid formulation is 20 mg/mL. The clear yellow to orange 
liquid is supplied in amber glass bottles with a 28 mm child resistant cap and tamper evident closure (60 mL 
or 100 mL per bottle).  
 
A site-supplied press-in bottle adapter is required for use with an oral syringe for dosing purposes.  
 
LOXO-101 (larotrectinib) will be given at 100 mg/m2 BID with a maximum of 100 mg per dose. 
Calculated doses ≤ 45 mg should be prepared in oral syringes ≤ 3 mL with dosing volumes of LOXO-101 
(larotrectinib) liquid formulation rounded to the nearest 0.1 mL (2 mg). Calculated doses > 45 mg should 
be prepared in oral syringes ≥ 5 mL with dosing volumes of LOXO-101 (larotrectinib) liquid 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: 
• 
Patient BSA 0.43 m2, Dose Level 1 (100 mg/m2) → Calculated Dose = 43 mg BID 
         
Calculated Volume (mL) = (100 mg/m2 x 0.43 m2) / (20 mg/mL) = 2.15 mL  
Final Dosing Volume (mL) =  2.2 mL (rounded to nearest 0.1 mL for doses ≤ 45 mg) 
Final Dose to be administered = 2.2 mL x 20 mg/mL = 44 mg 
• 
Patient BSA 0.85 m2, Dose Level 1 (100 mg/m2) → Calculated Dose = 85 mg BID 
 
             Calculated Volume (mL) = (100 mg/m2 x 0.85 m2) / (20 mg/mL) =4.25 mL  
Final Dosing Volume (mL) = 4.2 mL (rounded to the nearest 0.2 mL for dose > 45 mg) 
Final Dose to be administered = 4.2 mL x 20 mg/mL = 84 mg 
 
 
 
 

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Cycle 1  
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. For information related to prestudy observations please refer to Section 8.1. Studies on Day 
28/1 may be obtained within 72 hours prior to the start of the subsequent cycle. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
Treatment Details: Cycle 1 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later).  
 
 
a. 
History/Physical Exam (including VS). 
 
b. 
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. 
c. 
Electrolytes including Ca++, PO4, Mg++ 
d. 
Creatinine, ALT, bilirubin 
e. 
Albumin  
f. 
Pharmacokinetics (optional)-see Section 8.3 for details of PK studies.  
g. 
Ht/Wt/BSA 
h. 
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.   
 

  
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                                                                                                                                                        Page 2 of 2   
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Subsequent Cycles 
Required Observations in All Subsequent Cycles 
 
a. 
History/Physical Exam (including VS) 
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 
d. 
Electrolytes including Ca++, PO4, Mg++ 
e. 
Creatinine, ALT, bilirubin 
f. 
Albumin 
g. 
Tumor Disease Evaluation – Every other cycle x 3 then q 3 cycles. Tumor Disease Evaluation 
should be obtained on the next consecutive cycle after initial documentation of either a PR or 
CR.  Subsequent scans may restart 2 cycles after the confirmatory scan. If the institutional 
investigator determines that the patient has progressed based on clinical or laboratory evidence, 
he/she may opt not to confirm this finding radiographically 
h. 
Bone Marrow Aspirate and/or biopsy- 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. The medication diary should be 
collected weekly.  
j. 
Circulating Tumor DNA (ctDNA-optional)- With consent,  two samples will be collected on 
this protocol (Cycle 5 Day 1; and for patients receiving ≥ 5 cycles,  at progression or end of 
protocol therapy) see Section 8.4 for details of the ctDNA studies.  
k. 
Pharmacokinetics (optional)-see Section 8.3 for details of PK studies. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN 
OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 
 
Treatment Details: Subsequent Cycles 
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 5.2 are 
met (whichever occurs later). 
 

  
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APPENDIX VII: TARGET HISTOLOGIES FOR APEC1621A 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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APPENDIX VIII: EXAMPLES OF ACTIONABLE MUTATIONS FOR SUB-PROTOCOL 
APEC1621A 
INCLUSION 
 VARIANTS 
  
  
  
  Fusions 
  
  
  
  
Gene Name 
Variant ID 
Variant Type 
LOE 
Variant Description 
NTRK1 
NTRK1-DYNC2H1.N17D85 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPM3-NTRK1.T7N13 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
LMNA-NTRK1.L3N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPM3-NTRK1.T8N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPM3-NTRK1.T7N10.COSF1329 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPR-NTRK1.T21N10.COSF1326 
Fusion 
2 
NTRK1 Gene Fusion 
NTRK1 
TPR-NTRK1.T6N12.COSF1324 
Fusion 
2 
NTRK1 Gene Fusion 
NTRK1 
MPRIP-NTRK1.M14N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
MPRIP-NTRK1.M18N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
MPRIP-NTRK1.M21N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
SQSTM1-NTRK1.S5N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
SSBP2-NTRK1.S12N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TFG-NTRK1.T6N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
BCAN-NTRK1.B13N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
LMNA-NTRK1.L2N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
NFASC-NTRK1.N20N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
RNF213-NTRK1.R15N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
IRF2BP2-NTRK1.I1N10.1 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPR-NTRK1.T6N12.1 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
CD74-NTRK1.C7N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
SQSTM1-NTRK1.S2N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TP53-NTRK1.T10N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
LMNA-NTRK1.L10N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
RABGAP1L-NTRK1.R14N16 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
CHTOP-NTRK1.C5N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TP53-NTRK1.T8N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TP53-NTRK1.T9N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
PPL-NTRK1.P12N13 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TFG-NTRK1.T6N14 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TP53-NTRK1.T11N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
ARHGEF2-NTRK1.A21N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
EPHB2-NTRK1.E3N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
CHTOP-NTRK1.C5N10 
Fusion 
3 
NTRK1 Gene Fusion 

  
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NTRK1 
LMNA-NTRK1.L10N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPR-NTRK1.T21N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
EPS15-NTRK1.E21N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
PPL-NTRK1.P22N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
PPL-NTRK1.P22N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
EPS15-NTRK1.E21N9.1 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
LMNA-NTRK1.L11N11 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPM3-NTRK1.T7N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
LMNA-NTRK1.L5N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
LMNA-NTRK1.L6N12 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
MRPL24-NTRK1.M1N9.1 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
NTRK1-NTRK1.N6N8 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
MRPL24-NTRK1.M1N9 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPM3-NTRK1.T7N7.ins 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
CEL-NTRK1.C7N7.2 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK1 
TPR-NTRK1.T16int9N10 
Fusion 
3 
NTRK1 Gene Fusion 
NTRK2 
NACC2-NTRK2.N4N13.COSF1448 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
QKI-NTRK2.Q6N16.COSF1446 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
AFAP1-NTRK2.A14N12 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
AGBL4-NTRK2.A6N16 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
SQSTM1-NTRK2.S5N17 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
TRIM24-NTRK2.T12N15 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
VCL-NTRK2.V16N12 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
DAB2IP-NTRK2.D1N17 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
TRIM24-NTRK2.T12N16 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
NAV1-NTRK2.N15N11 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK2 
SLMAP-NTRK2.S14N16 
Fusion 
3 
NTRK2 Gene Fusion 
NTRK3 
NTRK3-HOMER1.N17H2 
Fusion 
3 
NTRK3 Gene Fusions 
NTRK3 
ETV6-NTRK3.E4N15.COSF823.2 
Fusion 
2 
NTRK3 Gene Fusions 
NTRK3 
ETV6-NTRK3.E5N15.COSF571.1 
Fusion 
2 
NTRK3 Gene Fusions 
NTRK3 
BTBD1-NTRK3.B4N14 
Fusion 
3 
NTRK3 Gene Fusions 
NTRK3 
COX5A-NTRK3.C1N15 
Fusion 
3 
NTRK3 Gene Fusions 
NTRK3 
ETV6-NTRK3.E4N14.1 
Fusion 
2 
NTRK3 Gene Fusions 
NTRK3 
ETV6-NTRK3.E5N14 
Fusion 
2 
NTRK3 Gene Fusions 
NTRK3 
FAT1-NTRK3.F2N7 
Fusion 
3 
NTRK3 Gene Fusions 
NTRK3 
EML4-NTRK3.E2N14 
Fusion 
3 
NTRK3 Gene Fusions 
NTRK3 
AKAP13-NTRK3.A14N14 
Fusion 
3 
NTRK3 Gene Fusions 
NTRK3 
LYN-NTRK3.L8N14 
Fusion 
3 
NTRK3 Gene Fusions 

  
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NTRK3 
RBPMS-NTRK3.R5N14 
Fusion 
3 
NTRK3 Gene Fusions 
 
 

  
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APPENDIX IX:  YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621A 
(For Children from 7 through 13 Years of Age) 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) in 
children with a cancer that has come back after treatment or is difficult to treat 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is 
being done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because other 
treatments did not get rid of the cancer. A research study is when doctors work together to try out 
new ways to help people who are sick. In this study, we are trying to learn more about how to 
treat the kind of cancer that you have.  
 
1. What will happen to me in the study? Children who are part of this study will be given LOXI-101 
(Larotrectinib) that could “match” your tumor. The doctors want to see if LOXO-101 
(Larotrectinib) will help children with your type of cancer get better. We don’t know if LOXO-101 
(Larotrectinib) will work well to get rid of your cancer. That is why we are doing the study. We will 
follow your health after you finish the study treatment. 
 
Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is that 
LOXO-101 (Larotrectinib) may cause your cancer to stop growing or to shrink for a period of 
time but we don’t know for sure if there is any benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have problems, or side effects 
from LOXO-101 (Larotrectinib). There may be risks that we don’t know about. 
 
4. 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. The doctors 
and nurses will still take care of you. 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. 
 
5. We are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the cancer will respond to treatment. You can still take part in this study even if you don't 
allow us to collect the extra blood samples for research.  
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY APEC1621A 
(For Teens from 14 through 17 Years of Age) 
We want to tell you all about this study. You and your family can decide if you want to be in it. 
Ask questions if you don’t understand. 
 
1. What is the name of the study? A study of Molecular Analysis for Therapy Choice (MATCH) in 
children with a cancer that has come back after treatment or is difficult to treat 
 
2. Who is in charge of the study? The study is being done by Children’s Oncology Group and is 
being done at other hospitals. 
 
3. What is the study about? We are asking you to take part in a research study because other 
treatments did not get rid of the cancer. A research study is when doctors work together to try out 
new ways to help people who are sick. In this study, we are trying to learn more about how to 
treat the kind of cancer that you have.  
 
4. What will happen to me in the study? Children who are part of this study will be given LOXI-101 
(Larotrectinib) that could “match” your tumor. The doctors want to see if LOXO-101 
(Larotrectinib) will help children with your type of cancer get better. We don’t know if LOXO-
101 (Larotrectinib) will work well to get rid of your cancer. That is why we are doing the study. 
We will collect information about your health after you finish the study treatment. 
 
 
Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is that 
LOXO-101 (Larotrectinib) may cause your cancer to stop growing or to shrink for a period of 
time but we don’t know for sure if there is any benefit of being part of this study. 
 
Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that you may have problems, or side effects 
from LOXO-101 (Larotrectinib). There may be risks that we don’t know about. 
 
5. Will I be paid to be in this study? You will not be paid for being in this study. 
 
6. Do I have to be in the study? You and your family can choose to be part of this study or not. You 
and your family can also decide to stop being in this study at any time once you start. The doctors 
and nurses will still take care of you. There may be other treatments for your illness that your 
doctor can tell you about. If you have any questions or don’t like what is happening, please tell 
your parent, the doctor or nurse. 
 
7. We are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the cancer will respond to treatment. You can still take part in this study even if you don't 
allow us to collect the extra blood samples for research.  
 
 

  
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APPENDIX X: CTEP AND CTSU REGISTRATION PROCEDURES  
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program 
(CTEP) Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In 
addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the  Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice 
sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 

  
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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must be rostered 
at the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at https://ctep.cancer.gov/
investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at 
RCRHelpDesk@nih.gov. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization (PO) 
on the protocol. One way to search for a protocol is listed below.  
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
 
Protocol-Specific Requirements For Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office 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.  

  
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• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Data Submission / Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation 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 

  
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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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APPENDIX XI: TOXICITY-SPECIFIC GRADING  
 
 
Bilirubin 
 
Grade 1: 
> ULN- ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN - 3 x ULN 
Grade 3: 
> 3 x ULN - 10 x ULN 
Grade 4: 
> 10 x ULN 
 
ALT: For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
> 45 U/L - ≤ 135 U/L 
Grade 2: 
136 U/L -  225 U/L 
Grade 3: 
226 U/L -  900 U/L 
Grade 4: 
> 900 U/L 
 
AST: For the purpose of this study, the ULN for AST is 50 U/L regardless of baseline. 
 
Grade 1: 
> 50 U/L - ≤ 150 U/L 
Grade 2: 
151 U/L - 250 U/L 
Grade 3: 
251 U/L - 1000 U/L 
Grade 4: 
> 1000 U/L 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5 x ULN- 5 x ULN 
Grade 3: 
> 5 x ULN- 20 x ULN 
Grade 4: 
> 20 x ULN