Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias
Phase: PHASE2
Conditions: Central Nervous System Neoplasm, Infantile Fibrosarcoma, Recurrent Acute Leukemia, Refractory Acute Leukemia, Solid Neoplasm
Sponsor: Children's Oncology Group

  
 
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CHILDREN'S ONCOLOGY GROUP 
 
 
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Larotrectinib (LOXO-101, NSC# 788607, 
) for Previously Untreated TRK Fusion Pediatric 
Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias 
 
 
 
A COG Groupwide Phase 2 Study 
 
IND Sponsor for Larotrectinib: COG 
 
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. 
 
 
 
 
 
 
  
  
  
 
   
 
 
 
 
 
 
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org 
 
 
Activated: 
09/18/19 
Version Date: 
3/03/2025 
Closed: 
12/02/2022      
 Amendment #:  
5 

  
 
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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 https://www.ctsu.org,    
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately by phone or 
email: 1-866-651-CTSU (2878), 
or CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
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 location on the CTSU members’ website (https://www.ctsu.org). 
 
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 Roster Maintenance application and in most cases viewable and 
manageable via the Roster Update Management System (RUMS) on the CTSU members’ website. 
For clinical questions (i.e., patient eligibility or treatment-related)  
Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (i.e., 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. 
For IROC Questions regarding imaging, dose calculations or documentation: 
Contact IROC Rhode Island QA Center at (401) 753-7600 or IROCRI@QARC.org 
 
 
 

  
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
CONTACT INFORMATION 
2 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
6 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
9 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Aim 
11 
1.2 
Secondary Aims 
11 
1.3 
Exploratory Aims 
11 
2.0 
BACKGROUND 
12 
2.1  
Rationale for Development 
12 
2.2 
Preclinical Studies 
14 
2.3 
Adult Studies 
16 
2.4 
Pediatric Studies 
17 
2.5 
Overview of Proposed Pediatric Phase 2 Trial 
20 
2.6 
Rationale for Correlative Biology Studies 
21 
2.7 
Rationale for Neurocognitive Studies 
22 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
23 
3.1 
Study Enrollment 
23 
3.2 
Eligibility: Inclusion Criteria 
27 
3.3 
Eligibility: Exclusion Criteria 
32 
3.4 
Regulatory 
34 
4.0 
TREATMENT PROGRAM 
35 
4.1 
Overview of Treatment Plan 
35 
4.2 
Cycle 1, Cohorts A & B 
38 
4.3 
Therapy Subsequent to Cycle 1 (Cycles 2+), Cohorts A & B 
43 
4.4 
Cycle 1, Cohort C 
49 
4.5 
Therapy Subsequent to Cycle 1 (Cycles 2+), Cohort C 
56 
5.0 
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY 
62 
5.1 
Definition of Dose-Limiting Toxicity (DLT) 
62 
5.2 
Dose Modifications for Hematological Toxicity 
63 
5.3 
Dose Modifications for Non-Hematological Toxicity 
63 
6.0  
DRUG INFORMATION 
64 
6.1 
Larotrectinib        (09/28/2022) 
64 
6.2 
Cytarabine                 (07/13/15) 
69 
6.3 
 Triples             (05/08/12) 
70 
6.4 
Methotrexate                 (11/27/17) 
72 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
75 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
75 
7.2 
Follow-up 
76 
7.3 
Correlative Biology Studies 
77 

  
 
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7.4 
Imaging Central Review 
84 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA85 
8.1 
Criteria for Removal from Protocol Therapy 
85 
8.2 
Off Study Criteria 
85 
9.0 
STATISTICAL CONSIDERATIONS 
85 
9.1 
Sample Size and Study Duration 
85 
9.2 
Study Design 
86 
9.3 
Methods of Analysis 
87 
9.4 
Evaluability for Response 
88 
9.5 
Evaluability for Toxicity 
88 
9.6 
Sex and Minority Accrual Estimates 
89 
9.7 
Analysis of CSF to Plasma Larotrectinib Concentrations 
89 
9.8 
Analysis of Biological and Correlative Endpoints 
90 
10.0 
 EVALUATION CRITERIA 
92 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
92 
Response Criteria 
92 
10.3 
Response Criteria for Patients with Solid Tumors (non-CNS) 
93 
10.4 
Best Response (Solid Tumors) 
94 
10.5 
Response Criteria for Patients with CNS Tumors 
94 
10.6 
Response Criteria for Patients with AML 
96 
10.7 
Response Criteria for Patients with ALL 
97 
10.8 
CNS Leukemia at Diagnosis for Patients with ALL 
98 
10.9 
CNS Leukemia at Diagnosis for Patients with AML 
99 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
99 
11.1 
Purpose 
99 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
99 
11.3 
Specific Examples for Expedited Reporting 
99 
11.4 
Reporting Requirements for Specialized AEs 
102 
11.5 
Exceptions to Expedited Reporting 
102 
11.6 
Reporting Requirements - Investigator Responsibility 
103 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
103 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
104 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
105 
11.10 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway105 
11.11 Routine Reporting of Adverse Events 
105 
12.0 
 STUDY REPORTING AND MONITORING 
106 
12.1 
CDUS 
106 
12.2 
Data and Safety Monitoring Committee 
106 
13.0 
 SURGICAL GUIDELINES 
106 
13.1 
Guidelines 
106 
13.2 
Definition of Margins 
107 
REFERENCES 
108 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
111 
APPENDIX II:  YOUTH INFORMATION SHEETS 
115 
APPENDIX III:  TISSUE STUDIES FORM 
117 
APPENDIX IV:  CIRCULATING TUMOR DNA 
118 

  
 
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APPENDIX V: LAROTRECTINIB DRUG INTERACTIONS 
119 
APPENDIX VI: CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
120 
APPENDIX VII-A: MEDICATION DIARY (LAROTRECTINIB CAPSULE FORMULATION) 
123 
APPENDIX VII-B: MEDICATION DIARY (LAROTRECTINIB LIQUID FORMULATION) 
126 
APPENDIX VIII: CSF AND PLASMA PHARMACOKINETIC STUDY FORM 
137 
APPENDIX IX: PERFORMANCE STATUS SCALES/SCORES 
139 
APPENDIX X-A: LAROTRECTINIB DOSING NOMOGRAM (CAPSULE FORMULATION) 
140 
APPENDIX X-B: LAROTRECTINIB DOSING PREPARATION (LIQUID FORMULATION) 
141 
APPENDIX XI: QOL AND NEUROCOGNITIVE ASSESSMENTS 
142 
APPENDIX XII: TOXICITY-SPECIFIC GRADING 
146 
 
 

  
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STUDY COMMITTEE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
      
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
  
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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AGENT 
 
NSC#  
IND# 
 
 
 
Agent Supplied by Bayer AG: 
 
Larotrectinib                  788607               
 
 
 
 
Commercial Agents: 
 
Cytarabine                     63878                Exempt 
 
Hydrocortisone              10483                Exempt 
 
Methotrexate                  740                    Exempt 
For Group Operations (GOC) and Statistics and  
 
Data Center (SDC) contacts see:  
 
http://members.childrensoncologygroup.org 
 
Telephone: (626) 447-0064 
 
 
 IND Sponsor: COG 
 
 
 
SEE SECTION 7.3 FOR SPECIMEN SHIPPING ADDRESSES 
 

  
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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 your 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 
Larotrectinib is a highly selective oral small molecule inhibitor of the TRK family of tyrosine kinases 
(TRKA, TRKB, and TRKC) which are encoded by the NTRK genes (NTRK1, NTRK2, and 
NTRK3).  Fusions of these genes (TRK fusions) occur across a wide range of pediatric and adult 
malignancies, and are nearly pathognomonic for infantile fibrosarcoma.  Preclinical studies have shown 
that larotrectinib is active in cancer cell lines harboring TRK fusions, while having no activity in cell lines 
without these fusions.  Ongoing clinical trials of larotrectinib in children and adults have shown a 75% 
centrally confirmed objective response rate in patients with relapsed or refractory TRK fusion cancers 
across a wide range of tumor types, including a 93% objective response rate in children with TRK fusion 
cancers on a Phase 1 trial. This study also established a pediatric recommended phase 2 dose.  Given the 
remarkable activity seen in the relapsed/refractory setting, this open label two-stage phase 2 trial will enroll 
newly diagnosed patients with any TRK fusion solid tumor.  The primary cohort will be patients with 
infantile fibrosarcoma, and patients with other TRK fusion solid tumors will be analyzed in a separate 
cohort.  This study will also include an exploratory cohort for patients with relapsed or refractory TRK 
fusion acute leukemias, and the results of this cohort will be reported descriptively.  Larotrectinib will be 
administered orally twice daily on a continuous dosing schedule of 28-day cycles at a dose of 100 
mg/m2/dose with a maximum of 100 mg/dose. Patients with localized tumors who achieve sufficient tumor 
shrinkage to allow complete resection and those who achieve a complete response will discontinue 
larotrectinib at protocol specified timepoints and continue to be followed for recurrence.  Patients who do 
not meet these criteria will receive 26 cycles (approximately 2 years) of therapy and then be followed for 
recurrence. The primary endpoint will be the objective response rate in patients with infantile fibrosarcoma. 
We will also evaluate event-free survival (EFS), duration of response (DOR), and overall survival (OS). 
These endpoints will be separately evaluated in patients with all other TRK fusion solid tumors combined. 
A Simon two-stage design that incorporates the best overall response within 6 months will be utilized. 
 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA 
Patients with solid tumors (Cohorts A and B):  
 
 
 
 
 
 
 
 
 
 
 

  
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Patients with leukemia (Cohort C):  
 
 
 
 

  
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GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim 
 
1.1.1 
To determine the objective response rate (ORR) of children with infantile 
fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control.   
 
1.2 
Secondary Aims 
 
1.2.1 
To determine event-free survival (EFS), overall survival (OS), and duration of 
response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior 
to local control. 
 
1.2.2 
To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK 
fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to 
local control.  
 
1.2.3 
To describe the toxicity of larotrectinib in children with solid tumors and acute 
leukemia.   
 
1.2.4  To determine the percentage of patients with TRK fusion solid tumors with 
detectable circulating tumor DNA at baseline and after 2 weeks, 4 weeks, 24 weeks 
of treatment, at the time of discontinuation of larotrectinib therapy, and at 
progression.  
 
 
1.3 
Exploratory Aims 
 
 
To determine the EFS, OS, and DoR of children with TRK fusion solid tumors 
other than IFS treated with adjuvant larotrectinib following upfront surgery with 
positive margins after neoadjuvant larotrectinib. 
 
 
To determine the EFS, OS, and DoR of children with TRK fusion solid tumors 
who experience a complete response to larotrectinib and subsequently discontinue 
larotrectinib therapy 
 
 
To determine the remission induction rate for patients with recurrent/refractory 
TRK fusion leukemia when treated with larotrectinib. 
 
 
To evaluate the surgical morbidity and extent of resection of initially unresectable 
tumors in patients with TRK fusion solid tumors who undergo surgical resection 
following neoadjuvant larotrectinib. 
 
 
To evaluate mechanisms of response and resistance to larotrectinib in children with 
TRK fusion cancers.  
 
 
To evaluate the morphologic features of TRK fusion solid tumors at time of initial 

  
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biopsy to further define criteria for pathologic diagnosis of these tumors.  
 
 
To evaluate immunohistochemistry for pan-TRK as a screening method for TRK 
fusion tumors and in resection specimens following neoadjuvant treatment with 
larotrectinib.  
 
 
To evaluate the histologic response to larotrectinib in resection specimens 
following neoadjuvant treatment.  
 
 
To evaluate circulating tumor DNA for the detection of the emergence of  
resistance mutations and recurrence in patients with TRK fusion solid tumors 
treated with larotrectinib. 
 
 To evaluate the ratio of CSF to concurrent plasma concentrations of larotrectinib 
in patients with leukemia.  
 
 To evaluate the change in neurocognitive/behavioral functioning over time 
between baseline and 5 years post-diagnosis of patients treated on this protocol 
using parent-reported adaptive functioning (ABAS-III General Adaptive 
Composite), executive function (BRIEF-P or BRIEF-2 Global Executive 
Composite Score), psychosocial functioning (BASC-3 Internalizing, Externalizing 
and Behavioral Symptoms Indices) and quality of life (PedsQL Total score). 
 
2.0 
BACKGROUND 
 
2.1  
Rationale for Development 
 
2.1.1 
Tropomyosin Receptor Kinase (TRK) Fusions 
The TRKA, TRKB, and TRKC family of neurotrophin tyrosine kinase receptors, 
encoded respectively by the Neurotrophic Receptor Tyrosine Kinase genes 
(NTRK1, NTRK2, and NTRK3), are involved in the growth, differentiation, and 
survival of neurons.2, 3 Chromosomal rearrangements involving NTRK1, NTRK2, 
and NTRK3 have been identified in a broad range of malignancies.4-14 These 
rearrangements generate fusions in which the 3’ region of the NTRK gene is joined 
with the 5’ region of an unrelated gene.  The resultant fusion proteins include the 
TRK kinase domain, joined in-frame with the N terminus of the fusion partner. 
Thus, the novel fusion oncoprotein is both aberrantly expressed and may have 
ligand independent kinase activity. TRK fusions have been identified in a range of 
pediatric cancers, including infantile fibrosarcoma (IFS),5, 12 cellular congenital 
mesoblastic nephroma (CMN),7, 8 other undifferentiated/spindle cell sarcomas,10 
high-grade gliomas,14 and papillary thyroid cancer.11 Recently, as discussed below, 
the highly selective TRK inhibitor larotrectinib has shown a high level of activity 
in children and adults with relapsed and refractory TRK fusion cancers, regardless 
of histology, in phase 1 and 2 clinical trials.  Thus, we will perform a non-
randomized study of larotrectinib in pediatric patients with newly diagnosed IFS 
and other TRK fusion solid tumors and relapsed/refractory TRK fusion leukemias. 
 
 
 
2.1.2 
Infantile Fibrosarcoma (IFS): 

  
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IFS is a soft tissue sarcoma occurring in young children.15, 16 While rare, IFS is the 
most common soft tissue sarcoma in children less than 1 year of age.17, 18  Despite 
histologic similarities, infantile fibrosarcoma is distinct from adult fibrosarcoma, 
with the infantile type harboring a highly recurrent ETV6-NTRK3 fusion in ~85% 
of cases.19  Further, case reports of other fusions involving NTRK1 or NTRK3 
have been described in ETV6-NTRK3 negative tumors, suggesting that TRK 
fusions are nearly universal drivers in this disease.10, 20  Clinically, IFS almost 
always presents as a localized tumor, although rare cases with metastases have 
been described.21, 22 Children with IFS generally have a good prognosis, with 
overall survival rates reported between 80-100%.23, 24 
 
The largest datasets on the therapy and outcome of children with IFS come from 
the European experience.  A retrospective analysis of 56 infants with IFS from the 
years 1979-2005 has been reported, and the European pediatric Soft tissue sarcoma 
Study Group (EpSSG) conducted a prospective study of a standardized treatment 
regimen for such children from 2005-2012.23, 24  These studies demonstrated that 
most children with completely resected tumors, with or without positive margins, 
remain disease free without further therapy.  Across both studies, only 1 of 21 
Intergroup Rhabdomyosarcoma Studies (IRS) Group 1 patients, and 3 of 19 of IRS 
Group 2 patients who did not receive adjuvant chemotherapy suffered a relapse.23, 
24 
 
Despite the good outcome with limited therapy in infants with Group 1 and 2 
disease, most infants had IRS Group 3 (incompletely resected) disease (57 of 105 
patients across the two series). 23, 24  There is a significant burden of therapy in 
these children. The majority of children with Group 3 disease are treated with 
chemotherapy.24  The prospective EpSSG study was conceived to attempt to reduce 
alkylator exposure and assess the ability to prevent morbid surgery in these 
patients.  On this protocol, IRS Stage 3 patients were treated with vincristine and 
actinomycin, and alkylators and/or doxorubicin were only added if there was 
disease progression or insufficient tumor response to allow subsequent surgical 
resection.  Despite this strategy, 5 of 27 IRS Group 3 patients had progressive 
disease, 1 suffered a metastatic relapse, 1 died of toxicity, 6 received alkylator 
based therapy, 3 developed venocclusive disease (VOD), 2 underwent limb 
amputation, and 1 underwent extenteration.23  The objective response rate (defined 
as a >33% reduction in tumor volume) to chemotherapy for these patients was 
62.9% (17/27 patients).  Of these 27 patients, 7 had an event (death, progressive 
disease, or relapse), for an estimated 74% event free survival.  Thus, there is the 
opportunity to improve outcome and there remains a significant burden of therapy 
for the IRS Group 3 patients. 
 
2.1.3 
Congenital Mesoblastic Nephroma (CMN): 
CMN is a rare pediatric renal tumor, which represents the most common kidney 
tumor in the first month of life.25, 26  A recent meta-analysis of the published CMN 
literature found a 96% overall survival rate among 276 described patients.27  The 
majority of patients were cured with nephrectomy alone, but 50 of the 263 patients 
for whom treatment details were described received post-operative chemotherapy. 
This meta-analysis identified a high risk of relapse in patients with Stage 3 disease, 
ranging from 29-58%.  The majority of patients with relapsed disease had the 
cellular subtype (8/11 cases) which commonly harbors the ETV6-NTRK3 fusion 

  
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(t(12;15)(p13;q22)).7, 8 Of the 18 patients with a documented t(12;15)(p13;q22) 
fusion on cytogenetics, 4 relapsed and 1 died of disease, for an estimated 78% 
event free survival. The ETV6-NTRK3 fusion appears to define a higher risk 
subset of patients, particularly in those with unresectable (Stage 3) disease. 
 
2.1.4 
Other TRK Fusion Solid Tumors:  
In addition to IFS and CMN, TRK fusions have been identified in other 
undifferentiated/spindle cell sarcomas,10 low and high-grade gliomas,14 papillary 
thyroid cancer,11 secretory breast cancer,28 mammary analogue secretory 
carcinoma (MASC),29 and spitzoid melanoma.30 For the these diseases, the 
outcome of patients with TRK fusions is unknown, as prior therapeutic trials have 
not evaluated for such fusions, and patients have been treated based on histology.  
Patients with undifferentiated/spindle cell sarcoma are often treated with risk based 
chemoradiotherapy in which patients with intermediate or high risk disease receive 
ifosfamide and doxorubicin per a recently completed Children’s Oncology Group 
protocol (ARST0332).  Among intermediate and high risk patients, this study 
demonstrated 4-year event free survival rates of 64% and 49% for patients treated 
with adjuvant and neoadjuvant chemoradiotherapy, respectively.   
 
 
 
2.1.5 
TRK Fusion Acute Leukemias: 
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, 
accounting for about 25% of all cancers diagnosed in children.31  Recently, a 
subtype of ALL called Ph-like ALL has been identified which has a gene 
expression profile similar to Philadelphia-chromosome positive ALL, but lacks the 
BCR-ABL fusion. The outcomes for patients with Ph-like ALL, which accounts 
for about 15% of pediatric ALL, are poor with a median 5-year event free survival 
of 58% in children and 42% in adolescents in newly diagnosed patients.32  For 
patients who relapse, the outcomes are even worse with most children succumbing 
to their disease.33  Multiple recurrent fusions involving kinases have been 
described in Ph-like ALL, including TRK fusions in a small subset of cases.32, 34 
The precise frequency of TRK fusions in Ph-like ALL is unknown, but such 
fusions are rare, with a total of 4 children identified in the sequencing effort at St. 
Jude as of June 2017 (personal communication C. Mulligan).  In addition, three 
adults with acute myeloid leukemia (AML) harboring TRK fusions (NTRK3 and 
NTRK2) have been described.34, 35 
 
 
2.2 
Preclinical Studies  
 
2.2.1 
Antitumor Activity 
Larotrectinib is a highly selective inhibitor of TRKA, TRKB, and TRKC with low-
nanomolar inhibition of these enzymes. Larotrectinib does not inhibit any other 
tested kinase at concentrations up to 1 uM.  Reflecting this specificity, larotrectinib 
demonstrates in vitro IC50s of less than 100 nM for colorectal, lung, AML, and 
engineered cell lines harboring fusions of NTRK1, NTRK2, and NTRK3, with 
essentially no growth inhibitory effects on a range of cancer cell lines not harboring 
NTRK alterations at concentrations up to 1 uM. In vivo, larotrectinib induces 
regressions of human colorectal, lung cancer, and AML xenografts harboring 
NTRK1 and NTRK3 fusions. 
 

  
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2.2.2 
Animal Toxicology 
In toxicology studies of larotrectinib conducted in the rat and monkey, the most 
sensitive organ in both species was the liver. Changes that were seen in included 
increased liver weights concomitant with hepatocellular hypertrophy and minor 
reversible increases in aminotransferases (AST and ALT). The rat was the more 
sensitive species and also developed dose-limiting chronic inflammation of the 
epidermis and dermis.  
 
Safety pharmacology studies have assessed effects on the cardiovascular (CV), 
central nervous system (CNS), respiratory, and gastrointestinal (GI) systems in 
vitro and in vivo in rats, dogs, and monkeys. There were no larotrectinib-related 
neurobehavioral or respiratory function effects in safety pharmacology studies. 
Larotrectinib accelerated the intestinal transit and significantly increased gastric 
secretion and acidity in rats. 
 
Cardiac safety was evaluated in an in vitro assay for human ether-à-go-go related 
gene (hERG) activity, in conscious telemetry-instrumented rats and monkeys. 
Larotrectinib had a 50% inhibitory concentration (IC50) value of 147 μM in the 
hERG assay, which is >200-fold higher than the maximum unbound concentration 
at the human recommended phase 2 dose. No adverse CV effects were noted in 
rats or monkeys in which telemetry-instrumented animals were dosed up to 300 
mg/kg and 100 mg/kg, respectively. 
 
Larotrectinib was not genotoxic in any of the assays conducted. Larotrectinib did 
not demonstrate any phototoxic potential. 
 
2.2.3 
Preclinical Pharmacology 
Pharmacokinetic studies of larotrectinib have been conducted in mice, rats, dogs, 
and monkeys. Oral larotrectinib bioavailability was approximately 30% to 100% 
across these models. The PK following multiple doses of larotrectinib in mice, rats, 
and monkeys were generally consistent with single-dose PK, with no unexpected 
accumulation.  In dogs, the AUC of larotrectinib was similar in fed and fasted 
animals. 
 
The solubility, permeability, and animal PK data suggest that larotrectinib is well 
absorbed from the GI tract. The compound distributes into tissues, with volumes 
of distribution ranging from 1–2 L/kg. A brain microdialysis study of larotrectinib 
in the rat showed that the unbound (free) brain concentration was approximately 
4% of the unbound plasma concentration.  However, higher CSF levels have been 
observed in the small number human patients treated with larotrectinib in whom 
CSF sampling has been obtained. 
 
Larotrectinib is metabolized by microsomal fractions and hepatocytes from mice, 
rats, rabbits, dogs, monkeys, and humans. The isoform of cytochrome P450 that 
metabolizes larotrectinib in human liver microsomes is primarily CYP3A4. 
Larotrectinib and its metabolites distribute freely between red blood cells and 
plasma; it binds moderately (70%) to plasma proteins independent of 
concentration. Larotrectinib and its metabolites are eliminated primarily by the 
renal and biliary routes. 
 

  
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2.3 
Adult Studies 
 
2.3.1 
Adult Phase 1 Studies 
In a phase 1 trial, there was no biomarker required for eligibility, but 8 of 59 
enrolled patients had TRK fusions.  This study identified a recommended phase 2 
dose in adults of 100 mg BID based on exposure, response, and toxicity, but no 
MTD was reached in adults treated at doses up to 200 mg BID.  Larotrectinib was 
well tolerated in this study, with the most common adverse events regardless of 
attribution being fatigue, dizziness, dyspnea, and anemia.  Few Grade 3/4 adverse 
events were observed, with fatigue, anemia, dyspnea, increased AST, decreased 
appetite, lymphocyte count decreased, and pneumonia being the only recurrent 
Grade 3 events, each occurring in less than 10% of patients.  Among the 8 patients 
with TRK fusions, 7 were evaluable for response as of the last data cut off 
(November 10, 2016).  Six of the 7 evaluable patients achieved confirmed partial 
responses and all patients remained in response at a median of >15 months of 
larotrectinib therapy.  The seventh patient with a TRK fusion did not have 
measurable disease at enrollment but remained on study with stable disease for 
>12 months.  No responses were seen in patients without TRK fusions. 
 
2.3.2 
Efficacy (Phase 2 and 3 studies) 
A phase 2 study of larotrectinib is ongoing in adolescents (age > 12 years) and 
adults with TRK fusion cancers.  Patients on this study are treated at a dose of 100 
mg BID.  Patients enrolled on this study were analyzed with the adults with TRK 
fusion cancers enrolled on the phase 1 study above, as well as the children with 
TRK fusion cancers enrolled on the pediatric phase 1 study described below.  Fifty-
five patients with TRK fusions (12 children, 43 adults, age range: 4 mo. - 76 yrs) 
were enrolled to these three studies as of July 2017.36  Fusions involved NTRK1 
(n=25), NTRK2 (n=1), and NTRK3 (n=29), and 14 unique upstream partners. 17 
discrete tumor types were included: salivary-gland tumor (n=12); non-
rhabdomyosarcoma soft tissue sarcoma (NRSTS) including myopericytoma, 
malignant peripheral nerve sheath tumor, spindle-cell tumor, infantile 
myofibromatosis, inflammatory myofibroblastic tumor of the kidney, and soft 
tissue sarcoma NOS (n=11); infantile fibrosarcoma (n=7); thyroid (n=5); colon 
(n=4); lung (n=4); melanoma (n=4); GIST (n=4); cholangiocarcinoma (n=2); 
appendix tumor (n=1); breast cancer (n=1); and pancreatic tumor (n=1). By blinded 
independent radiology review, the ORR for these 55 patients was 75% (95% CI: 
61%–85%) which was concordant with the investigator assessed 80% ORR. 
Responses appeared independent of which NTRK gene was involved, the 5’ fusion 
partner, or the tumor histology. Responses occurred very rapidly, with a median 
time to first response of 1.8 months, consistent with the first response evaluation 
mandated in the protocols. A median duration of response had not been reached 
with 83% of patients with ongoing responses at 6 months and 71% at 12 months. 
The longest responder remains on treatment for > 2 years. NTRK solvent front 
mutations were detected in all 9 patients who have developed acquired resistance 
and had repeat testing. The most common treatment related adverse events were 
increased AST/ALT (38%), dizziness (25%), constipation, nausea, and fatigue 
(16% each). Eight of 55 (15%) patients required dose reductions for toxicity; all 
maintained their response at the lower dose level.  
 

  
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The high response rate to larotrectinib was consistent across the histologic 
diagnoses of patients expected to enroll on this clinical trial. Among the 7 patients 
with infantile fibrosarcoma, the response rate was 100% (best responses were 2 
CR, 5 PR). Among the 11 patients with NRSTS, the response rate was 91% (best 
responses were 1 CR, 9 PR, 1 PD).  
 
In addition to these patients enrolled on prospective clinical trials, an adult with 
AML harboring an ETV6-NTRK2 fusion achieved a partial response to 
compassionate access larotrectinib.34 
 
Based on these data, the US Food and Drug Administration (FDA) approved 
larotrectinib for the treatment of adult and pediatric patients with solid tumors that 
have a neurotrophin receptor tyrosine kinase (NTRK) gene fusion without a known 
acquired resistance mutation, are metastatic or where surgical resection is likely to 
result in severe morbidity, and have no satisfactory alternative treatments or that 
have progressed following treatment.  
 
 
2.4 
Pediatric Studies 
 
2.4.1 
Pediatric Phase 1 Studies 
A pediatric phase 1/2 study of larotrectinib is ongoing.  The phase 1 dose escalation 
component of this study has now completed enrollment and has been published.1 
This study used a modified rolling 6 design and enrolled children > 1 month to 21 
years of age.  Patients were treated with larotrectinib oral suspension or capsules.  
As of July 17, 2017, 24 patients with a median age of 4.5 years (0.1 – 18 years) 
have enrolled to 3 dose levels.1 The most common diagnoses were infantile 
fibrosarcoma (n=8) and other soft tissue sarcoma (n=7). 17 patients had TRK 
fusions. The most common drug related AEs were generally mild increases in liver 
enzyme levels (AST and ALT in 10 [42%] of 24 patients each, 8 [33%] Grade 1), 
hematological toxicity (leukocyte count decreased and neutrophil count decreased 
in 5 [21%] of patients each) and vomiting in 5 (21%) of patients. Fatigue was 
observed in 3 (13%) of 24 patients; other neurological toxicities were rarely seen. 
Grade 3 treatment-related adverse events occurred in 4 (17%) of 24 patients: 1 each 
of ALT elevation, nausea, neutropenia, and ejection fraction decreased.  No other 
cardiotoxicity was seen in the pediatric phase 1 study or on the adult phase 1 or 2 
studies.  There were no drug related Grade 4 or 5 adverse events. One DLT (Grade 
3 ALT elevation in a patient with neuroblastoma without a TRK fusion) occurred 
at dose level 3 which led to larotrectinib discontinuation.  No other patients 
discontinued larotrectinib for adverse events and a MTD was not identified.  One 
patient had dose reduction for Grade 3 neutropenia in cycle 2.  A recommended 
phase 2 dose of 100 mg/m2/dose BID with a maximum of 100 mg/dose was 
identified based on pharmacokinetics, response, and safety of this dose level.  As 
of July 17, 2017, 22 patients were evaluable for response.  Fourteen of the 15 (93%) 
evaluable patients with TRK fusions had PR (n=10) or CR (n=4). Responses were 
seen in patients with fusions involving each of the 3 NTRK genes and in patients 
with both infantile fibrosarcoma and other sarcomas. Responses were seen at all 
dose levels, but due to intrapatient dose escalation, only 3 patients with TRK fusion 
tumors were treated with larotrectinib at doses of less than 80% of the 
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cancer enrolled on study.  Neither had measurable disease at enrollment.  Both 
experienced a reduction in tumor burden (SD by RECIST) and remain on study.  
With a median follow-up of 8.2 months, only 3 patients with TRK fusions have 
discontinued larotrectinib.  Two of these patients had responses that enabled 
complete surgical resections with negative margins and continue to be followed on 
study but off larotrectinib without recurrence.  Only 1 of 15 patients with a TRK 
fusion has progressed on therapy to date with the development of a pG623R 
solvent front resistance mutation in NTRK3. A second patient who electively 
stopped larotrectinib after 12 cycles of therapy with a PR and without surgical 
resection of tumor demonstrated progressive disease off larotrectinib. This patient 
restarted larotrectinib and responded again. No responses were seen in patients 
without TRK fusion (n=7). 
 
Responses to larotrectinib in children have been very rapid, with a median time to 
first RECIST response among patients with measurable disease of 1.7 months, 
consistent with the first protocol mandated response assessment.  In patients whose 
tumors could be evaluated by physical exam, reductions in tumor size were 
apparent in some patients within days of starting larotrectinib. Of the 15 patients 
with TRK fusions and measurable disease, 12 (80%) had a RECIST response by 
imaging within 4 months of starting larotrectinib.  Therefore, we believe that 
evaluating the best response within the first six 28-day cycles of therapy will 
provide a good assessment of the activity of larotrectinib in the upfront setting. 
 
Five children with locally advanced sarcoma (IFS, n=3; other soft tissue sarcoma, 
n=2) achieved partial responses to therapy with larotrectinib by imaging and 
underwent on-study resection on the pediatric phase 1 study. Patients received a 
median of 6 cycles of larotrectinib (range: 4-9 cycles) before surgery. Per protocol, 
larotrectinib was held for 24 hours prior to surgery. Two of these patients had 
pathological clear margins and discontinued larotrectinib. One of these patients 
had no viable tumor on microscopic examination and was reclassified as a 
pathological complete response. Both patients with negative margin resections 
continue to be followed on-study without recurrence; now more than 6 months off 
larotrectinib. A third patient had an R1 resection with no viable tumor seen and 
also remains in active follow-up more than 6 months off larotrectinib. The other 
two patients had marginal or gross residual disease after surgery and remain on 
therapy with larotrectinib. There were no post-operative or wound healing 
complications observed in these patients. 
 
In addition to the ongoing clinical trials in children and adults, larotrectinib has 
been provided to some patients on a compassionate access basis. A 14-year old girl 
from Bangladesh with secretory carcinoma of the breast harboring an ETV6-
NTRK3 fusion received compassionate access larotrectinib and had a near 
complete response to therapy.37  A 3 year old child with an ETV6-NTRK3 fusion 
high grade glioma also had a near complete response to compassionate access 
larotrectinib.38  
 
Based on these data, the US Food and Drug Administration (FDA) approved 
larotrectinib for the treatment of adult and pediatric patients with solid tumors that 
have a neurotrophin receptor tyrosine kinase (NTRK) gene fusion without a known 
acquired resistance mutation, are metastatic or where surgical resection is likely to 

  
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result in severe morbidity, and have no satisfactory alternative treatments or that 
have progressed following treatment.  
 
Larotrectinib is included in the Pediatric MATCH study (APEC1621A) for 
children with recurrent disease and a documented TRK fusion. The Phase 2 portion 
of the Loxo Oncology sponsored phase 1/2 trial is ongoing.  Both of these studies 
will provide additional pediatric data with this agent. 
 
No clinical trials have evaluated larotrectinib in patients with leukemia.  
 
2.4.2 
Pharmacology/Pharmacokinetics/Correlative Biological Studies 
The pharmacokinetics of larotrectinib have been evaluated in pediatric and adult 
patients enrolled on the clinical trials described in Section 2.3.1 and Section 2.4.1 
(see Figure 1).  These studies have demonstrated rapid absorption of larotrectinib 
after an oral dose, dose proportional increase in Cmax and AUC, and a half-life of 
approximately 2 hours with no accumulation with continued BID dosing.   
 
 
 
The pediatric recommended phase 2 dose was chosen because pharmacokinetic 
studies demonstrated similar Cmax and AUC between children treated at a dose of 
100 mg/m2 and adults treated at the recommended phase 2 dose of 100 mg. Given 
the very high response rate in patients with TRK fusion tumors, it has not been 
possible to define a dose-efficacy relationship for larotrectinib.  
 
Exposure at a dose of 100 mg/m2 is consistent across the pediatric age range. 
Patients enrolled to the pediatric phase 1 study were age 31 days to 18 years.  When 
patients were separated by age: <2 years (n=6), 2-11 years (n=9), and 12-18 years 
(n=5), a dose of 100 mg/m2 provided an AUC comparable to adults treated at the 
recommended phase 2 dose of 100 mg in each cohort. The ongoing Loxo Oncology 
sponsored phase 1/2 pediatric trial has been amended to allow newborns to enroll, 
providing additional information to span the entire age range proposed for this trial.  
Figure 11: Larotrectinib pharmacokinetics in 
children (peds) and adults. 

  
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CSF larotrectinib concentrations were determined in two patients who had 
standard of care CSF sampling while on the pediatric phase 1 study.  In both 
patients larotrectinib was detectable in the CSF with CSF:plasma concentrations 
of 8% (28% after correcting for protein binding) and 123%. 
 
2.5 
Overview of Proposed Pediatric Phase 2 Trial 
This is a non-randomized study evaluating the objective response rate (ORR) of 
larotrectinib in patients with IFS and other TRK fusion solid tumors, including CNS tumors 
other than high grade gliomas (HGG). Patients will be treated with larotrectinib at the 
established pediatric phase 2 dose of 100 mg/m2/dose BID with a cap of 100 mg/dose in 
28-day cycles.  
 
The primary analytic cohort will be newly diagnosed or previously untreated patients with 
unresectable infantile fibrosarcoma (IFS).  Secondary cohorts, which will not be included 
in the analysis of the primary objective, will enroll patients with any other newly diagnosed 
TRK fusion solid tumor except HGG, and patients with relapsed/refractory TRK fusion 
acute leukemia. Patients with HGG are excluded as they have potentially curative therapy 
options available with resection and chemotherapy, and there is less data available on the 
activity of larotrectinib in such patients.  
 
A key objective of this study is to avoid morbidity from aggressive attempts at surgical 
resection.  However, given the <25% chance of recurrence for patients with completely 
resected IFS and CMN in prior studies, patients who are able to undergo complete resection 
without predicted functional, neurologic, or significant cosmetic impairment will not be 
eligible.23, 24, 27  Patients who relapse after surgery alone, without prior systemic therapy, 
will be eligible at that time. 
 
Given the high response rate seen in the relapsed setting in children with solid tumors, we 
anticipate a high ORR to larotrectinib that will enable surgical resection without predicted 
functional, neurologic, or significant cosmetic impairment in many of these patients. 
Surgical resection of patients with localized, resectable tumors will be performed after at 
least 6 cycles of therapy. Patients who achieve a complete resection (with negative margins 
for patients with diagnoses other than IFS and CMN) will be observed on protocol without 
further therapy unless they experience recurrence.   
 
Patients with metastatic disease, those whose tumors don’t become amenable to resection, 
and those with residual disease following an attempted surgical resection will continue 
larotrectinib for up to 26 cycles (approximately 2 years) on this protocol. Such patients will 
subsequently complete planned therapy and enter Follow-up. Patients who are continuing 
to experience benefit from larotrectinib at the completion of 26 cycles of therapy and for 
whom their treating physician determines it is not in their best interest to discontinue 
therapy and be observed may be able to continue treatment utilizing commercial supply (if 
approved by the local health authority), an expanded access protocol, or single patient 
protocol as appropriate and available at that time. 
 
Patients with localized disease who achieve a complete response to therapy will continue 
receiving larotrectinib for a minimum of 12 cycles (approximately 1 year) or 6 cycles after 
achieving the complete response (whichever is later).  Subsequently, such patients will be 
observed on study off of therapy unless they experience recurrence. 

  
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Patients with TRK fusion leukemias have not been included on any clinical trials of 
larotrectinib.  However, we hypothesize there will be a high level of activity in such 
patients based on the responses seen in patients with TRK fusion solid tumors, the partial 
response reported in an adult with an NTRK2 fusion AML, and the responses to kinase 
inhibition seen in children and adults with leukemias harboring BCR-ABL fusions. Children 
with relapsed/refractory leukemias with TRK fusions will be treated with larotrectinib at 
the established pediatric phase 2 dose of 100 mg/m2/dose BID with a cap of 100 mg/dose.  
Following 1 cycle (28 days) of this therapy, patients will undergo a disease evaluation to 
assess response.  Patients without progressive disease may continue to receive larotrectinib 
at their treating physician’s discretion for a maximum of 26 cycles. 
 
This is a non-randomized study given the high response rate seen in the relapsed setting 
and rarity of the patient population.  With an expected enrollment of ~6-8 patients with IFS 
per year, a randomized study with sufficient power to show equivalence or superiority of 
larotrectinib to standard of care chemotherapy is not feasible within a reasonable accrual 
timeframe. 
 
The FDA approved larotrectinib during the course of the study, but the study will proceed 
as written.  
 
2.6 
Rationale for Correlative Biology Studies 
 
2.6.1 
Central Next Generation Sequencing  
Primary and secondary resistance to larotrectinib in the context of documented 
TRK fusion appears to be a rare occurrence.1, 36, 39  In order to understand 
mechanisms of resistance, archival tumor material will be obtained for next 
generation sequencing to evaluate for the presence of TRK fusions in a central 
laboratory, clonal or subclonal resistance mutations at initial diagnosis and, for 
patients who have follow-up tissue obtained, following treatment with 
larotrectinib. 
 
2.6.2 
Central Pathology Review and TRK Immunohistochemistry  
Given the high response rate of larotrectinib in the context of TRK fusions, 
identifying patients with tumors harboring these fusions is a high priority.  To 
improve early recognition of these tumors, we will include a retrospective 
pathology review of diagnostic material to better define the pathologic features of 
this group of tumors. While FISH and sequencing approaches are the current 
standard approach, turnaround times may pose clinical challenges. Therefore, 
archival tumor material will be used to perform immunohistochemistry for TRK 
proteins to understand the performance characteristics of this assay in the context 
of TRK fusions. Similarly, little is known about histologic tumor response post-
neoadjuvant larotrectinib. Retrospective pathology review to describe patterns of 
response (i.e., necrosis, fibrosis, maturation) and correlation with radiographic 
response is critical. Pan-TRK immunohistochemistry may be informative as to 
whether single tumor cells remain in a largely necrotic post-treatment specimen 
and to inform patterns of response with consideration to margin status and disease 
recurrence. 
 

  
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2.6.3 
Circulating Tumor DNA  
Novel approaches to detect circulating tumor DNA (ctDNA) may enable a method 
of minimally invasive detection of TRK fusions at diagnosis, quantification of 
disease burden over time, and a tool to interrogate the somatic cancer genome 
serially in response to selective pressure of targeted therapies. Resistance 
mutations in NTRK genes have been detected in ctDNA in patients in TRK fusion 
solid tumors treated with larotrectinib who progressed after initial response.36  
Similarly, detection of circulating tumor DNA has been reported in children with 
other newly diagnosed fusion driven cancers, with a rapid fall in response to 
treatment and increase at the time of relapse,1, 40, 41 and patients with Ewing 
sarcoma and detectable ctDNA have worse outcomes.  
 
In the current study, ctDNA samples will be collected at baseline to quantify and 
characterize the ability to detect TRK fusions in this population. Serial samples 
will be collected after 2 weeks , 4 weeks, and 24 weeks of treatment (prior to local 
control) to quantify and characterize the kinetics of the change in ctDNA in 
response to larotrectinib therapy. Finally, samples will be obtained at the time of 
discontinuation of larotrectinib therapy and at progression to evaluate mechanisms 
of resistance to treatment. Each ctDNA collection time point occurring after the 
start of therapy can be collected within 72 hours, for any minor and unavoidable 
issues that prevent ctDNA being collected at the specified time points as listed in 
Section 7.3.2 and Appendix IV.    
 
2.7 
Rationale for Neurocognitive Studies 
Studies inducing genetic knock-out of each of the NTRK genes in mice embryos have 
shown CNS developmental abnormalities consistent with the role of neurotrophin growth 
factors and their receptors in embryonic development of the brain and nervous system.42-44  
Similarly, humans with germline genetic loss of NTRK1 or NTRK2 demonstrate 
developmental delay.45, 46 The severe effects of NTRK gene loss appear to be primarily 
limited to the developing nervous system in utero.  To date, central nervous system side 
effects reported on clinical trials of larotrectinib have been generally mild and primarily 
consisted of fatigue and dizziness.36  No larotrectinib-related neurodevelopmental concerns 
have been reported, despite treating infants as young as 1 month of age and treating some 
children for > 2 years. However, prior studies of larotrectinib have not included formal 
neuropsychiatric testing.  Given the presence of TRK fusion cancers in young infants and 
the high response rate and durable responses observed with larotrectinib to date, there is a 
strong potential for young children to be treated with larotrectinib for months to years on 
this protocol.  Therefore, formal neurocognitive assessments will be performed from 
baseline to 5 years after enrollment on this study to better evaluate developmental 
outcomes. 
 
2.7.1 
Rationale for Extending Neurocognitive Assessments until 5 Years after 
Enrollment 
ADVL1823 has now completed accrual and demonstrated that larotrectinib was 
highly active in patients with newly diagnosed infantile fibrosarcoma and other 
NTRK-fusion positive sarcomas.47ADVL1823 incorporated neurocognitive 
assessments for the first 2 years after enrollment. Compliance with these 
assessments has been high, but given the young age of patients enrolled to this 
study (median age at enrollment was 8 months), there are limitations in the ability 
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enrollment, as the median age of patients at this timepoint is < 3 years.  As such, 
we will add an additional timepoint for assessment of neurocognitive outcomes at 
4-5 years after enrollment (prior to the 5th anniversary at which point patients are 
off study). We have included a relatively broad time window to simplify data 
collection during a routine visit for these patients, many of whom may not be 
receiving any therapy. 
 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies 
open to the National Clinical Trials Network (NCTN) and NCI Community 
Oncology Research Program (NCORP) Research Bases. In addition, U.S.-based 
sites must accept the NCI CIRB review to activate new studies at the site after 
March 1, 2019. Local IRB review will continue to be accepted for studies that are 
not reviewed by the CIRB, or if the study was previously open at the site under the 
local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
 

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

  
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1-866-651-CTSU (2878), or CTSURegHelp@coccg.org in order to receive further 
instruction and support. For general (non-regulatory) questions call the CTSU 
General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating in 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.  
 
3.1.3 
Reservation Requirements  
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system. Patients must 
be enrolled within 5 calendar days of making a reservation. 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with patient enrollment in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the patient. 
Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘Slot Reservation Site User Guide’ posted under the ‘Help’ tab in 
OPEN for detailed instructions:  
https://www.ctsu.org/open/Site_Resources/Training/Users_Manual/CTSU-
OPEN-SlotReservationSiteUserGuide.pdf 
 
3.1.4 
Study Enrollment 
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 LPOs’ registration/randomization systems or the Theradex 
Interactive 
Web 
Response 
System 
(IWRS) 
for 
retrieval 
of 
patient 
registration/randomization assignment. OPEN will populate the patient enrollment 
data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   

  
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• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems;  
• 
To perform enrollments or request slot reservations:  Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an Associate 
Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars 
must hold the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the Institutional Review Board (IRB) number 
used on the site’s IRB approval on their Form Food and Drug Administration 
(FDA) 1572 in the Registration and Credential Repository (RCR). If a DTL is 
required for the study, the IVR or NPIVR must be assigned the appropriate OPEN-
related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; 
and  
• 
All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of the 
CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional 
questions, 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. Patients who are started on protocol therapy prior to study 
enrollment will be considered ineligible and will not be able to receive further 
protocol therapy. The only exception to this is for intrathecal methotrexate, 
intrathecal cytarabine, or intrathecal triples, which can be given within 1 week 
prior to the patient’s first dose of larotrectinib for patients on Part C ONLY. If 
intrathecal methotrexate, intrathecal cytarabine, or intrathecal triples are given 
prior to enrollment, a separate institutional consent must be obtained.  
 
See Section 3.2 for timing requirements for eligibility studies. Note: Repeat 
laboratory and imaging studies may be required if obtained prior to the 
protocol mandated window. 
 

  
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3.1.6 
Pathology and Molecular Diagnostic Report 
Immediately following enrollment, the pathology report for the diagnosis under 
which the patient is being enrolled and molecular diagnostic (FISH, PCR, or NGS) 
report confirming the presence of a TRK fusion must be uploaded into Rave. In 
addition, pathology reports (including reports of surgical margins) from any 
surgical procedures including tumor resections or tumor/metastatic/recurrent site 
biopsies done while the patient is on study must be uploaded into RAVE.  The 
reports must include the associated study number and COG patient registration and 
accession numbers. Personal identifiers, including the patient’s name and initials 
must be removed from the reports prior to submission.  
 
3.1.7 
Neurocognitive, Behavioral, and QoL Assessments  
Parent-report measures of neurocognitive, behavioral, and QoL functioning are 
required to be completed at 4 separate time points: (1) within 4 weeks after 
enrollment; (2) 6 months ( 4 weeks) after enrollment; (3) 12 months ( 4 weeks) 
after enrollment; (4) 24 months ( 4 weeks), and (5) 4-5 years after enrollment. 
The appropriate packet of measures will be mailed to the site CRA prior to each 
assessment window, once a patient has been enrolled on study.  Please see 
Appendix XI for further details. 
 
At least one parent or guardian must have receptive and expressive language skills 
in English to complete the parent-reported neurocognitive, behavioral, and QoL 
assessments (See Appendix XI). Patients who do not meet these criteria are still 
eligible to enroll on study, but will not complete the neurocognitive, behavioral and 
QoL assessments.  
 
 
3.2 
Eligibility: Inclusion Criteria  
 
Important note: The inclusion criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record. These source documents must be available for verification at the time of audit.  
 
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 > 7 days old, 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 and bone marrow biopsy and/or 
aspirate, if applicable, must be obtained within 28 days prior to start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
3.2.1 
Age:  Patients must be  30 years of age at the time of study entry. 
 

  
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3.2.2 
Diagnosis:  
i. 
Cohort A: Patients must have a histologic diagnosis of infantile 
fibrosarcoma with an NTRK1, NTRK2, or NTRK3 fusion identified in a 
CLIA/CAP certified laboratory. Fusions may be identified by FISH or 
molecular techniques (RT-PCR using primers flanking the fusion junction or 
next generation sequencing). For fusions identified by FISH, an ETV6 
rearrangement is sufficient for eligibility in Cohort A. Identification of the 
upstream TRK fusion partner is not required. 
 
ii. Cohort B: Patients must have a histologic diagnosis of any solid tumor 
other than infantile fibrosarcoma, including CNS tumors but excluding high 
grade gliomas. An NTRK1, NTRK2, or NTRK3 fusion must be identified in a 
CLIA/CAP certified laboratory. Fusions may be identified by FISH or 
molecular techniques (RT-PCR using primers flanking the fusion junction or 
next generation sequencing). For fusions identified by FISH, there must be an 
identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 
rearrangement is not sufficient for eligibility) unless the patient has a diagnosis 
of congenital mesoblastic nephroma in which case an ETV6 rearrangement is 
sufficient for eligibility. Identification of the upstream TRK fusion partner is 
not required.  
 
iii. Cohort C: Patients must have a histologic diagnosis of relapsed or 
refractory acute leukemia with an NTRK1, NTRK2, or NTRK3 fusion identified 
in a CLIA/CAP certified laboratory. Fusions may be identified by FISH or 
molecular techniques (RT-PCR using primers flanking the fusion junction or 
next generation sequencing). For fusions identified by FISH, there must be an 
identified rearrangement in NTRK1, NTRK2, or NTRK3 (e.g., an ETV6 
rearrangement is not sufficient for eligibility). Identification of the upstream 
TRK fusion partner is not required.  
 
 
3.2.3 
Disease Status  
i. 
Solid Tumors (Cohorts A & B): Patients must have measurable disease 
(see Section 10.3.1 for definition). Patients must have disease that cannot be 
completely resected without a predicted functional, neurologic, or significant 
cosmetic deficit in the opinion of the investigator.   
 
ii. Leukemia (Cohort C): Patients must have > 5% blasts in the bone marrow. 
Extramedullary disease is permitted. 
 
3.2.4 
Performance Level  
Patients must have a Lansky or Karnofsky performance status score of ≥ 50, 
corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients > 16 years 
of age and Lansky for patients ≤ 16 years of age. NOTE: Neurologic deficits in 
patients with CNS tumors must have been stable for at least 7 days prior to study 
enrollment. Patients who are unable to walk because of paralysis, but who are up 
in a wheelchair, will be considered ambulatory for the purpose of assessing the 
performance score. 
(See Appendix IX) 
 

  
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3.2.5 
Prior Therapy 
▪ 
Cohorts A & B: No prior anti-cancer therapy, including radiotherapy, other than 
surgical resection is permitted.  
o Patients who experience recurrence after surgery alone and no 
other anti-cancer therapy will be eligible. 
o If not eligible due to prior anticancer therapy, patients may be 
eligible for the larotrectinib arm of Pediatric MATCH 
(APEC1621A) or treatment with commercial larotrectinib off 
study.  
 
▪ 
Cohort C: The following apply to patients with relapsed/refractory leukemia:  
 
3.2.5.1 
Patients with relapsed leukemia (Cohort C) 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 DVL homepage for the Myelosuppressive, 
Non-Myelosuppressive, and Antibody Anti-Cancer Agents table 
(https://cogmembers.org/Site/Disc/DevTherapeutics/Default.aspx). 
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. 
• 
A waiting period prior to enrollment is not required for 
patients receiving standard cytotoxic maintenance 
chemotherapy (i.e., corticosteroid, vincristine, 6MP, 
and/or methotrexate). 
• 
A waiting period is not required for patients receiving a 
single dose of intrathecal methotrexate, hydrocortisone, 
and/or cytarabine within 7 days prior to enrollment 
• 
≥ 14 days must have elapsed after the completion of other 
cytotoxic therapy, with the exception of hydroxyurea, for 
patients not receiving standard maintenance therapy. 
Additionally, patients must have fully recovered from all 
acute toxic effects of prior therapy. 
 
Note: Cytoreduction with hydroxyurea must be discontinued 
≥ 24 hours prior to the start of protocol therapy. 
  
 
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 DVL homepage for the Myelosuppresive, Non-
Myelosuppressive, 
and 
Antibody 
Anti-Cancer 
Agents 
table 
(https://cogmembers.org/Site/Disc/DevTherapeutics/Default.aspx). 
For agents not listed, the duration of this interval must be discussed 
with the study chair and the study-assigned Research Coordinator 

  
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prior to enrollment.  
 
c. Anti-cancer agents that are 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. There is an 
exception for blinatumomab infusions, for which patients must have 
been off for at least 3 days and all drug related toxicity must have 
resolved to Grade 2 or lower as outlined in the inclusion/exclusion 
criteria. See DVL Homepage for the Myelosuppressive, Non-
Myelosuppressive, 
and 
Antibody 
Anti-Cancer 
Agents 
table 
(https://cogmembers.org/Site/Disc/DevTherapeutics/Default.aspx).  
 
d. Corticosteroids: See Section 3.3.2.1. If used to modify immune 
adverse events related to prior therapy, ≥ 14 days must have elapsed 
since last dose of corticosteroid. A waiting period prior to enrollment 
is not required for patients receiving corticosteroid for leukemia 
therapy/cytoreduction.  
 
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 agents that have known adverse events occurring 
beyond 7 days after administration, this period must be extended 
beyond the time during which adverse events are known to occur.  The 
duration of this interval must be discussed with the study chair and the 
study-assigned Research Coordinator. 
 
f. Interleukins, Interferons and Cytokines (other than Hematopoietic 
Growth Factors): ≥ 21 days after the completion of interleukins, 
interferon or cytokines (other than Hematopoietic Growth Factors ) 
 
g. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 
days after infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion:  ≥ 42 
days. 
 
h. Cellular Therapy: ≥ 42 days after the completion of any type of 
cellular therapy (e.g., modified T cells, NK cells, dendritic cells, etc.) 
 
i. 
XRT/External Beam Irradiation including Protons: ≥ 14 days after 
local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to 
 50% of the pelvis; ≥ 42 days if other substantial BM radiation. 
 
j. 
Radiopharmaceutical therapy (e.g., radiolabeled antibody): ≥ 42 days 
after systemically administered radiopharmaceutical therapy. 
 
k. Patients must not have received prior exposure to TRK inhibitors 
(including larotrectinib, LOXO-195, entrectinib, lorlatinib, crizotinib, 

  
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or lestaurtinib). 
 
 
3.2.6 
Organ Function Requirements 
 
3.2.6.1 
Adequate Bone Marrow Function Defined As: 
a. For patients with solid tumors without known bone marrow   
involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, 
defined as not receiving platelet transfusions for at least 7 days  
prior to enrollment) 
- 
Hemoglobin  8.0 g/dL at baseline (may receive RBC 
transfusions) 
 
b. Patients with solid tumors with known bone marrow metastatic 
disease will be eligible for study provided they meet the blood counts 
in Section 3.2.6.1.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. 
 
c. For patients with leukemia: 
- 
Platelet count  20,000/mm3 (may receive platelet transfusions).  
- 
Hemoglobin  8.0 g/dL at baseline (may receive RBC 
transfusions) 
- 
These patients must not be known to be refractory to red cell or 
platelet transfusion.  
 
3.2.6.2 
Adequate Renal Function Defined As: 
a. Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or a 
serum creatinine based on age/sex as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
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.48 
• 
For patients <1 month of age, serum creatinine levels must be 
<1.5x the treating institution’s creatinine ULN for patients <1 
month of age or the creatinine clearance or radioisotope GFR must 
be > 70 mL/min/1.73 m2.  
 

  
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3.2.6.3 
Adequate Liver Function Defined As: 
 
 
 
 
i.       Patients with solid tumors: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper 
limit of normal (ULN) for age. After approval of the study 
chair or designee, infants with a higher total bilirubin due to 
physiologic or breast milk jaundice are eligible if the 
conjugated (direct) bilirubin is < 2 mg/dL. 
- 
SGPT (ALT) ≤ 135 U/L. For the purpose of this study, the 
ULN for SGPT is 45 U/L. 
- 
Serum albumin ≥ 2 g/dL.  
                                           
ii. 
Patients with leukemias: 
- 
Conjugated (direct) bilirubin   1.5 x upper limit of normal 
(ULN) for age.  
- 
SGPT (ALT)  225 U/L.  For the purpose of this study, the 
ULN for SGPT is 45 U/L.  
- 
Serum albumin  2 g/dL. 
 
3.2.6.4 
Central Nervous System Function Defined As: 
- 
Patients 
with 
seizure 
disorder 
may 
be 
enrolled 
if 
on                           
a stable antiepileptic regimen for > 14 days and well controlled. 
-    Nervous system disorders (CTCAE v5) except tendon reflex 
decreased resulting from prior therapy must be  Grade 2. 
 
 
3.3 
Eligibility: Exclusion Criteria 
 
Important note: The exclusion criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record. These source documents must be available for verification at the time of audit.  
 
3.3.1 
Pregnancy or Breast-Feeding 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal/human studies, OR because 
there is yet no available information regarding human fetal or teratogenic 
toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. 
Female patients of reproductive potential may not participate unless they have 
agreed to use a highly effective contraceptive method for the duration of study 
therapy and for at least one month after the final dose of larotrectinib. Males of 
reproductive potential with a non-pregnant female partner of child-bearing 
potential must use a highly effective contraception for the duration of the study 
and for at least one month after the final dose of larotrectinib.  
 
Because of the unknown risk of larotrectinib in nursing infants, nursing women 
should discontinue breastfeeding during treatment with larotrectinib and for 3 days 
following the final dose.  
 

  
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3.3.2 
Concomitant Medications:  
3.3.2.1 
Corticosteroids:  Patients with solid tumors, including CNS tumors, 
requiring corticosteroids who have not been on a stable or decreasing 
dose of corticosteroid for at least 7 days prior to enrollment are not 
eligible. Patients with leukemia may receive systemic corticosteroids for 
cytoreduction up to 24 hours prior to the start of protocol therapy. If used 
to modify immune adverse events related to prior therapy, ≥ 14 days 
must have elapsed since last dose of corticosteroid.  
 
3.3.2.2 
Investigational Drugs: Patients who are currently receiving another 
investigational drug are not eligible. 
 
3.3.2.3 
Anti-cancer Agents:  Patients who are currently receiving other anti-
cancer agents are not eligible [except leukemia patients receiving 
corticosteroids or hydroxyurea, which may be continued until 24 hours 
prior to start of protocol therapy]. Patients with leukemia should receive 
a single dose of intrathecal cytarabine, hydrocortisone, and/or 
methotrexate within 7 days prior to Day 1 of Cycle 1 at the time of the 
baseline lumbar puncture. 
 
3.3.2.4 
Anti-GVHD agents post-transplant: Patients who are receiving 
cyclosporine, tacrolimus or other agents to prevent graft-versus-host 
disease post bone marrow transplant are not eligible for this trial. 
 
3.3.2.5 
CYP3A4 Inducers/Inhibitors: Patients currently receiving a strong 
CYP3A4 inducer or inhibitor are not eligible (see Appendix VI). Strong 
inducers or inhibitors of CYP3A4 should be avoided from 14 days prior 
to enrollment to the end of the study. Note: CYP3A4 inducing anti-
epileptic drugs and dexamethasone for CNS tumors or metastases, on a 
stable dose, are allowed.  
 
3.3.3 
Malabsorption:  
Patients with malabsorption syndrome or other conditions that significantly limit 
enteral absorption are not eligible.  
 
3.3.4 
Swallow or Gastric Access: 
Patients who are unable to swallow capsules or liquid and do not have gastric 
access via a nasogastric or gastrostomy tube are not eligible.  
 
3.3.5 
Infection:  
 Patients who have an uncontrolled infection are not eligible. 
 
3.3.6 
Solid Organ Transplant: 
Patients who have received prior solid organ transplantation are not eligible.  
 
3.3.7 
Safety Monitoring:  
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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3.3.8 
Diagnosis:  
Patients with High Grade Gliomas (HGG) are not eligible.  
 
 
3.4 
Regulatory 
 
3.4.1 
All patients and/or their parents or legal guardians must sign a written informed 
consent. 
 
3.4.2 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
  
 

  
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4.0 
TREATMENT PROGRAM 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations for valid clinical, patient and family logistical, or facility, procedure 
and/or anesthesia scheduling issues are acceptable (except where explicitly prohibited within the 
protocol). 
4.1 
Overview of Treatment Plan 
 
Treatment Schedule 
Days 1 – 28 
Larotrectinib 100 mg/m2/dose 
orally/NG/G-tube twice daily 
(maximum 100 mg/dose BID) 
Day 28 
End of Cycle 
 
This is an open label study of larotrectinib administered at 100 mg/m2/dose PO BID 
(maximum of 100 mg/dose BID) on a continuous dosing schedule (one cycle = 28 days). 
Dosing will be performed based on body surface area (BSA) for patients of all ages and 
may be administered as a capsule or liquid formulation.  Patients with infantile 
fibrosarcoma will be enrolled in Cohort A, the primary analytic cohort.  Patients with all 
other TRK fusion solid tumors will be enrolled in Cohort B.  Patients with 
relapsed/refractory TRK fusion leukemia will be enrolled in Cohort C. 
 
Patients with solid tumors who meet the criteria described in Section 4.3.3 may stop 
larotrectinib while continuing on study in the Follow-up Period. All other patients will 
continue therapy until tumor progression or unacceptable toxicity for a maximum of 26 
cycles, after which they will also enter the Follow-up Period. 
 
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 X-A for capsule and Appendix X-B for liquid formulations). 
Only use larotrectinib provided for investigational use specifically for ADVL1823.   
 
4.1.1 
Dose Reduction 
Up to three dose reductions of larotrectinib will be allowed for dose limiting 
toxicities as outlined in Section 5.0 for patients who recover and meet starting 
criteria as outlined in Section 3.2.6 within 21 days following drug discontinuation: 
• 
1st dose reduction: 75 mg/m2/dose BID (maximum of 75 mg/dose BID)  
• 
2nd dose reduction: 50 mg/m2/dose BID (maximum of 50 mg/dose BID) 
• 
3rd dose reduction: 25 mg/m2/dose BID (maximum of 25 mg/dose BID) 
 
Patients who do not recover to meet starting criteria within 21 days will be 
removed from protocol therapy. Patients who experience DLT as outlined in 
Section 5.0 after three dose reductions will be removed from protocol therapy.  
 

  
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4.1.2 
Dose Escalation 
There will be no drug dose escalation except for those based on growth of the 
patient to maintain the same dose on a mg/m2 basis. The dose of larotrectinib 
should be recalculated at the start of each cycle based on a recent (within 7 days) 
height and weight.  
 
4.1.3 
Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days, up to a maximum of 26 cycles. 
Larotrectinib will be administered continuously without breaks unless the patient 
meets criteria for holding or discontinuing larotrectinib as defined in Section 5.1. 
Patients who experience progressive disease at any time on protocol therapy will 
be taken off therapy. Patients with solid tumors (Cohorts A & B) who do not have 
progressive disease will follow the guidelines outlined in Section 4.1.3.1, Section 
4.1.3.2 and Section 4.1.3.3. 
 
4.1.3.1 
Patients with Localized Disease who Achieve Stable Disease or a Partial 
Response that Renders Disease Resectable:  
Patients with localized disease who achieve sufficient tumor shrinkage 
to have disease resection (for whom a complete resection is anticipated 
to be likely without functional, neurologic, or significant cosmetic 
deficit) will undergo surgical resection of their residual tumor after a 
minimum of 6 cycles of therapy (see Section 13.1 for surgical 
guidelines).  Such patients may receive up to 1 additional cycle of 
therapy after their tumor is deemed resectable during surgical planning.  
Larotrectinib will be held for 24 hours prior to surgery.  Following 
surgery, patients with IFS or CMN who achieve a gross total resection 
and all other patients with solid tumors who achieve a resection with 
negative margins (Section 13.2) will have completed planned therapy 
and enter Follow-up (Section 7.2).  Patients who have an incomplete 
resection or positive margins for diagnoses other than IFS/CMN will 
resume protocol therapy following surgery.  Therapy may be resumed as 
soon as 24 hours post-operatively once it has been determined that the 
patient meets protocol criteria to resume therapy and the patient is 
tolerating enteral fluids. 
 
4.1.3.2 
Patients who Achieve Stable Disease or a Partial Response and Do Not 
Have Localized, Resectable Disease: 
Patients who have stable disease or a partial response and do not have 
localized, resectable disease will continue on larotrectinib therapy for up 
to 26 cycles. This group includes all patients who enroll with metastatic 
disease and do not achieve a complete response. After 26 cycles, such 
patients will have completed planned therapy and enter Follow-up 
(Section 7.2). Patients who are continuing to experience benefit from 
larotrectinib at the completion of 26 cycles of therapy and for whom their 
treating physician determines it is not in their best interest to discontinue 
therapy and be observed may be able to continue treatment utilizing 
commercial supply (if approved by the local health authority), an 
expanded access protocol, or single patient protocol as appropriate and 
available at that time. 
 

  
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ADVL1823 
 
Version Date: 3/03/2025 
 
         37 
 
 
4.1.3.3 
Patients who Achieve a Complete Response:  
Patients who achieve a complete response from only larotrectinib 
therapy (without surgery) will receive 6 additional cycles of therapy after 
achieving CR or a minimum of 12 cycles of therapy (whichever occurs 
later).  Such patients will subsequently have completed planned therapy 
and enter Follow-up (Section 7.2). 
 
4.1.3.4 
Patients with Progressive Disease:  
Patients who have progressive disease at any time will be taken off 
therapy.  
 
4.1.4 
Concomitant Therapy 
 
4.1.4.1 
No other cancer chemotherapy, radiotherapy, immunomodulating 
agents, or biologic therapy will be used. If these treatments are 
administered the patient will be removed from protocol therapy. 
 
4.1.4.2 
CYP3A4 inhibitors or inducers: Strong CYP3A4 inhibitors or inducers 
are prohibited from 14 days prior to enrollment to the end of the study 
(See Appendix VI for list of agents). Note: CYP3A4 inducing anti-
epileptic drugs and dexamethasone for CNS tumors or metastases, on a 
stable dose, are allowed. Avoid grapefruit or grapefruit juice as these 
may also increase plasma concentrations of larotrectinib. 
 
4.1.4.3 
Use caution in patients who are taking concomitant medications that are 
strong inducers or inhibitors of P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP).  
 
4.1.4.4 
Use with caution in patients who are taking concomitant medications that 
are sensitive or narrow therapeutic range substrates of CYP3A4 (see 
Appendix VI). Note: Patient handout on possible drug interactions with 
larotrectinib can be found in Appendix V.  
 
4.1.4.5 
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 or designee should be notified before growth 
factors are initiated.  
 
4.1.4.6 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes 
and general supportive care are to be used as necessary. Refer to COG 
Supportive 
Care 
Guidelines 
at 
https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines or treat per institutional standards.  
 
 
 

  
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         38 
 
 
Cycle 1, Cohorts A & B 
 
4.2 
Cycle 1, Cohorts A & B  
4.2.1    Therapy Delivery Map – Cycle 1, Cohorts A & B 
This Therapy Delivery Map (TDM) relates to Cycle 1 for Cohorts A & B. Each cycle lasts 28 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 4.1.3. Extensive treatment details are in Section 4.2.3.  
This TDM is 5 pages in length. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Larotrectinib 
IND# 141824 
Oral/Nasogastric/Gastrostomy 
Tube 
100 mg/m2/dose BID 
1 – 28 
Maximum dose = 100 mg/dose BID. See Appendix 
X-A and Appendix X-B for dosing nomograms.  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Larotrectinib 
AM dose: ____ mg 
PM dose: ____ mg 
Studies 
 
 
 
Enter calculated dose above and 
actual dose administered below 
 
 
 
Pre- 
      AM Dose                PM Dose 
a – l, n 
 
 
1 
_________ mg    _________ mg 
 
  
 
d 
 
 
2 
_________ mg 
_________ mg 
 
 
 
3 
_________ mg    _________ mg 
 
 
 
4 
_________ mg    _________ mg 
 
 
 
5 
_________ mg    _________ mg 
 
 
 
6 
_________ mg    _________ mg 
 
 
 
7 
_________ mg 
_________ mg 
 
 
 
8 
_________ mg 
_________ mg 
 
d 
 
 
9 
_________ mg 
_________ mg 
 
 
 
10 
_________ mg 
_________ mg 
 
 
 
11 
_________ mg 
_________ mg 
 
 
 
12 
_________ mg 
_________ mg 
 
 
 
13 
_________ mg 
_________ mg 
 
 
 
14 
_________ mg 
_________ mg 
 
 
 
15 
_________ mg 
_________ mg 
 k 
d 
 
 
16 
_________ mg 
_________ mg 
 
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         39 
 
 
Cycle 1, Cohorts A & B 
 
 
17 
_________ mg 
_________ mg 
 
 
 
18 
_________ mg 
_________ mg 
 
 
 
19 
_________ mg 
_________ mg 
 
 
 
20 
_________ mg 
_________ mg 
 
 
 
21 
_________ mg 
_________ mg 
 
 
 
22 
_________ mg 
_________ mg 
 
d 
 
 
23 
_________ mg 
_________ mg 
 
 
 
24 
_________ mg 
_________ mg 
 
 
 
25 
_________ mg 
_________ mg 
 
 
 
26 
_________ mg 
_________ mg 
 
 
 
27 
_________ mg 
_________ mg 
 
 
 
28 
_________ mg 
_________ mg 
m 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 2 of 5 

  
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         40 
 
 
Cycle 1, Cohorts A & B 
 
4.2.2 
Required Observations in Cycle 1, Cohorts A & B 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below.  
 
a.    Hx/Wt /Ht/BSA. Within 7 days prior to Cycle 1.  
b. Performance status. Prior to Cycle 1.  
c. 
Physical exam (including VS and neurologic examination). Prior to Cycle 1.  
d. CBC/diff/platelets: Prior to Cycle 1 and every week during Cycle 1. If patients have 
Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
e. 
Electrolytes including Ca++. Prior to Cycle 1.  
f. 
Creatinine, ALT, bilirubin. Prior to Cycle 1. 
g. Albumin. Prior to Cycle 1. 
h.    Disease evaluation. Prior to Cycle 1. 
i. 
Pregnancy test. Prior to Cycle 1. Female patients of childbearing potential require a 
negative pregnancy test prior to starting treatment; sexually active patients must use an 
acceptable method of birth control. 
j.    Bone marrow evaluation. Prior to Cycle 1. Bone marrow aspirate and/or biopsy 
should only be performed on patients with solid tumors with known bone marrow 
metastasis on the basis of history, symptoms, laboratory evaluation or other clinical 
data.  
k.     Circulating tumor DNA. Prior to Cycle 1 and on Day 15 of Cycle 1. See Section 
7.3.2 for details.  
l.   Tumor tissue submission. Prior to Cycle 1. If tissue blocks or slides are unavailable, 
the study chair must be notified prior to study enrollment. See Section 7.3.1 for 
details. 
m.    Patient diary. Uploaded into RAVE at the end of Cycle 1. See Appendix VII-A and 
Appendix VII-B for details.  
n.    Neurocognitive assessments. Within 4 weeks after enrollment. See Section 3.1.7 and 
Appendix XI for details.  
 
This listing only includes evaluations necessary to answer the primary and secondary aims. OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Page 3 of 5 

  
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         41 
 
 
Cycle 1, Cohorts A & B 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
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ADVL1823 
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         42 
 
 
Cycle 1, Cohorts A & B 
 
4.2.3 
Treatment Details: Cycle 1, Cohorts A & B 
 
Larotrectinib: Oral/Nasogastric/Gastrostomy 
Days: 1 - 28 
Dose: 100 mg/m2/dose BID (maximum of 100 mg/dose BID).  
 
Only use larotrectinib provided for investigational use specifically for ADVL1823.   
 
Note that this study will enroll very young children, but the dose will be based on body surface area for all patients regardless 
of age.  
 
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.  
 
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 X-A).  Doses of larotrectinib capsules should 
be rounded to the nearest 25 mg (Appendix X-A). Calculated dosing volumes of larotrectinib liquid formulation should be 
rounded to the nearest 0.1 mL (2 mg) for doses ≤ 45 mg (in oral syringes ≤ 3 mL) and 0.2 mL (4 mg) for doses > 45 mg (in 
5-10 mL oral syringes) for the actual deliverable dose (Appendix X-B).  
 
All patients taking larotrectinib must complete a patient diary (Appendix VII-A and Appendix VII-B). 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 4.1.3 are met 
(whichever occurs later). Larotrectinib will be administered continuously without breaks between cycles unless the patient 
meets criteria for holding or discontinuing larotrectinib (Section 5.1). 
 
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         43 
 
 
Cycles 2+, Cohorts A & B  
4.3 
Therapy Subsequent to Cycle 1 (Cycles 2+), Cohorts A & B 
4.3.1   Therapy Delivery Map – Cycles 2+, Cohorts A & B 
This Therapy Delivery Map (TDM) relates to Cycles 2+ for Cohorts A & B. Each cycle lasts 28 days. 
Patients may continue on larotrectinib therapy per the guidelines in Section 4.3.3 up to a maximum of 26 
cycles.  
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
Criteria to start each cycle are listed in Section 4.1.3. Extensive treatment details are in Section 4.3.3.  
This TDM is 6 pages in length.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Larotrectinib 
IND# 141824 
Oral/Nasogastric/Gastrostomy 
Tube 
100 mg/m2/dose BID 
1 – 28 
Maximum dose = 100 mg/dose BID. See Appendix 
X-A and Appendix X-B for dosing nomograms.  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
CYCLE # _______ 
 
 
Date Due 
Date 
Given 
Day 
Larotrectinib 
AM dose: ____ mg 
PM dose: ____ mg 
Studies 
 
 
 
Enter calculated dose above and 
actual dose administered below 
 
 
 
Pre- 
      AM Dose                PM Dose 
a – h, i, j, l, m 
 
 
1 
_________ mg 
_________ mg 
i 
 
 
2 
_________ mg 
_________ mg 
 
 
 
3 
_________ mg 
_________ mg 
 
 
 
4 
_________ mg 
_________ mg 
 
 
 
5 
_________ mg 
_________ mg 
 
 
 
6 
_________ mg 
_________ mg 
 
 
 
7 
_________ mg 
_________ mg 
 
 
 
8 
_________ mg 
_________ mg 
 
 
 
9 
_________ mg 
_________ mg 
 
 
 
10 
_________ mg 
_________ mg 
 
 
 
11 
_________ mg 
_________ mg 
 
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         44 
 
 
Cycles 2+, Cohorts A & B  
 
 
12 
_________ mg 
_________ mg 
 
 
 
13 
_________ mg 
_________ mg 
 
 
 
14 
_________ mg 
_________ mg 
 
 
 
15 
_________ mg 
_________ mg 
 
 
 
16 
_________ mg 
_________ mg 
 
 
 
17 
_________ mg 
_________ mg 
 
 
 
18 
_________ mg 
_________ mg 
 
 
 
19 
_________ mg 
_________ mg 
 
 
 
20 
_________ mg 
_________ mg 
 
 
 
21 
_________ mg 
_________ mg 
 
 
 
22 
_________ mg 
_________ mg 
 
 
 
23 
_________ mg 
_________ mg 
 
 
 
24 
_________ mg 
_________ mg 
 
 
 
25 
_________ mg 
_________ mg 
 
 
 
26 
_________ mg 
_________ mg 
 
 
 
27 
_________ mg 
_________ mg 
 
 
 
28 
_________ mg 
_________ mg 
i, k 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  
 
 
 
Page 2 of 6 

  
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ADVL1823 
Version Date: 3/03/2025 
 
         45 
 
 
Cycles 2+, Cohorts A & B  
4.3.2 
Required Observations for Cycles 2+, Cohorts A & B  
a.    Hx/Wt /Ht/BSA. Within 7 days prior to subsequent cycles and at the end of study 
treatment.   
b. Performance status. Prior to subsequent cycles.  
c. 
Physical exam (including VS and neurologic examination). Prior to subsequent 
cycles and at the end of study treatment.   
d. CBC/diff/platelets: Prior to subsequent cycles. If patients have Grade 4 neutropenia 
then CBCs should be checked every 3 to 4 days until recovery to Grade 3 or until 
meeting the criteria for dose limiting toxicity. 
e. 
Electrolytes including Ca++. Prior to subsequent cycles.  
f. 
Creatinine, ALT, bilirubin. Prior to subsequent cycles.  
g.    Disease evaluation. After cycles 2, 4, 6, 9, 12, 16, 20, and 24. 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. 
Please refer to Section 10.4 for Confirmation of objective response by RECIST 1.1. 
h.    Bone marrow evaluation. With Disease evaluation. Bone marrow aspirate and/or 
biopsy should only be performed on patients with solid tumors with bone marrow 
involvement at baseline. If the institutional investigator has determined the patient 
has progressed based on clinical or laboratory evidence, he/she may opt not to 
confirm this finding on marrow pathology.   
i.     Circulating tumor DNA. On Day 1 of Cycle 2, at the end of cycle 6 (Day 1 of Cycle 
7 or prior to local control), and at the time of progression. See Section 7.3.2 for 
details. 
j.     Tumor tissue submission. Submission of tumor tissue from any surgical resection or 
bone marrow evaluation for patients with involvement by tumor while on study is 
required. For patients who undergo resection of their tumor while on study, 
operative reports and hospital discharge summaries must be uploaded into RAVE 
following surgical resection. Submission of tumor tissue from any biopsy after 
progression is optional. See Section 7.3.1 for details.  
k.    Patient diary. Uploaded into RAVE at the end of each cycle. See Appendix VII-A 
and Appendix VII-B for details.  
l.     Pregnancy test. Prior to subsequent cycles. Sexually active patients must use an 
acceptable method of birth control. 
m.   Neurocognitive assessments. 6 months (+ 4 weeks) after enrollment, 12 months (+ 4 
weeks) after enrollment, 24 months (+ 4 weeks), and 4-5 years after enrollment. See 
Section 3.1.7 and Appendix XI for details.  
Page 3 of 6 

  
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ADVL1823 
Version Date: 3/03/2025 
 
         46 
 
 
Cycles 2+, Cohorts A & B  
 
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) 
 
 
 
 
 
Page 4 of 6 

  
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ADVL1823 
Version Date: 3/03/2025 
 
         47 
 
 
Cycles 2+, Cohorts A & B  
4.3.3 
Treatment Details: Cycles 2+, Cohorts A & B 
 
Larotrectinib: Oral/Nasogastric/Gastrostomy 
Days: 1 - 28 
Dose: 100 mg/m2/dose BID (maximum of 100 mg/dose BID).  
 
Only use larotrectinib provided for investigational use specifically for ADVL1823. 
 
Note that this study will enroll very young children, but the dose will be based on body surface area for all patients 
regardless of age.   
 
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.  
 
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 X-A).  Doses of larotrectinib capsules should 
be rounded to the nearest 25 mg (Appendix X-A). Calculated dosing volumes of larotrectinib liquid formulation should be 
rounded to the nearest 0.1 mL (2 mg) for doses ≤ 45 mg (in oral syringes ≤ 3 mL) and 0.2 mL (4 mg) for doses > 45 mg (in 
5-10 mL oral syringes) for the actual deliverable dose (Appendix X-B).  
 
All patients taking larotrectinib must complete a patient diary (Appendix VII-A and Appendix VII-B). 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Patients will have disease evaluation at the end of cycles 2, 4, 6, 9, 12, 16, 20, and 24.  Patients with progressive disease at 
any time will discontinue protocol therapy. 
 
Patients who achieve a complete response will receive 6 additional cycles of therapy after achieving CR or a minimum of 
12 cycles of therapy (whichever occurs later).  Such patients will subsequently enter Follow-up (Section 7.2). 
 
Patients who achieve sufficient tumor shrinkage to have localized, resectable disease (for whom a complete resection is 
anticipated to be likely without predicted functional, neurologic, or significant cosmetic deficit) will undergo surgical 
resection of their residual tumor after a minimum of 6 cycles of therapy. See Section 13.1 for surgical guidelines. Such 
Page 5 of 6 

  
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         48 
 
 
Cycles 2+, Cohorts A & B  
patients may receive up to 1 additional cycle of therapy after their tumor is deemed resectable during surgical planning.  
Larotrectinib will be held for 24 hours prior to surgery. For patients who undergo resection of their tumor while on study, 
operative reports and hospital discharge summaries must be uploaded into RAVE following surgical resection. Following 
surgery, patients with IFS or CMN who achieve a gross total resection and all other patients with solid tumors who 
achieve a resection with negative margins (Section 13.2) will enter Follow-up (Section 7.2).  Patients who have an 
incomplete resection or positive margins for diagnoses other than IFS/CMN (Section 13.2) will resume protocol therapy 
following surgery.  Therapy may be resumed as soon as 24 hours post-operatively once it has been determined that the 
patient meets protocol criteria to resume therapy and the patient is tolerating enteral fluids. 
 
For all other patients, following completion of this cycle, the next cycle starts on Day 29 or when the criteria in Section 
4.1.3 are met (whichever occurs later).  Larotrectinib will be administered continuously without breaks between cycles 
unless the patient has progressive disease or meets criteria for holding or discontinuing larotrectinib (Section 5.1). 
 
 
 
 
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ADVL1823 
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         49 
 
 
Cycle 1, Cohort C 
4.4 
Cycle 1, Cohort C 
4.4.1    Therapy Delivery Map – Cycle 1, Cohort C 
This Therapy Delivery Map (TDM) relates to Cycle 1 for Cohort C. Each cycle lasts 28 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 4.1.3. Extensive treatment details are in Section 4.4.3.  
This TDM is 7 pages in length.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Methotrexate 
 
OR 
 
Cytarabine  
 
OR 
 
Triples 
(methotrexate/ 
hydrocortisone/ 
cytarabine)  
Methotrexate 
 
Intrathecal 
Age (yrs)            Dose 
< 1                    7.5 mg 
1-1.99                8 mg 
2-2.99               10 mg  
3-8.99               12 mg 
> 9                    15 mg 
-7 to -1 
 
 
 
8,  
Patients should receive one dose of 
intrathecal therapy between Days -7 to -1 
at their physician’s discretion. 
 
Day 8  for all patients. Continue weekly 
thereafter ONLY for patients with ALL 
who are CNS 2 (see Section 10.8) at 
enrollment until two consecutive clear 
CSF samples are obtained 
Cytarabine  
Intrathecal 
Age (yrs)           Dose 
< 1                   20 mg  
1-1.99              30 mg 
2-2.99              50 mg 
> 3                   70 mg 
 
-7 to -1 
 
 
 
8, 15, 
22 
Patients should receive one dose of 
intrathecal therapy between Days -7 to -1 
at their physician’s discretion. 
 
Days 8 and weekly thereafter only for 
patients with AML who have positive 
CSF (see Section 10.9) at enrollment 
until two consecutive clear CSF samples 
are obtained. 
Triples 
(methotrexate/ 
hydrocortisone/ 
cytarabine) 
 
Intrathecal 
Age (yrs)             Dose 
< 1                   MTX: 7.5 mg, HC: 7.5 mg, ARAC: 15 mg 
1-1.99              MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2-2.99              MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3-8.99              MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
> 9                 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
-7 to -1 
 
 
 
8, 15, 
22 
Patients should receive one dose of 
intrathecal therapy between Days -7 to -1 
at their physician’s discretion. 
 
Days 8, 15, and 22 only for patients with 
ALL who are CNS 3 (see Section 10.8) 
at enrollment and regardless of whether 
or not the patient clears. Patients who do 
not clear by the end of cycle 1 will be 
removed from protocol therapy.  
Page 1 of 7 

  
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ADVL1823 
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         50 
 
 
Cycle 1, Cohort C 
Larotrectinib 
IND# 141824 
Oral/Nasogastric/
Gastrostomy 
Tube 
100 mg/m2/dose BID 
1 – 28 
Maximum dose = 100 mg/dose BID. See 
Appendix X-A and Appendix X-B for 
dosing nomograms.  
 
 
 
 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date Due 
Date 
Given 
Day 
Larotrectinib 
AM dose: ____ mg 
PM dose: ____ mg 
Methotrexate 
____mg 
Cytarabine 
____mg 
Hydrocortisone 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
Pre- 
      AM Dose                PM Dose 
 
_________ mg 
_________ mg 
_________ mg 
a – j, l, m, o 
 
 
1 
_________ mg 
_________ mg 
 
 
 
 
d 
 
 
2 
_________ mg 
_________ mg 
 
 
 
 
 
 
3 
_________ mg 
_________ mg 
 
 
 
 
 
 
4 
_________ mg 
_________ mg 
 
 
 
 
 
 
5 
_________ mg 
_________ mg 
 
 
 
 
 
 
6 
_________ mg 
_________ mg 
 
 
 
 
 
 
7 
_________ mg 
_________ mg 
 
 
 
 
 
 
8 
_________ mg 
_________ mg 
_________ mg 
_________ mg 
_________ mg 
j, k 
d 
 
 
9 
_________ mg 
_________ mg 
 
 
 
 
 
 
10 
_________ mg 
_________ mg 
 
 
 
 
 
 
11 
_________ mg 
_________ mg 
 
 
 
 
 
 
12 
_________ mg 
_________ mg 
 
 
 
 
 
 
13 
_________ mg 
_________ mg 
 
 
 
 
 
 
14 
_________ mg 
_________ mg 
 
 
 
 
 
 
15 
_________ mg 
_________ mg 
_________ mg 
_________ mg 
_________ mg 
j – l  
d 
 
 
16 
_________ mg 
_________ mg 
 
 
 
 
 
 
17 
_________ mg 
_________ mg 
 
 
 
 
 
 
18 
_________ mg 
_________ mg 
 
 
 
 
 
 
19 
_________ mg 
_________ mg 
 
 
 
 
 
 
20 
_________ mg 
_________ mg 
 
 
 
 
 
 
21 
_________ mg 
_________ mg 
 
 
 
 
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ADVL1823 
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         51 
 
 
Cycle 1, Cohort C 
 
 
22 
_________ mg 
_________ mg 
_________ mg 
_________ mg 
_________ mg 
j, k 
d 
 
 
23 
_________ mg 
_________ mg 
 
 
 
 
 
 
24 
_________ mg 
_________ mg 
 
 
 
 
 
 
25 
_________ mg 
_________ mg 
 
 
 
 
 
 
26 
_________ mg 
_________ mg 
 
 
 
 
 
 
27 
_________ mg 
_________ mg 
 
 
 
 
 
 
28 
_________ mg 
_________ mg 
 
 
 
h, j, k, n 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
 
4.4.2 
Required Observations in Cycle 1, Cohort C 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below.  
 
a.    Hx/Wt /Ht/BSA. Within 7 days prior to Cycle 1.  
b. Performance status. Prior to Cycle 1.  
c. 
Physical exam (including VS and neurologic examination). Prior to Cycle 1.  
d. CBC/diff/platelets: Prior to Cycle 1 and every week during Cycle 1. If patients have 
Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery 
to Grade 3 or until meeting the criteria for dose limiting toxicity. 
e. 
Electrolytes including Ca++. Prior to Cycle 1.  
f. 
Creatinine, ALT, bilirubin. Prior to Cycle 1. 
g. Albumin. Prior to Cycle 1. 
h.    Bone marrow evaluation, lumbar puncture, and evaluation of any sites of 
extramedullary disease. Prior to Cycle 1 and at the end of Cycle 1.  
i. 
Pregnancy test. Prior to Cycle 1. Female patients of childbearing potential require a 
negative pregnancy test prior to starting treatment; sexually active patients must use an 
acceptable method of birth control. 
j.    Cerebral spinal fluid (CSF) cell count and differential. Within 7 days prior to Cycle 1 
and at the end of Cycle 1. CSF will be obtained on Days 8, 15, and 22 only for 
patients who are receiving intrathecal therapy on that date.  
k.    Cerebral spinal fluid (CSF) and peripheral blood pharmacokinetics. At the end of 
Cycle 1 at the time of the first disease evaluation for all patients with leukemia, and 
on Days 8, 15, and 22 for patients who are receiving intrathecal therapy. See Section 
7.3.3 for details.  
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ADVL1823 
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         52 
 
 
Cycle 1, Cohort C 
l.   Circulating tumor DNA. Prior to Cycle 1 and on Day 15 of Cycle 1.See Section 7.3.2 
for details.  
m.    Tumor tissue submission. Prior to Cycle 1. If tissue blocks or slides are unavailable, 
the study chair must be notified prior to study enrollment. See Section 7.3.1 for 
details.  
n.    Patient diary. Uploaded into RAVE at the end of Cycle 1. See Appendix VII-A and 
Appendix VII-B for details.  
o.    Neurocognitive assessments. Within 4 weeks after enrollment. See Section 3.1.7 and 
Appendix XI for details.  
 
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) 
 
 
 
 
4.4.3 
Treatment Details: Cycle 1, Cohort C 
 
Baseline Methotrexate, Cytarabine, OR Triples (Methotrexate/Hydrocortisone/Cytarabine): Intrathecal 
Day: -7 to -1 
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Cycle 1, Cohort C 
Dose: A single dose of intrathecal methotrexate or triples should be administered at the treating physician’s discretion within 
7 days of Day 1 of Cycle 1 of therapy for patients in Cohort C with ALL. A single dose of intrathecal cytarabine should be 
administered at the treating physician’s discretion within 7 days of Day 1 of Cycle 1 of therapy for patients in Cohort C 
with AML.  
 
See age-based dosing recommendations below. Note: Intrathecal therapy received prior to enrollment within 7 days prior 
to Day 1 of Cycle 1 will replace the pre-Cycle 1 intrathecal, even if administered at different doses.   
 
Methotrexate: Intrathecal 
Days: 8 for all patients. Continue weekly thereafter ONLY for patients with ALL who are CNS 2 (see Section 10.8) 
at enrollment until two consecutive clear CSF samples are obtained. 
 
 
 
Age (yrs) 
Dose 
 
 
<1 
 
7.5 mg 
 
 
1-1.99  
8 mg 
 
 
2-2.99  
10 mg 
 
 
3-8.99  
12 mg 
 
 
> 9 
 
15 mg 
 
 
 
Cytarabine: Intrathecal 
Days: 8 and weekly thereafter ONLY for patients with AML who have positive CSF (see Section 10.9) at enrollment 
until two consecutive clear CSF samples are obtained. 
 
 
 
Age (yrs) 
Dose 
 
< 1 
 
20 mg 
 
1-1.99   
30 mg 
 
2-2.99  
50 mg 
 
≥ 3 
 
70 mg 
 
 
 
 
 
 
 
 
 
 
Methotrexate (MTX)/Hydrocortisone (HC)/Cytarabine (ARAC): Intrathecal 
Days: 1, 8, 15, and 22 ONLY for patients with ALL who are CNS 3 (see Section 10.8) at enrollment. Thereafter, 
weekly intrathecals should continue until 2 clear CSF samples are obtained, and regardless of whether or not the 
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Cycle 1, Cohort C 
patient clears. Thereafter, weekly intrathecals should continue until 2 clear CSF samples are obtained. Patients who 
do not clear by the end of cycle 1 will be removed from protocol therapy.  
 
 
 
 
Age (yrs) 
Dose 
 
 
 
 
 
<1 
 
MTX: 7.5 mg, HC: 7.5 mg, ARAC: 15 mg 
 
 
 
 
 
1-1.99  
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
 
 
 
 
 
2-2.99  
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
 
 
 
 
 
3-8.99  
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
 
 
 
 
 
> 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
 
Larotrectinib: Oral/Nasogastric/Gastrostomy 
Days: 1 - 28 
Dose: 100 mg/m2/dose BID (maximum of 100 mg/dose BID).  
 
Only use larotrectinib provided for investigational use specifically for ADVL1823.  
 
Note that this study will enroll very young children, but the dose will be based on body surface area for all patients regardless 
of age.  
 
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.  
 
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 X-A).  Doses of larotrectinib capsules should 
be rounded to the nearest 25 mg (Appendix X-A). Calculated dosing volumes of larotrectinib liquid formulation should be 
rounded to the nearest 0.1 mL (2 mg) for doses ≤ 45 mg (in oral syringes ≤ 3 mL) and 0.2 mL (4 mg) for doses > 45 mg (in 
5-10 mL oral syringes) for the actual deliverable dose (Appendix X-B).  
 
All patients taking larotrectinib must complete a patient diary (Appendix VII-A and Appendix VII-B). 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 

  
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Cycle 1, Cohort C 
Following completion of Cycle 1, patients with leukemia will have a disease evaluation.  Patients with progressive disease 
or treatment failure will discontinue protocol therapy.   
 
For all other patients, the next cycle (Section 4.6) starts on Day 29 or when the criteria in Section 4.1.3 are met 
(whichever occurs later).  Patients achieving a response may discontinue protocol therapy at their physician’s discretion to 
receive consolidative therapy (e.g. transplant).  
 
Larotrectinib will be administered continuously without breaks between cycles unless the patient meets criteria for 
holding or discontinuing larotrectinib (Section 5.1).  
 
 
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Cycles 2 +, Cohort C 
4.5 
Therapy Subsequent to Cycle 1 (Cycles 2+), Cohort C  
4.5.1    Therapy Delivery Map – Cycles 2+, Cohort C 
This Therapy Delivery Map (TDM) relates to Cycles 2+ for Cohort C. Each cycle lasts 28 days. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Criteria to start each cycle are listed in Section 4.1.3. Extensive treatment details are in Section 4.5.3.  
This TDM is on 7 pages.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Methotrexate 
 
OR 
 
Cytarabine  
 
OR 
 
Triples 
(methotrexate/ 
hydrocortisone/ 
cytarabine)  
Methotrexate 
 
Intrathecal 
Age (yrs)            Dose 
< 1                    7.5 mg 
1-1.99                8 mg 
2-2.99               10 mg  
3-8.99               12 mg 
> 9                    15 mg 
-3 to 1 
Patients with ALL ONLY. Patients 
should receive one dose of intrathecal 
therapy between Days -3 to 1 of each 
cycle.  
 
 
 
Cytarabine 
Intrathecal 
Age (yrs)           Dose 
< 1                   20 mg  
1-1.99              30 mg 
2-2.99              50 mg 
> 3                   70 mg 
-3 to 1 
Patients with AML ONLY. Patients 
should receive one dose of intrathecal 
therapy between Days -3 to 1 of each 
cycle.  
 
 
Triples 
(methotrexate/ 
hydrocortisone/ 
cytarabine) 
 
Intrathecal 
Age (yrs)             Dose 
< 1                   MTX: 7.5 mg, HC: 7.5 mg, ARAC: 15 mg 
1-1.99              MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
2-2.99              MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
3-8.99              MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
> 9                   MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
-3 to 1 
Patients with ALL who are CNS 3 (see 
Section 10.8) at enrollment may 
receive either methotrexate or triples at 
their physician’s discretion. Patients 
should receive one dose of intrathecal 
therapy between Days -3 to 1 of each 
cycle.  
 
Larotrectinib 
IND# 141824 
Oral/Nasogastric/
Gastrostomy 
Tube 
100 mg/m2/dose BID 
1 – 28 
Maximum dose = 100 mg/dose BID. 
See Appendix X-A and Appendix X-B 
for dosing nomograms.  
 
 
 
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Cycles 2 +, Cohort C 
 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
CYCLE # _______ 
 
 
Date Due 
Date 
Given 
Day 
Larotrectinib 
AM dose: ____ mg 
PM dose: ____ mg 
Methotrexate 
____mg 
Cytarabine 
____mg 
Hydrocortisone 
____mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
Pre- 
      AM Dose                PM Dose 
 
 
_________ mg 
 
_________ mg 
 
_________ mg 
a – j, l – n  
 
 
1 
_________ mg 
_________ mg 
i 
 
 
2 
_________ mg 
_________ mg 
 
 
 
 
 
 
3 
_________ mg 
_________ mg 
 
 
 
 
 
 
4 
_________ mg 
_________ mg 
 
 
 
 
 
 
5 
_________ mg 
_________ mg 
 
 
 
 
 
 
6 
_________ mg 
_________ mg 
 
 
 
 
 
 
7 
_________ mg 
_________ mg 
 
 
 
 
 
 
8 
_________ mg 
_________ mg 
 
 
 
 
 
 
9 
_________ mg 
_________ mg 
 
 
 
 
 
 
10 
_________ mg 
_________ mg 
 
 
 
 
 
 
11 
_________ mg 
_________ mg 
 
 
 
 
 
 
12 
_________ mg 
_________ mg 
 
 
 
 
 
 
13 
_________ mg 
_________ mg 
 
 
 
 
 
 
14 
_________ mg 
_________ mg 
 
 
 
 
 
 
15 
_________ mg 
_________ mg 
 
 
 
 
 
 
16 
_________ mg 
_________ mg 
 
 
 
 
 
 
17 
_________ mg 
_________ mg 
 
 
 
 
 
 
18 
_________ mg 
_________ mg 
 
 
 
 
 
 
19 
_________ mg 
_________ mg 
 
 
 
 
 
 
20 
_________ mg 
_________ mg 
 
 
 
 
 
 
21 
_________ mg 
_________ mg 
 
 
 
 
 
 
22 
_________ mg 
_________ mg 
 
 
 
 
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Cycles 2 +, Cohort C 
 
 
23 
_________ mg 
_________ mg 
 
 
 
 
 
 
24 
_________ mg 
_________ mg 
 
 
 
 
 
 
25 
_________ mg 
_________ mg 
 
 
 
 
 
 
26 
_________ mg 
_________ mg 
 
 
 
 
 
 
27 
_________ mg 
_________ mg 
 
 
 
 
 
 
28 
_________ mg 
_________ mg 
 
 
 
k 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
 
4.5.2 
Required Observations for Cycles 2+, Cohort C 
 
a.    Hx/Wt/Ht/BSA. Within 7 days prior to subsequent cycles and at the end of study 
treatment.   
b. Performance status. Prior to subsequent cycles and at the end of study treatment.  
c. 
Physical exam (including VS). Prior to subsequent cycles and at the end of study 
treatment.   
d. CBC/diff/platelets: Prior to subsequent cycles. If patients have Grade 4 neutropenia 
then CBCs should be checked every 3 to 4 days until recovery to Grade 3 or until 
meeting the criteria for dose limiting toxicity. 
e. 
Electrolytes including Ca++. Prior to subsequent cycles.  
f. 
Creatinine, ALT, bilirubin. Prior to subsequent cycles.  
g.    Disease evaluation, lumbar puncture, and evaluation of any sites of extramedullary 
disease. After Cycles 2, 4, 6, 9, 12, 16, 20, and 24. Please refer to Section 10.4 for 
Confirmation of objective response by RECIST 1.1. 
h.    Bone marrow evaluation. With Disease evaluation. If the institutional investigator 
has determined the patient has progressed based on clinical or laboratory evidence, 
he/she may opt not to confirm this finding on marrow pathology.   
i.     Circulating tumor DNA. On Day 1 of Cycle 2, before Cycle 7, and at the time of 
progression. See Section 7.3.2 for details.  
j.     Tumor tissue submission. Submission of tumor tissue from any bone marrow 
evaluation while on study is required. Submission of tumor tissue from any biopsy 
after progression is optional. See Section 7.3.1 for details.  
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Cycles 2 +, Cohort C 
k.    Patient diary. Uploaded into RAVE at the end of each cycle. See Appendix VII-A 
and Appendix VII-B for details.  
l.     Pregnancy test. Prior to subsequent cycles. Sexually active patients must use an 
acceptable method of birth control. 
m.   Cerebral spinal fluid (CSF) cell count and differential. With disease evaluation.  
n.    Neurocognitive assessments. 6 months (+ 4 weeks) after enrollment, 12 months (+ 4 
weeks) after enrollment, 24 months (+ 4 weeks), and 4-5 years after enrollment. See 
Section 3.1.7 and Appendix XI for details.  
    
 
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) 
 
 
 
 
 
 
 
 
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Cycles 2 +, Cohort C 
4.5.3 
Treatment Details: Cycles 2+, Cohort C 
 
Methotrexate OR Cytarabine OR Triples (Methotrexate/Hydrocortisone/Cytarabine): Intrathecal 
Days: -3 to 1  
Dose: A single dose of IT therapy will be administered with each cycle 2+. 
Note that patients who do not clear their CSF by the end of Cycle 1 will be removed from protocol therapy.  
 
 
 
Methotrexate 
Patients with ALL ONLY.  
 
 
 
Age (yrs) 
Dose 
 
 
<1 
 
7.5 mg 
 
 
1-1.99  
8 mg 
 
 
2-2.99  
10 mg 
 
 
3-8.99  
12 mg 
 
 
> 9 
 
15 mg 
 
 
 
Cytarabine 
 
Patients with AML ONLY.  
 
 
 
Age (yrs) 
Dose 
 
< 1 
 
20 mg 
 
1 – 1.99  
30 mg 
 
2 – 2.99 
50 mg 
 
≥ 3 
 
70 mg 
 
 
 
 
 
Methotrexate (MTX)/Hydrocortisone (HC)/Cytarabine (ARAC) 
 
Patients with ALL who were CNS 3 (see Section 10.8) at enrollment may receive either methotrexate or triples at 
 
their physician’s discretion. 
 
 
 
Age (yrs) 
Dose 
 
 
 
 
 
<1 
 
MTX: 7.5 mg, HC: 7.5 mg, ARAC: 15 mg 
 
 
 
 
 
1-1.99  
MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 
 
 
 
 
 
2-2.99  
MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 
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Cycles 2 +, Cohort C 
 
 
 
 
 
3-8.99  
MTX: 12 mg, HC: 12 mg, ARAC: 24 mg 
 
 
 
 
 
> 9 
 
MTX: 15 mg, HC: 15 mg, ARAC: 30 mg 
 
 
 
Larotrectinib: Oral/Nasogastric/Gastrostomy 
Days: 1 - 28 
Dose: 100 mg/m2/dose BID (maximum of 100 mg/dose BID).  
 
Only use larotrectinib provided for investigational use specifically for ADVL1823.  
 
Note that this study will enroll very young children, but the dose will be based on body surface area for all patients regardless 
of age.  
 
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.  
 
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 X-A).  Doses of larotrectinib capsules should 
be rounded to the nearest 25 mg (Appendix X-A). Calculated dosing volumes of larotrectinib liquid formulation should be 
rounded to the nearest 0.1 mL (2 mg) for doses ≤ 45 mg (in oral syringes ≤ 3 mL) and 0.2 mL (4 mg) for doses > 45 mg (in 
5-10 mL oral syringes) for the actual deliverable dose (Appendix X-B).  
 
All patients taking larotrectinib must complete a patient diary (Appendix VII-A and Appendix VII-B). 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Patients will have disease evaluation at the end of Cycles 2, 4, 6, 9, 12, 16, 20, and 24.  Patients with progressive disease, 
treatment failure, or relapse at any time will discontinue protocol therapy. 
 
For all other patients, the next cycle starts on Day 29 or when the criteria in Section 4.1.3 are met (whichever occurs 
later).  Patients achieving a response may discontinue protocol therapy at their physician’s discretion to receive 
consolidative therapy (e.g., transplant).  
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5.0 
DEFINITIONS AND DOSE MODIFICATION FOR TOXICITY 
 
All dose modifications should be based on the worst preceding toxicity. The severity of adverse 
events will be graded utilizing the NCI CTCAE, Version 5. 
 
5.1 
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.   
 
 
5.1.1 
Non-Hematological Dose-Limiting Toxicity 
5.1.1.1 
Any Grade 3 or greater non-hematological toxicity with the specific 
exception of: 
- 
Grade 3 fatigue, nausea, or vomiting of < 3 days duration 
- 
Grade 3 ALT/AST/GGT that return to levels that meet initial eligibility 
criteria within 7 days of study drug interruption and that do not recur upon 
re-challenge with study drug. Note: For the purposes of this trial the ULN 
for ALT is defined as 45 U/L and the ULN for AST as 50 U/L. See 
Appendix XII for values that represent thresholds between CTCAE 
grades.  
- 
Grade 3 or 4 total bilirubin elevation in infants who enrolled with 
physiologic jaundice and in patients with leukemia. For such patients, only 
the conjugated (direct) bilirubin will be considered a dose limiting toxicity.  
- 
Grade 3 or 4 fever  
- 
Grade 3 infection < 5 days duration 
- 
Grade 3 weight gain 
- 
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia and/or 
hypomagnesemia responsive to oral supplementation 
5.1.1.2 
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 will be considered a 
dose limiting toxicity.  
- 
Grade 2 allergic reactions that necessitate discontinuation of study drug 
will not be considered a dose-limiting toxicity. 
 
5.1.2 
Hematological dose limiting toxicity  
5.1.2.1 
Hematological dose limiting toxicity is defined as:  
 
a) In patients with solid tumors evaluable for hematological toxicity (see Section 
3.2.6.1a), 
• 
Grade 4 thrombocytopenia (platelet count < 25,000/µL) or Grade 4 
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 
 

  
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b) In patients with leukemia, DLT will be defined as failure to recover a 
peripheral ANC > 500/µL and platelets > 20,000/µL without transfusion by 42 
days after the first treatment day, not due to malignant infiltration.  
 
Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-limiting 
toxicity.  
 
 
5.2 
Dose Modifications for Hematological Toxicity 
 
5.2.1 
If a patient experiences hematological dose limiting toxicity as defined in Section 
5.1.2, the treatment will be held. Counts should be checked every 3-4 days during 
this time. If the toxicity resolves to meet eligibility parameters within 21 days of 
drug discontinuation, the patient may resume treatment with a dose reduction. The 
first dose reduction will be to 75 mg/m2/dose BID (cap of 75 mg/dose BID), the 
second dose reduction will be to 50 mg/m2/dose BID (cap of 50 mg/dose BID), 
and a third dose reduction of 25 mg/m2/dose BID (cap of 25 mg/dose BID). Doses 
reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity 
with the reduced dose, except as required due to patient growth to maintain the 
same BSA-based dose.   
 
5.2.2 
If toxicity does not resolve to meet eligibility parameters within 21 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
5.2.3 
Up to 3 dose reductions are permitted per patient.  If hematological dose-limiting 
toxicity recurs in a patient who has resumed treatment following three dose 
reductions, the patient must be removed from protocol therapy. 
 
5.3 
Dose Modifications for Non-Hematological Toxicity 
 
5.3.1 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.1.1, the treatment will be held. When the toxicity resolves to meet 
eligibility parameters or baseline within 21 days of drug discontinuation, the 
patient may resume treatment with a dose reduction. The first dose reduction will 
be to 75 mg/m2/dose BID (cap of 75 mg/dose BID), the second dose reduction will 
be to 50 mg/m2/dose BID (cap of 50 mg/dose BID), and a third dose reduction of 
25 mg/m2/dose BID (cap of 25 mg/dose BID). Doses reduced for toxicity will not 
be re-escalated, even if there is minimal or no toxicity with the reduced dose, 
except as required due to patient growth to maintain the same BSA-based dose.  
 
5.3.2 
If toxicity does not resolve to meet eligibility or baseline parameters within 21 days 
of drug discontinuation, the patient must be removed from protocol therapy. 
 
5.3.3 
Up to 3 dose reductions are permitted per patient.  If a dose-limiting toxicity recurs 
in a patient who has resumed treatment following three dose reductions, the patient 

  
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must be removed from protocol therapy. 
 
 
6.0  
DRUG INFORMATION 
 
6.1 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  

  
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• 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  

  
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6.2 
Cytarabine 
 
 
 
 
 
 
 
         (07/13/15) 
(Cytosine arabinoside, Ara-C, Cytosar®) NSC# 63878 
 
6.2.1 
Source and Pharmacology 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, 
but significant, incorporation of cytarabine into both DNA and RNA has also been 
reported. It exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S-phase) and under certain conditions blocking the progression of cells 
from the G1 phase to the S-phase. Cytarabine is metabolized by deoxycytidine 
kinase and other nucleotide kinases to the nucleotide triphosphate (Ara-CTP), an 
effective inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine 
nucleoside deaminase, which converts it to the nontoxic uracil derivative (Ara-U). 
It appears that the balance of kinase and deaminase levels may be an important 
factor in determining sensitivity or resistance of the cell to cytarabine. It has an 
initial distributive phase t½ of about 10 minutes, with a secondary elimination 
phase t½ of about 1 to 3 hours. Peak levels after intramuscular or subcutaneous 
administration of cytarabine occur about 20 to 60 minutes after injection and are 
lower than IV administration. Intrathecally administered doses are metabolized 
and eliminated more slowly with a t½ of about 2 hours. 
 
6.2.2 
Toxicity: (Intrathecal)  
 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoiditis 
Rash, somnolence, 
meningismus, convulsions, 
paresis 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
 
Myelosuppression, ataxia 
Delayed: 
Any time later during 
therapy, excluding 
the above condition 
 
 
Necrotizing 
leukoencephalopathy, 
paraplegia, blindness (in 
combination with XRT & 
systemic therapy) 
 
6.2.3 
Formulation 
Cytarabine for Injection is available as a preservative free solution 20 mg/mL (5 
mL, 50 mL per vial) or 100 mg/mL (20 mL vial). Hydrochloric acid and/or sodium 
hydroxide may be added to adjust the pH. Store intact vials of solution at 15°-30°C 
(59°-86°F). Cytarabine solutions should be protected from light. 
 
6.2.4 
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol. 
 
Intrathecal:  
 
 
 
For intrathecal administration, dilute with 5-10 mL (or volume per institutional  
 
 
 
practice) preservative free 0.9% sodium chloride injection, lactated Ringer’s  

  
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injection, Elliot’s B solution. The volume of CSF removed should be equal to at  
 
 
 
least ½ the volume delivered. 
 
Patient Age 
(years) 
Recommended 
volume 
10% CSF volume 
CSF Volume * 
1 – 1.99 
5 – 10 mL 
5 mL 
50 + 10 mL (babies) 
2 – 2.99 
5 – 10 mL 
8 mL 
80 + 20 mL (younger children) 
3 – 8.99 
5 – 10 mL 
10 mL 
100 + 20 mL (older children) 
9 or greater 
5 – 10 mL 
13 mL 
130 + 30 mL (adults) 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 
267:1273-8 
 
 
 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume,  
 
 
 
isovolumetric delivery, with the patient remaining prone after the procedure may  
 
 
` 
facilitate drug distribution. These procedures have not been validated in clinical  
 
 
 
trials. They are allowed but not mandated for patients on COG studies. 
 
Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B 
 
solution is stable for 24 hours at 25ºC but contains no preservative and should be 
 
administered as soon as possible after preparation. 
 
6.2.5 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information.  
 
 
6.3 
 Triples       
 
 
 
 
 
 
(05/08/12) 
(Methotrexate/Hydrocortisone/Cytarabine, IT-3)  
 
6.3.1 
Source and Pharmacology 
The intrathecal route of administration of a drug produces more consistent CSF 
drug concentrations at relatively smaller doses because of the volume difference 
between the CSF and blood compartments (140 mL vs. 3500 mL in an adult). (The 
CSF volume of children after the first 3 years is equivalent to that of an adult). 
Drug half-lives are longer as well because clearance is related to flow rather than 
metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination 
curve from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT 
injection of cytarabine the elimination of the drug from the CSF is biphasic with a 
t½ of 1 and 3.4 hours respectively which is 8-fold longer than the clearance from 
plasma. The elimination of hydrocortisone is similarly prolonged. 
 
6.3.2 
Toxicity  
 
Intrathecal Triple Therapy (Methotrexate/Hydrocortisone/Cytarabine) Toxicity:  
 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, fever, 
headache 
Arachnoditis: 
(headache, fever, 
Rash, anaphylaxis (L), paresis, 
bleeding into subarachnoid or 
subdural space (risk > with 

  
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vomiting, meningismus 
and pleocytosis)  
platelet counts <20,000), 
confusion, fatigue, 
disorientation, seizures 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 
Myelosuppression, somnolence, 
ataxia, cranial nerve palsy, 
transient and rarely permanent 
paraplegia (L), speech disorders 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
Cognitive 
disturbances (L), learning 
disabilities (L) 
Demyelating 
leukoencephalopathy1 (L), 
blindness1  
Late: 
Any time after the 
completion of treatment 
 
 
Progressive CNS deterioration1 
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial irradiation. 
 (L) Toxicity may also occur later. 
 
6.3.3 
Formulation and Stability  
Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg 
preservative free sterile powder for injection vial. Cytarabine 100 mg preservative 
free sterile powder for injection. Hydrocortisone sodium succinate 100 mg vial 
sterile powder for injection. 
 
6.3.4 
Guidelines for Administration 
See Treatment and Dose Modification sections of the protocol. 
 
For intrathecal administration, dilute each agent with 5-10 mL preservative free 
NS, lactated ringers or Elliot’s B solution or as per institutional standard of 
practice. The volume of CSF removed should be equal to at least half the volume 
delivered. 
 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection. N Engl J Med 1962 Dec 20; 
267:1273-8 
 
 
 
 
Of note: Larger volumes approximating at least 10% of the CSF volume,   
 
 
 
isovolumetric delivery, with the patient remaining prone after the procedure may  
 
 
 
facilitate drug distribution. These procedures have not been validated in clinical trials. 
 
 
 
They are allowed but not mandated for patients on COG studies. 
 
Patient Age 
(years) 
Doses 
(MTX/Hydrocortisone/Ara-C) 
 
Recommended 
volume 
10% CSF 
volume 
CSF Volume * 
0 – 0.99 
7.5 mg / 7.5 mg / 15 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
1 – 1.99 
8 mg / 8 mg / 16 mg 
5-10 mL 
5 mL 
50 + 10 mL  
(babies) 
2 – 2.99 
10 mg / 10 mg / 20 mg 
5-10 mL 
8 mL 
80 + 20 mL  
(younger children) 
3 – 8.99 
12 mg / 12 mg / 24 mg 
5-10 mL 
10 mL 
100 + 20 mL  
(older children) 
9 or greater 
15 mg / 15 mg / 30 mg 
5-10 mL 
13 mL 
130 + 30 mL  
(adults) 

  
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Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative  
 
 
 
and should be administered as soon as possible after preparation. 
 
6.3.5 
Supplier  
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.4 
Methotrexate  
   
 
 
 
 
 
       (11/27/17) 
(MTX, amethopterin, Trexall®) NSC# 000740  
 
6.4.1 
Source and Pharmacology 
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme 
that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate 
formation limits the availability of one carbon fragments necessary for the 
synthesis of purines and the conversion of deoxyuridylate to thymidylate in the 
synthesis of DNA and cell reproduction. The polyglutamated metabolites of MTX 
also contribute to the cytotoxic effect of MTX on DNA repair and/or strand breaks. 
MTX cytotoxicity is highly dependent on the absolute drug concentration and the 
duration of drug exposure. MTX is actively transported across cell membranes. At 
serum methotrexate concentrations exceeding 0.1 µmol/mL, passive diffusion 
becomes a major means of intracellular transport of MTX. The drug is widely 
distributed throughout the body with the highest concentration in the kidney, liver, 
spleen, gallbladder and skin. Plasma concentrations following high dose IV MTX 
decline in a biphasic manner with an initial half-life of 1.5-3.5 hours, and a terminal 
half life of 8-15 hours. About 50% is bound to protein. After oral administration, 
approximately 60% of a 30 mg/m2 dose is rapidly absorbed from the GI tract, with 
peak blood levels at 1 hour. At doses > 30 mg/m² absorption decreases 
significantly. Even at low doses absorption may be very erratic, varying between 
23% and 95%. The elimination of MTX from the CSF after an intrathecal dose is 
characterized by a biphasic curve with half-lives of 4.5 and 14 hours. After 
intrathecal administration of 12 mg/m², the lumbar concentration of MTX is ~100 
times higher than in plasma. (Ventricular concentration is ~ 10% of lumbar 
concentration). MTX is excreted primarily by the kidneys via glomerular filtration 
and active secretion into the proximal tubules. Renal clearance usually equals or 
exceeds creatinine clearance. Small amounts are excreted in the feces. There is 
significant entero-hepatic circulation of MTX. The distribution of MTX into third-
space fluid collections, such as pleural effusions and ascitic fluid, can substantially 
alter MTX pharmacokinetics. The slow release of accumulated MTX from these 
third spaces over time prolongs the terminal half-life of the drug, leading to 
potentially increased clinical toxicity. 
 
6.4.2 
Toxicity  
 
Intrathecal Therapy (Methotrexate Single Agent) 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of 
every 100 

  
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Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, headache 
Arachnoditis: 
(headache, fever, 
vomiting, meningismus, 
nuchal rigidity, and 
pleocytosis) 
Anaphylaxis, vomiting, 
seizures(L), malaise, confusion, 
back pain, rash, bleeding into 
subarachnoid or subdural space 
(risk > with platelet counts 
< 20,000), 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
 
 
Myelosuppression, ataxia, 
somnolence, cranial nerve palsy, 
subacute myelopathy 
(paraparesis/paraplegia), speech 
disorders, pain in the legs, bladder 
dysfunction 
Delayed: 
Any time later during 
therapy, excluding the 
above condition 
 
Cognitive disturbances 
(L)1, 
learning disability (L)1 
 
 
Leukoencephalopathy1 (L) 
Late: 
Any time after the 
completion of treatment 
 
 
Progressive CNS deterioration1 
1 May be enhanced by HDMTX and/or cranial irradiation. 
(L) Toxicity may also occur later. 
 
 
 
 
6.4.3 
Formulation and Stability 
Methotrexate for Injection is available as a 25 mg/mL solution in 2, 10, and 40 mL 
preservative free vials. The 2, 10, and 40 mL solutions contain approximately 0.43, 
2.15, and 8.6 mEq sodium per vial, respectively. 
 
Sterile methotrexate solution is stable at 20º-25ºC (68º-77ºF); excursions permitted 
to 15º-30ºC (59º-86Fº). Protect from light. 
 
6.4.4 
Guidelines for Administration 
See Treatment and Dose Modifications sections of protocol.  
 
For Intrathecal Use: Use preservative free 25 mg/mL solution. 
 
For intrathecal administration, dilute with 5-10 mL preservative free NS, lactated 
Ringer’s, or Elliot’s B solution as per institutional standard of practice. The volume 
of CSF removed should be equal to at least half the volume delivered. 
 
 
Patient Age 
(years) 
Methotrexate 
dose 
Recommended volume 
10% CSF volume 
CSF Volume * 
1–1.99 
8 mg 
5–10 mL 
5 mL 
50 + 10 mL 
(babies) 
2–2.99 
10 mg 
5-10 mL 
8 mL 
80 + 20 mL 
(younger children) 
3–8.99 
12 mg 
5-10 mL 
10 mL 
100 + 20 mL 
(older children) 
9 or greater 
15 mg 
5-10 mL 
13 mL 
130 + 30 mL 
(adults) 

  
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*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 
267:1273-8 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, 
isovolumetric delivery, with the patient remaining prone after the procedure may 
facilitate drug distribution. These procedures have not been validated in clinical 
trials. They are allowed but not mandated for patients on COG studies. 
 
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC 
but contains no preservative and should be administered as soon as possible after 
preparation. 
 
6.4.5 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information. 
 

  
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
See Section 3.2 for eligibility requirements and for requirements to initiate protocol therapy. 
Laboratory tests used to determine eligibility may be counted as the Week 1 studies if the tests 
were drawn within 7 days of treatment start and there have been no significant changes in the 
patient’s clinical status.  
   
STUDIES TO BE 
OBTAINED 
Pre-Study 
Cycle 1 
Prior to 
Subsequent 
Cycles^  
End of 
Study 
Treatment 
History 
X 
 
X 
X 
Physical exam with vital 
signs, including neurologic 
examination 
X 
 
X 
X 
Height, weight, BSA 
X 
 
X 
X 
Performance status 
X 
 
X 
X 
CBC, differential, platelets1 
X 
Weekly 
X 
X 
Electrolytes including Ca++ 
X 
 
X 
X 
Creatinine, ALT, bilirubin 
X 
 
X 
X 
Albumin 
X 
 
 
 
Pregnancy test2 
X 
 
X 
X 
Disease evaluation3 
X 
 
X3 
X 
Bone marrow evaluation7,8 
X 
 
With Disease 
Evaluation 
 
Cerebral spinal fluid cell 
count and differential11 
X 
X 
With Disease 
Evaluation 
 
Circulating tumor DNA4 
X 
X 
X 
X 
Tumor tissue submission5 
X 
 
 X9 
X10 
Patient diary6 
 
X 
X 
 
CSF and plasma 
pharmacokinetics12 
 
X 
 
 
Neurocognitive 
assessments13 
 
X 
X 
X 
^ 
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 If patients develop Grade 4 neutropenia then CBCs should be checked every 3 to 4 days until recovery to Grade 3 
or until meeting the criteria for dose limiting toxicity. 
2 Women of childbearing potential require a negative pregnancy test prior to starting protocol therapy; sexually 
active patients may not participate unless they have agreed to use an effective double barrier contraceptive 
method.  Abstinence is an acceptable method of birth control. 

  
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3 Disease evaluation includes CT or MRI of all known sites of disease. For patients with solid tumors, disease 
evaluation will be performed after Cycles 2, 4, 6, 9, 12, 16, 20 and 24.  For patients with leukemia, disease 
evaluation will occur after Cycles 1, 2, 4, 6, 9, 12, 16, 20, and 24. Please note that for solid tumor patients, 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. . Please refer to Section 10.4 for Confirmation of objective 
response by RECIST 1.1. Patients who enter follow-up after completion of planned therapy per Section 4.1 should 
follow the disease evaluation schedule defined in Section 7.2 and do not require disease evaluation at the time of 
discontinuation of larotrectinib. 
4 See Section 7.3.2 for timing of circulating tumor DNA (ctDNA) studies. ctDNA will be obtained at enrollment, 
Day 15 of Cycle 1 of larotrectinib therapy, Day 1 of Cycle 2 of larotrectinib therapy, at the end of Cycle 6 of 
larotrectinib therapy (prior to Cycle 7 or local control), at the end of study treatment, and at the time of progression.  
5 See Section 7.3.1 for details regarding tumor tissue submission. If tissue blocks or slides are unavailable, the study 
chair must be notified prior to study enrollment. 
6 Patient diary (see Appendix VII-A and Appendix VII-B) should be reviewed and uploaded into RAVE at the end 
of each cycle.   
7 Bone marrow aspirate and/or biopsy only required in patients with leukemia or solid tumors with known bone 
marrow metastasis on the basis of history, symptoms, laboratory evaluation or other clinical data.   
8 Bone marrow aspirate and/or biopsy should only be performed on patients with leukemia or solid tumors with bone 
marrow involvement at baseline. If the institutional investigator has determined the patient has progressed based 
on clinical or laboratory evidence, he/she may opt not to confirm this finding on marrow pathology. 
9 Submission of tumor tissue from any surgical resection or bone marrow evaluation for patients with bone marrow 
involvement by tumor, including patients with leukemia, while on study is required. For patients who undergo 
resection of their tumor while on study, operative reports and hospital discharge summaries must be uploaded into 
RAVE following surgical resection.  
10 Submission of tumor tissue from any biopsy after progression is optional.   
11 CSF sampling for cell count and differential will be performed only for patients with leukemia. To be performed 
within 7 days prior to Cycle 1 and at the time of each disease evaluation. CSF will also be obtained on Days 8, 15, 
and 22 of Cycle 1 for those patients who are receiving intrathecal therapy.  
12 See Section 7.3.3. CSF and plasma pharmacokinetics will be obtained at the end of Cycle 1 at the time of disease 
evaluation for all patients with leukemia. Additionally, CSF and plasma pharmacokinetics will also be obtained on 
Days 8, 15, and 22 of cycle 1 for patients who are receiving intrathecal therapy. 
13 See Appendix XI. Within 4 weeks after enrollment; 6 months (+ 4 weeks) after enrollment, 12 months (+ 4 weeks) 
after enrollment; 24 months (+ 4 weeks) after enrollment, and 4-5 years after enrollment. Timing should be based 
on enrollment, regardless of whether the patient is receiving larotrectinib or is in Follow-up. 
 
7.2 
Follow-up 
 
 
STUDIES TO BE OBTAINED 
While in Follow-up after 
Completion of Planned 
Therapy per Section 4.11 
While in Follow-up for 
Other Reasons6  
History, including any anti-cancer therapy 
received 
X2 
X 
Physical exam with VS, including neurologic 
examination  
X2 
X 
Ht, Wt, BSA 
X2 
X 
Disease evaluation 
X2 
X 
Circulating tumor DNA 
X3 
 
Tumor tissue submission  
X4 
X4 
Neurocognitive assessments  
X5 
 
1  Patients who have progressive disease while in Follow-up after completion of planned therapy will be subsequently   
monitored per the table for patients in Follow-up for other reasons.  
2  At 3, 6, 12, 18, 24, 30, 36, and 48 months after discontinuation of larotrectinib, and annually thereafter for up to 5 
years from the date of study entry. Studies may be obtained + 14 days of the indicated timepoint.  

  
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3 
See Section 7.3.2 for timing of circulating tumor DNA (ctDNA) studies. For patients in Follow-up, ctDNA will be 
obtained at the time of progression.  
4    Submission of tumor tissue from any biopsy after progression is optional.  
5  See Appendix XI. For patients in Follow-up, neurocognitive tests will be obtained 6 months (+ 4 weeks) after 
enrollment, 12 months (+ 4 weeks) after enrollment, 24 months (+ 4 weeks) after enrollment, and 4-5 years after 
enrollment. Timing should be based on enrollment, regardless of whether the patient is receiving larotrectinib or 
is in Follow-up.  
6  Follow-up for patients who discontinue therapy on this study for reasons other than completion of planned therapy 
(Section 8.0) is required at 30 days, 6 months, and 12 months from the last date of protocol therapy, and annually 
thereafter for up to five years from the date of study entry.   
 
 
 
See COG Late Effects Guidelines for recommended post treatment Follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
 
7.3 
Correlative Biology Studies 
 
7.3.1 
Tumor Assessment (Archival: Required and Biopsy: Optional) 
 
7.3.1.1    Description of Studies 
Histological 
review, 
next 
generation 
sequencing, 
and 
immunohistochemistry will be performed on tumor tissue from the time 
of diagnosis to evaluate the morphology of TRK fusion cancers and 
retrospectively confirm the presence of TRK fusions. Tumor tissue from 
post-therapy resection specimens will be reviewed to determine 
histologic response to therapy. Tissue from diagnosis and (if obtained) 
time of disease progression/recurrence will be used to evaluate resistance 
mechanisms to TRK inhibition.  
  
7.3.1.2 Sample Collection and Handling Instructions (Appendix III) 
a. 
Submission of archival tumor tissue from the initial diagnostic 
procedure is required and will be requested to be sent following 
patient enrollment. Patients without diagnostic tumor available 
may enroll with prior approval of the principal investigator or 
designee.  
b. 
Tumor tissue submission is required following resection at time 
of local control and from bone marrow evaluations for patients 
with bone marrow involvement by tumor, including patients with 
leukemia.   
c. 
In the event that a patient experiences disease progression and 
undergoes clinically-indicated biopsy or surgery, tumor tissue will 
be requested for analysis of TRK fusions and resistance 
mechanisms.  
7.3.1.3   Sample Requirements 
a.  
All samples must be labeled with two unique identifiers and all 
data should be recorded on the Tissue Studies Form (Appendix 
III) including a copy of the pathology report, which must 
accompany the sample.  
b. 
For patients with solid tumors: 

  
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i. 
In total, 1 H&E stained slide from all available formalin-
fixed paraffin embedded (FFPE) tissue blocks and 15 
unstained slides from the most representative block (10 
unstained slides will be accepted in cases with limited 
tissue) or the block itself should be submitted from each 
surgical procedure (initial diagnosis, post-therapy 
resection 
and 
tumor 
progression/recurrence 
[if 
applicable]). The unstained slides must be from FFPE 
block(s) for which H&E slides are submitted.  From post-
therapy resections, unstained slides should include viable 
tumor if present. Further, if viable tumor is present near 
margin, these slides should be prioritized to allow for 
immunohistochemical assessment of isolated tumor cells. 
These slides will used for the following analyses: 
• 
Histology 
review 
and 
TRK 
immunohistochemistry: 1 H&E stained slide 
from all available formalin-fixed paraffin 
embedded (FFPE) tissue blocks and 2 unstained 
slides.  
• 
Fusion sequencing assay: 10 unstained slides 
derived from formalin-fixed paraffin embedded 
(FFPE) tissue (5 unstained slides will be accepted 
in cases with limited tissue). 
• 
Sequencing to identify the fusion breakpoint for 
ctDNA analysis and to evaluate mechanisms of 
resistance to TRK inhibition: 3 unstained slides 
derived from formalin-fixed paraffin embedded 
(FFPE) tissue 
c. 
For patients with leukemia or solid tumors with bone marrow 
involvement without suitable FFPE tumor tissue available:  
i. 
In total, 1 Wright Giemsa stained bone marrow aspirate 
smear, 1 Wright Giemsa stained peripheral blood smear 
(if available), 1 H&E stained slide from the bone marrow 
biopsy (if available), 1 H&E stained slide from clot 
section (if available), 2 unstained slides from the clot 
section or core biopsy (if available), and 5-8 unstained 
bone marrow aspirate smears should be submitted from 
the baseline bone marrow evaluation and from each bone 
marrow evaluation while on study.  These slides will used 
for the following analyses: 
• 
Histology 
review 
and 
TRK 
immunohistochemistry: 1 Wright Giemsa stained 
bone marrow aspirate smear, 1 Wright Giemsa 
stained peripheral blood smear (if available), 1 
H&E stained slide from the bone marrow biopsy, 
1 H&E stained slide from clot section (if 
available), and 2 unstained slides from the clot 
section or core biopsy. 
• 
Fusion sequencing assay: 2-5 unstained bone 
marrow aspirate smears. 

  
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• 
Sequencing to identify the fusion breakpoint for 
ctDNA analysis and to evaluate mechanisms of 
resistance to TRK inhibition: 3 unstained bone 
marrow aspirate smears. 
7.3.1.4 
Sample Shipping Instructions  
a. 
For FFPE slides (stained and unstained) and bone marrow aspirate 
smears, ship to the following address: 
 
Boston Children’s Hospital, Dept. of Pathology BCH3027 
Laboratory for Molecular Pediatric Pathology (LaMPP) 
300 Longwood Ave. 
Boston, MA 
02115 
  
7.3.2 
Circulating tumor DNA (Optional)  
 
7.3.2.1 
Description of Studies 
Blood will be collected to evaluate the ability to detect TRK fusions at 
enrollment, the clearance of detectable circulating tumor DNA (ctDNA) 
during therapy, and resistance mutations at progression. 
 
7.3.2.2 
Sampling Schedule (see Appendix IV) 
Plasma samples will be collected in consenting patients at the following 
time points:  
- 
Post-enrollment, prior to start of protocol therapy 
- 
Cycle 1, Day 15: Prior to AM Larotrectinib dose 
- 
Cycle 2, Day 1: Prior to AM Larotrectinib dose  
- 
Cycle 6, Day 29 (Cycle 7, Day 1 or prior to local control): prior to 
AM larotrectinib dose 
- 
End of study treatment 
- 
At the time of progression  
 
7.3.2.3 
Streck Tube Acquisition 
Site personnel should email ADVL1823@dfci.harvard.edu and copy the 
study-assigned ADVL1823 Protocol Coordinator as soon as possible 
following patient consent to the ctDNA correlative to request Streck 
tubes. Sites will be sent enough Streck tubes to cover every ctDNA 
collection time point. Sites should specify their preferred shipping 
address in their initial email request.  
   
7.3.2.4 
Sample Collection and Handling Procedures  
For patients who choose to participate in both the ctDNA studies and PK 
studies, the ctDNA sample should be collected prior to the PK sample on 
Cycle 1, Day 15 to avoid heparin contamination of the ctDNA sample.  
 
Peripheral blood samples for circulating tumor DNA should be obtained 
as follows:  
• 
For patients > 10 kg, collect 20 mL (10 ml per tube x 2 tubes) 
• 
For patients > 5 kg but < 10kg, collect 10 mL (1 tube) 
• 
For patients < 5 kg, collect 5 mL (1 tube)  

  
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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 5 mL 
increments (i.e., 0, 5, 10, or 20 mL should be collected such that each 
Streck Cell-Free DNA blood collection tube [BCT] has a minimum of 5 
mL).  
 
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. 
• 
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.  
 
7.3.2.5 
Sample Shipping Instructions 
Streck tubes must be labeled with the patient’s study registration number, 
the study I.D., the specimen type (blood) and the date and time the 
sample was drawn.  
Streck tubes should be shipped by FedEx Priority Overnight at room 
temperature to the Crompton laboratory for immediate separation, 
extraction, and storage of plasma and cellular DNA. Samples should be 
shipped from Monday through Thursday for Tuesday through Friday 
delivery. If blood is collected in the Streck tube on Friday, over the 
weekend or on the day before a holiday, the sample can be stored at room 
temperature until shipped on the next business day.  
Data should be recorded on the ctDNA Correlative Study Form 
(Appendix IV), which must accompany the sample(s).  
Ship specimens to the following address:  
 

  
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7.3.3 
CSF and Plasma Pharmacokinetics (Required for Patients in Cohort C, N/A 
for Patients in Cohorts A & B) 
 
7.3.3.1 
Description of Studies 
Plasma and CSF concentrations of larotrectinib will be determined to 
evaluate the penetration of larotrectinib across the blood brain barrier in 
patients having lumbar punctures for intrathecal chemotherapy 
administration.  
 
7.3.3.2 
Sampling Schedule (See Appendix VIII) 
CSF samples (0.5 ml) will be collected at the following time points for 
patients with leukemia: 
- 
First disease evaluation after starting therapy 
 
In addition, CSF samples (0.5 ml) will be collected at the following time 
points ONLY for leukemia patients receiving intrathecal therapy:   
- 
Cycle 1, Day 8 
- 
Cycle 1, Day 15 
- 
Cycle 1, Day 22 
 
CSF samples will be collected at the time of lumbar puncture. A plasma 
sample (3 ml) will be obtained as close as possible to the same time as 
the CSF sample. There is no required time window from the most recent 
larotrectinib dose, but the dose and time of administration will be 
recorded. When possible, it is preferred that the lumbar puncture occur 
>1 hour after the most recent larotrectinib dose.  
 
7.3.3.3 
Sample Collection and Handling Instructions  
NOTE: Sites are expected to use their own standard materials for PK 
sample collection. Kits will not be provided for the PK studies for this 
study. 
 
7.3.3.3.1 CSF Samples 
 
Supplies  
• 
1 Medium biohazard bag 
• 
2 Cryovials (2 mL each) 
• 
1 Plastic transfer pipette 
• 
2 Cryolabels 
• 
2 Absorbent Pads 

  
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• 
1 Federal Express Return Shipping Label 
(Alturas) 
• 
1 Dry Ice label 
• 
CSF collection kit 
• 
Alcohol swab for cleansing site 
• 
Dry sterile gauze 
• 
Needle disposal container 
 
 
Collection Procedure 
1. Collect 0.5 mL of CSF using your 
institution's recommended procedure for 
standard CSF collection technique. Record 
the exact time that the sample is drawn along 
with the exact time that the drug is 
administered.  
 
2. Complete the cryovial labels with subject ID 
and visit. Adhere the cryovial labels to each 
of the cryovials. 
3. Divide CSF equally between two cryovials. 
Screw on the lid.  
a. Place the labeled cryovials with CSF into an 
81-well cryovial box. 
4. Immediately transfer the cryovials filled with CSF to 
a -80°C freezer. 
a. Only 1 cryovial should be shipped 
within 1 week to Alturas after each 
collection. The other should be 
stored on site in case there is an 
issue with the first vial.   
 
7.3.3.3.2 Plasma Samples 
 
Collection Procedure 
Blood samples (3 ml) will be collected in K2 EDTA 
lavender top tubes for PK evaluation. This sample should 
be collected as close as possible to the same time as the 
corresponding CSF sample. Record the exact time that the 
sample is drawn along with the exact time that the drug is 
administered.  
 
Following collection, the sample will be immediately 
gently mixed by inversion 8 – 10 times. The sample will 
be stored on wet ice until centrifugation. The sample will 
be centrifuged at 1500 x g for 15 minutes at 4° C within 
60 minutes after the sample is drawn. The plasma will be 
transferred to a cryovial, ensuring no RBC contamination, 
and frozen as soon as possible at -80° C. If a -80° C 
freezer is not immediately available, the cryovial may be 

  
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stored on dry ice for short term storage, but must be 
placed in the appropriate freezer within 24 hours of the 
draw-time. The cryovial should be shipped within 1 week 
to Alturas after each collection.  
 
7.3.3.4 
Documentation 
1. Ensure the cryovials are properly labeled. 
 
2. Complete the Specimen Submittal Form (Appendix VIII) 
 
3. Complete the dry ice sticker. 
 
a. 
On the day of shipment, fill out the dry ice sticker 
with the shipper’s name, address, and weight of dry 
ice. Ensure at least 15 pounds (~ 7 kg.) of dry ice 
for shipment. 
 
7.3.3.5 
Sample Shipping Instructions  
1. Specimens may be shipped to Alturas, Monday through 
Wednesday only: 
 
 
 
 
 
 
Alturas Analytics, Inc. 
 
 
 
 
 
1324 Alturas Dr.  
 
 
 
 
 
Moscow, ID 83843 
 
 
 
 
 
Phone: (208) 883-3400 
 
 
 
 
 
Fax: (208) 974-4475 
 
2. Obtain a large Styrofoam shipping box of adequate size to 
hold 15-20 pounds (~7-9 kg.) of dry ice along with the 81-
well box containing the frozen cryovials. 
 
3. Fill the Styrofoam shipping box half full (~10 pounds) of dry ice. 
 
4. Transfer samples from the freezer to the dry ice. Ensure the 
container is sufficiently surrounded by dry ice. Do not 
allow the samples to thaw. 
 
5. Fill the rest of the container with dry ice. Ensure that the 
container is sufficiently filled with dry ice (at least 15 
pounds) and the samples are completely covered. 
 
6. Place the completed Specimen Submittal Form (Appendix 
VIII) inside the cardboard shipping box (but outside the 
Styrofoam to avoid getting the paper wet). Close and seal 
shipping box lid with packing tape. 
 
7. Attach the FedEx Return shipping label to the shipper kit box. 
 
a. Ensure the return shipping label for Alturas is selected for 
shipping. 

  
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8. Attach the dry ice sticker to the shipper kit box. 
 
9. Contact Federal Express for shipment (1-800-GOFEDEX or 1-800-
466-6669; toll free in the US). 
 
10. Email a copy of the Specimen Submittal Form (Appendix 
VIII) to the following email addresses: 
 
  
samplecustodian@alturasanalytics.com  
 
11. Include the Protocol ID, Patient ID, and FedEx Tracking 
Number in the email. Please write the tracking number 
without spaces (i.e. Correct = 000100020003; Incorrect 
= 0001 0002 0003). 
 
 
7.4 
Imaging Central Review 
 
Central imaging review will be conducted for all imaging through Cycle 6.  Additional 
central review of imaging evaluations performed for study participants during therapy or 
follow up on individual basis will occur as determined by the study committee and study 
radiologist. COG Operations Center will notify the Imaging Research Center of any patient 
requiring central review. The Imaging Research Center will then request that the treating 
institution forward the pertinent images for central review. The central image evaluation 
results will be entered into Rave for review for data analysis. Central imaging review will 
be performed retrospectively and will not be used to guide individual patient management.  
 
The images are to be forwarded electronically to the Imaging Research Center at Children’s 
Hospital Los Angeles via the ImageInBox. 
 
COG institutions that are not connected via the ImageInBox can send the images on hard 
copy film, CD ROM, DVD, USB flash drive or by FTP. Submitted imaging studies should 
be clearly marked with the COG patient ID, study number (ADVL1823) and date, and 
shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CCRP 
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
Phone:  (323) 361-3898 
Fax: 
(323) 361-3054 
Email: saamer@chla.usc.edu 
 
 
 

  
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
8.1 
Criteria for Removal from Protocol Therapy 
 
a) Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease or treatment failure while on study (See Section 10.3.3, 
Section 10.5.2, Section 10.5.3, Section 10.6.6, and Section 10.7.5).   
b) Adverse Events requiring removal from protocol therapy, as stated in Section 5.0. 
c) Patients who receive concurrent investigational therapy or anticancer therapy, as stated in 
Section 3.3.2.3 and Section 3.3.2.4. 
d) Refusal of further protocol therapy by patient/parent/guardian.  
e) Physician determines it is in patient’s best interest. 
f)  Repeat eligibility studies (if required) are outside the parameters required for eligibility 
prior to the start of larotrectinib (Section 3.2.6). 
g) Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
h) Patients who develop a second malignant neoplasm. 
i) Study is terminated by sponsor. 
j) Pregnancy 
k) Completion of planned therapy per Section 4.1. 
l) Patients with leukemia who have persistent CNS disease that does not clear by the end 
of Cycle 1.  
 
Patients who are removed from protocol therapy are to be followed until they meet the criteria 
for Off Study (Section 8.2). Follow-up data will be required unless consent was withdrawn.   
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG anti-cancer therapeutic study (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
f) The patient does not receive protocol treatment after study enrollment.  
 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
Sample Size and Study Duration 
 
One disease stratum (infantile fibrosarcoma, Cohort A) has been identified as the primary 
cohort for reporting upon completion of evaluation.  The evaluation rule is described in 
Section 9.2 below. In addition to the main stratum, enrollment into each of the following tumor 

  
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groups (“secondary strata”): (B) Other newly-diagnosed TRK fusion solid tumors, and (C) 
Relapsed/refractory acute leukemias; will be open to accrual. If nine response-evaluable 
patients of a particular histology are enrolled in either of the secondary strata, the two-stage 
design described in Section 9.2 below will be applied to that particular histology. (That is, up 
to twelve additional response-evaluable patients with that tumor type may be studied.) Upon 
completion of enrollment to Cohort A, the study committee will make a decision on whether 
to continue enrollment to the secondary strata or to close the study. This will be based on the 
enrollment and response rates observed in the strata up until that date.  
 
Review of SEER data indicates the following entry rate can be expected, assuming that 33% 
of patients with infantile fibrosarcoma have resectable disease at diagnosis, and 33% of the 
remaining patients don’t enroll on this study for other reasons: 
 
Disease Group/Strata 
 
    Patients/Year 
Infantile fibrosarcoma 
 
             8 
 
Assuming an annual enrollment rate of 8 patients/year in Cohort A, the probability of 
accruing 9 patients to complete the initial stage of evaluation within 17 months is 80% and 
within 26 months is 90%. The corresponding probability for enrolling 21 patients in 37 
months is 80% and within 47 months is 90%. Allowing for a 10% inevaluability rate, a 
minimum of 9 and a maximum of 70 patients will be enrolled. The study will likely require 
3 to 4 years for sufficient patient enrollments to evaluate larotrectinib in IFS. 
 
Assuming all three cohorts fill completely, a maximum of 63 evaluable patients will enroll. 
Accounting for up to an estimated 10% of patients in Cohort A who do not meet the 
definition of evaluable for response and therefore require replacement, a maximum of 70 
total patients will enroll.  
 
 
9.2 
Study Design 
 
The primary endpoint will be objective response according to the disease specific criteria 
in Section 10. The best response of disease to larotrectinib will be examined separately in 
the primary disease stratum and the secondary strata if sufficient enrollment occurs.  The 
following Simon’s minimax two-stage design will be used in each stratum. 
 
 
Cumulative Number 
of Responses 
Decision 
Stage 1: Enter 9 patients 
5 or fewer 
Terminate the trial: agent ineffective 
 
6 or more 
Inconclusive result, continue trial  
 
 
(proceed to Stage 2) 
Stage 2: Enter 12 additional 
patients 
15 or fewer     
Terminate the trial: agent ineffective 
 
16 or more 
Terminate the trial: agent effective 
 
We will consider larotrectinib not of sufficient interest for further evaluation in a disease 
category if the true response rate is 60% and of sufficient activity if the true response rate 
is 85%. If larotrectinib has a true response rate of 60%, the rule described above will 

  
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identify it of sufficient activity for further study with probability 9.05% (type I error), and 
the trial will have an expected sample size of 14.8 with 51.74% probability of early 
termination. If larotrectinib has a true response rate of 85%, the rule described above will 
identify it of sufficient activity for further study with probability 90.40% (power against 
the alternative hypothesis p = 0.85). 
 
If there are 9 confirmed objective responses before observing any nonresponders in Cohort 
A, consideration of closing Cohort A to enrollment will be discussed by all approved 
parties (i.e., DSMC, Bayer, and CTEP) following release of the response data by the 
DSMC. Nine responses among the first 9 response evaluable patients will exclude a true 
response rate of 60% with p = 0.014. If at any time there are 16 confirmed responses in a 
cohort, then enrollment to that cohort will be closed as the efficacy endpoint for that cohort 
has been met.  
 
 
 
9.3 
Methods of Analysis 
 
Response criteria are described in Section 10.2. A responder is defined as a patient who 
achieves a best response (as defined in Section 10.3.4) 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 accounting for the two-stage design. 
 
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 attribution(s) to the study regimen.   
 
Time-to-event analyses (time to progression, progression-free survival, overall survival, 
and duration of response) will be computed one year after the last enrollment in a stratum. 
Duration of response will be defined among patients with a confirmed best response of 
either PR and CR, and will be defined as the time from the first observation of either PR 
or CR until either the first observation of PD (event) or last known observation of the 
patient (censored observation).  
 
9.3.1 
Adverse Event Monitoring Rule  
We will use a Bayesian rule to monitor for protocol-specific toxicities (list given 
below). We will assume a beta prior distribution with α = 0.52 and β = 2.08. At 
least once per month, we will calculate the posterior probability (given the data) 
that the probability of protocol-specific toxicity exceeds the 20% threshold: 
 
 
( )
( )
0.48
1.08
1
protocol-specified toxicities
1
0.2
0.48
1.08
0
(
P
(2.6)
(1
)
(1
)
(0.52)
2.08)
Data)
(
(
20%
2.6)
(1
)
(1
)
(0.52) (2.08)
x
n x
x
n x
p
p
p
dp
q
q
n p
x
p
n q
q
dq
x
−
−
−
−

−
−


=



−
−



∣
 
 
 
Here n is the number of protocol-specific toxicity-evaluable cycles and x is the 
number of such cycles on which a protocol-specific toxicity event is observed. If 
there is strong evidence (posterior probability of at least 70% with at least 2 
observed toxicities) that there is a per course protocol-specific toxicity probability 

  
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of more than 20%, such information will be presented to the DSMC.  Examples of 
situations in which this rule will indicate protocol-specific toxicities have been 
noted and are presented below: 
 
Number of failures Number of patient-cycles 
2 
6 
3 
10 
4 
14 
5 
19 
6 
23 
7 
28 
8 
32 
9 
37 
10 
41 
11 
46 
12 
51 
13 
55 
14 
60 
 
Protocol-specific toxicities of interest include CTCAE v5 Grade 3 or higher fatigue, ataxia, 
dizziness, ALT increase, AST increase, neutropenia, thrombocytopenia, nausea, and 
vomiting.  For the purpose of this toxicity monitoring rule, patients with leukemia or solid 
tumors with bone marrow metastases are not evaluable for hematologic toxicities 
(neutropenia or thrombocytopenia) unless these persist for greater than 14 days after a bone 
marrow is negative for malignancy and the patient does not have evidence of recurrent 
disease. 
 
9.4 
Evaluability for Response 
 
Any patient who is enrolled and receives at least one dose of larotrectinib will be 
considered evaluable for response provided: (1) the patient demonstrates progressive 
disease or death while on protocol therapy; or (2) the patient is observed on protocol 
therapy for at least one cycle and the tumor is not removed surgically prior to the time 
complete response or partial response is confirmed, or (3) the patient demonstrates a 
complete or partial response as confirmed according to protocol criteria. Patients who 
demonstrate a complete or partial response confirmed by central review will be considered 
to have experienced a response for the application of the rule given in Section 9.2. All other 
patients will be considered non-responders. The evaluation period for determination of the 
best response will be 6 treatment cycles. 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. See Section 7.4 regarding 
shipping instructions. 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. 
 
9.5 
Evaluability for Toxicity 
 
All patients who either (1) receive at least 85% of the required dose of larotrectinib 
according to protocol guidelines in any cycle of treatment or (2) experience a toxicity at 
least possibly related to the study regimen will be considered in the evaluation of toxicity. 

  
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9.6 
Sex and Minority Accrual Estimates  
 
The sex and minority distribution of the study population is expected to be: 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ 
Alaska 
Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander 
 
 
 
 
 
Black or African 
American 
8 
6 
 
 
14 
White 
13 
19 
9 
10 
51 
More Than One 
Race 
 
 
 
 
 
Total 
21 
25 
9 
10 
65 
 
INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ 
Alaska 
Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander 
 
 
 
 
 
Black or African 
American 
 
 
 
 
 
White 
2 
3 
 
 
5 
More Than One 
Race 
 
 
 
 
 
Total 
2 
3 
 
 
5 
 
This distribution was derived from all patients enrolled on prior COG DVL Phase 2 trials.  
 
9.7 
Analysis of CSF to Plasma Larotrectinib Concentrations 
 
Larotrectinib concentration in plasma and CSF will be quantified by a validated LC-MS 
assay for patients with leukemia who have sampling while on study. The ratio of non-
protein bound larotrectinib concentration in the plasma and CSF will be calculated. These 
ratios will be summarized with simple summary statistics, including means, medians, 
ranges, and standard deviations (if numbers and distribution permit).   

  
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9.8 
Analysis of Biological and Correlative Endpoints 
 
9.8.1 
Histology and Immunohistochemistry  
A descriptive review of tumor histology will be performed. This will include 
central review of all cases at the time of diagnosis. The pattern of 
immunohistochemical staining with a pan-TRK antibody will be correlated with 
fusion type, to evaluate use as a surrogate marker of fusion status and better define 
the patterns of expression as they relate to individual fusion partners and amongst 
various tumor types. Post-therapy specimens will be reviewed to document 
patterns of tumor response to therapy and provide centralized review of margin 
status where applicable. When possible pan-TRK immunohistochemistry will be 
performed to aid in evaluation of the infiltrative border of the tumor and to confirm 
the persistence of pan-TRK protein expression in the setting of neoadjuvant 
larotrectinib.   
 
9.8.2 
Central Confirmation of TRK Fusions by Next Generation Sequencing  
 
Anchored multiplex PCR (AMP) is a method for detecting gene rearrangements 
without prior knowledge of fusion partners (2). Double-stranded cDNA is end-
repaired, adenylated, and ligated to universal half functional adapters. Two rounds 
of nested low-cycle PCR then enriches targets and renders the adapters on the 
enriched targets functional for sequencing. The assay assesses nucleic acid 
sequences with a target-specific nested primer on one side, and a universal adapter 
on the other, such that a priori knowledge of one fusion partner is needed. The 
assay used in this study includes target-specific primers for all three NTRK genes 
and thus can detect TRK fusions with both known and novel 5’ fusion 
partners.  The method is effective with low nucleic acid input from formalin fixed 
paraffin-embedded specimens. 
 
VALIDATION: Validation will be completed by December 2018.  Thus 
far we have run over 100 cases, including 60 unique fusion-positive 
samples. 100% of samples successfully completed library preparation 
with acceptable QC metrics, including samples derived from both FFPE 
(5 unstained slides per case) and fresh/frozen tissue as well as samples 
across a range of nucleic acid input (down to 10 ng of total nucleic 
acid). So far, fusions have been correctly identified in over 95% of 
cases. A detailed report will be available when validation is complete. 
 
SPECIFIC QUALITY CONTROL AND QUALITY ASSURANCE 
PARAMETERS TO DETERMINE SATISFACTORY PERFORMANCE 
OF THE BIOINFORMATICS PIPELINE:  
1.     Percentage of nucleated cells that are tumor cells 
2.     Nucleic acid concentration 
3.     Library nucleic acid quantification 
4.     Cluster density 
5.     Percentage of bases higher than the minimum Phred score       
 
        (Q30) of all bases called 
6.     Demultiplexing success 
7.     Percentage of reads passing a minimum Phred score (Q30) 

  
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8.     Mean on-target coverage of reads 
9.     AT/GC mapping bias 
10.  Depth of coverage  
11.  Observed sex matches reported sex 
12.  Specific version of bioinformatics pipeline 
13.  Integrity of data files during transfer between systems  
  
 
       (sequencer to pipeline; pipeline to knowledge database) using 
 
       a hash/checksum method 
 
9.8.3 
Circulating tumor DNA  
A combination of hybrid-capture next-generation sequencing (NGS) and digital 
droplet PCR (ddPCR) will be used to detect and quantify circulating tumor DNA 
(ctDNA) in blood samples obtained from patients enrolled on this study. NGS will 
be performed using capture probes targeting the genomic introns involved in 
NTRK gene fusions and the coding regions of the three NTRK genes. Our assay 
was designed using the SureSelect Advanced Design Wizard (Agilent 
Technologies). Normalized and pooled barcoded sequencing libraries are enriched 
using the SureSelectXT Fast Target Enrichment System (Agilent Technologies) 
with this bait set. Post-enrichment captures are sequenced with an intended 
coverage at target regions of 500X.  Identification of targeted translocations are 
detected using BreaKmer.49 To quantify the number of translocations and wild-
type reads detected in each sample, a custom algorithm designed to realign all 
sequencing reads to either the reference human genome or the patient-specific 
translocation positive reference sequence (obtained from tumor sequencing) will 
be used (https://github.com/vanallenlab/peds_ctDNA).40 The algorithm will report 
the number of reads aligned at the patient-specific translocation breakpoint and 
the number of wild-type reads at the equivalent genomic base-pair location within 
the human reference genome. Because each cancer genome contains one 
translocated and one wild-type allele, whereas germline genomes contain two 
wild-type alleles, we used the following formula to calculate the percentage of 
ctDNA, where T equals the number of translocation reads and W equals the 
number of wild-type reads:  
 
% ctDNA
2
T
W
T
T
−
+
=
 
 
ddPCR will be performed using PCR primers designed with Primer3Plus 
(http://www.bioinformatics.nl/cgi-bin/primer3plus/primer3plus.cgi) to amplify 
patient-specific translocations identified from tumor DNA sequencing.  Sample 
specific primer pairs will be validated with tumor DNA or synthetic DNA as a 
positive control (Integrated DNA Technologies) and an unrelated human cell line 
DNA as a negative control. Primers for the housekeeping gene RPP30 designed by 
Bio-Rad will be used as a reference gene. ddPCR will be performed with 5 ng of 
pre-capture sequencing libraries for all samples using QX200 EvaGreen SuperMix 
and the QX200 Droplet Digital PCR system (Bio-Rad). Analysis will be performed 
using the QuantaSoft program (Bio-Rad). Samples will be performed in duplicate. 
For each replicate, translocation-positive droplets will be divided by half of the 
average number of RPP30-positive droplets for that sample and then averaged. 
 

  
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The percentage of ctDNA and frequency with which patients have detectable 
ctDNA prior to the start of therapy and at times during therapy when subsequent 
serial samples are obtained will be summarized with simple summary statistics, 
including means, medians, ranges, and standard deviations (if numbers and 
distribution permit).  In cases of treatment resistance, we will also perform 
exploratory deep sequencing of ctDNA to determine whether this method can 
detect the emergence of resistance mutations. 
  
VALIDATION: The above hybrid capture technique has been used to successfully 
detect NTRK-rearrangements in tumor biopsy samples validating that the assay is 
a technical success. A similar strategy has also been successfully used to detect 
translocations in the blood of patients Ewing sarcoma. The hybrid-capture 
approach is able to detect these translocations when the circulating tumor DNA 
makes up as little as 1% of the total cell-free DNA extracted from a plasma 
sample.40 Similarly, ddPCR has been used to detect Ewing translocations in the 
plasma of patients and is sensitive when circulating tumor DNA makes up as little 
as 0.01% of the cell-free DNA extracted from plasmas.50 Furthermore, detection 
of larotrectinib resistance mutations in ctDNA has been shown in the first two 
patients to develop acquired resistance on the industry sponsored clinical trials of 
larotrectinib, demonstrating feasibility of this strategy.39, 40 
 
9.8.4 
Neurocognitive Outcomes  
Neurocognitive functions will be analyzed using linear mixed-effects models with 
exponential covariance measures between observations within each patient. 
Measures to be analyzed will be the ABAS-III (General Adaptive Composite), 
BRIEF-P or BRIEF-2 (Global Executive Composite Score), the BASC-
3 (Internalizing, Externalizing and Behavioral Symptoms Indices) and Peds QL 
Total Score (see Appendix XI). 
 
 
10.0 
 EVALUATION CRITERIA 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. The descriptions and grading scales found in the revised CTCAE 
version 5.0 will be utilized for reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0, which can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., v5.02 and all subsequent iterations prior to 
version 6.0). 
 
10.2       Response Criteria  
As outlined, patients will be assigned to one of the following categories for assessment of 
response:  a) solid tumor and measurable disease (Section 10.3, Section 10.4, and Section 
10.5); b) AML (Section 10.6); c) ALL (Section 10.7). Note: Neuroblastoma patients who do 
not have MIBG positive lesions or bone marrow involvement should be assessed for response 
as solid tumor patients with measurable or evaluable disease.  
 

  
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10.3 
Response Criteria for Patients with Solid Tumors (non-CNS) 
Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).51 Key points are 
that 5 target lesions are identified and that changes in the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST v 1.1 criteria. 
 
10.3.1 Measurable Disease  
The presence of at least one lesion that can be accurately measured in at least one 
dimension with the longest diameter at least 10 mm (CT scan slice thickness no 
greater than 5 mm). The investigator will identify up to 5 measurable lesions to be 
followed for response. Patients with previously irradiated lesions are not eligible 
for Cohorts A and B of this protocol. 
 
Serial measurements of lesions are to be done with appropriate imaging modalities, 
e.g., CT or MRI. Bone scans cannot be used to measure lesions. The same method 
of assessment is to be used to characterize each identified and reported lesion at 
baseline and during follow-up. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
10.3.2 Quantification of Disease Burden 
The sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the disease measurement. 
 
10.3.3 End-of-Cycle Response 
Note:  Please also see Table 1 in Section 10.4. 
 
a) Complete Response (CR)  
Disappearance of all target and non-target lesions. Normalization of urinary 
catecholamines (for patients with neuroblastoma), immunocytologic findings, 
or other tumor markers if abnormal or elevated at study enrollment.  
 
b) Partial Response (PR) 
At least a 30% decrease in the disease measurement, taking as reference the 
disease measurement done to confirm measurable disease at study enrollment. 
No new lesions or progression of any non-target measurable lesion. 
 
c) Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest disease measurement since the 
treatment started. 
 
d) Progressive Disease (PD)  
At least a 20% increase in the sum of the disease measurements for measurable 
lesions, taking as reference the smallest disease measurement recorded since 
the start of treatment, or the appearance of one or more new lesions. 
 
 
10.3.4 Overall Best Response Assessment   
Each patient will be classified according to their “best response” for the purposes 
of analysis of treatment effect. For this analysis, the best response refers to the 

  
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response to larotrectinib only and not surgical resection. Best response is 
determined from the sequence of the objective statuses described in Section 10.4. 
 
 
10.4 
Best Response (Solid Tumors) 
Two objective status determinations of disease status, by CT or MRI, 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. 
 
 
Table 1: 
Sequences of objective statuses with corresponding best response. 
1st Status 
2nd Status 
3rd Status 
Best Response 
Progression 
 
 
Progressive disease 
Stable, PR, CR 
Progression 
 
Progressive disease 
Unknown 
Progression 
 
Progressive disease 
Stable 
Stable 
Progression 
Stable 
Stable, Unknown 
PR, CR 
Progression 
Stable 
Stable, Unknown 
Unknown 
Progression 
Unknown 
PR 
PR 
Progression 
PR 
PR 
CR 
Progression 
PR 
PR, CR 
Unknown 
Progression 
Unknown 
CR 
CR 
Progression 
CR 
Unknown 
Stable 
Progression 
Stable 
 
10.5 
Response Criteria for Patients with CNS Tumors 
 
10.5.1 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. 
 

  
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10.5.2 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 and non-target lesions. 
 
• 
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. 
 
• 
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. 
 
• 
Progressive Disease (PD): 25% or more increase in the product of 
perpendicular diameters of ANY target lesion, taking as reference the smallest 
product observed since the start of treatment, or the appearance of one or more 
new lesions. 
 
10.5.3 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. 
 
 
10.5.4 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
10.5.5 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 

  
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PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect. Best response is determined as outlined in Section 
10.4 from a sequence of overall response assessments. 
 
10.6 
Response Criteria for Patients with AML 
 
The AML response criteria are derived from the revised AML International Working 
Group (IWG) Criteria.52 
 
10.6.1. Complete Remission (CR)  
Attainment of an M1 bone marrow (< 5% blasts) with no evidence of circulating 
blasts or extramedullary disease and with recovery of peripheral blood counts 
(ANC ≥ 1000/mm3 and platelet count ≥ 100,000/mm3). Occasionally, a rare 
peripheral blood blast may be identified during marrow regeneration; however, the 
marrow must be M1 status and with no Auer rods. Flow cytometry may also be 
useful to distinguish between leukemia and a regenerating bone marrow. There is 
no requirement for bone marrow cellularity. 
 
10.6.2 CR With Partial Recovery of Platelet Count (CRp)  
Attainment of an M1 bone marrow (< 5% blasts) with no Auer rods, no evidence 
of circulating blasts or extramedullary disease and with recovery of ANC 
≥ 1000/mm3 and platelet transfusion independence (defined as: no platelet 
transfusions x 1 week). 
 
10.6.3 CR with incomplete blood count recovery (CRi)  
Attainment of an M1 bone marrow (< 5% blasts) with no Auer rods, no evidence 
of circulating blasts or extramedullary disease and with ANC < 1000/mm3 or 
platelet count < 100,000/mm3 without platelet transfusion independence (defined 
as: no platelet transfusions x 1 week). 
 
10.6.4 Cytogenetic Complete Remission (CRc)  
The patient must also have attained and be assigned to response of morphologic 
CR or CRp or CRi as defined above. In addition, reversion to a normal karyotype 
with a minimum analysis of 20 metaphases.  
 
10.6.5 Partial Response (PR) 
A decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone 
marrow aspirate. Bone marrow must have adequate cellularity (e.g., > 15%) to 
determine response. PR status will not be included in calculation of response to the 
regimen. A repeat bone marrow aspiration after several weeks may be required to 
distinguish between a PR and increased blasts caused by bone marrow 
regeneration. A value of < 5% blasts may also be considered a PR if Auer rods are 
present. 
 
 

  
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10.6.6 Treatment Failure (TF)  
Any M3 marrow and any M2 marrow that does not qualify for PR status. A M1 
marrow with evidence of circulating blasts or extramedullary disease also indicates 
treatment failure. 
 
10.6.7 Relapse  
Morphologic relapse after CR/CRp/CRi is defined as a reappearance of leukemic 
blasts in the peripheral blood or ≥ 5% blasts in the bone marrow not attributable to 
any other cause (e.g., bone marrow regeneration after consolidation therapy). In 
the setting of recent treatment, if there are no circulating blasts and the bone 
marrow contains 5% to 20% blasts, a repeat bone marrow performed at least a 
week later is necessary to distinguish relapse from bone marrow regeneration. 
Should flow cytometric analyses suggest relapse (by the reappearance of a similar 
immunophenotype to the original leukemia) in the presence of < 5% blasts, or ≥ 
5% blasts in a regenerating marrow, a repeat bone marrow(s) performed at least a 
week later is necessary to confirm relapse by morphologic methods. In such 
instances the date of recurrence is defined as the first date that more than 5% blasts 
were observed in the marrow. The reappearance or development of cytologically 
proven extramedullary disease also indicates relapse. Molecular and/or genetic 
relapse is characterized by reappearance of a cytogenetics or molecular 
abnormality.  
 
10.6.8 Unevaluable  
Aplastic or severely hypocellular marrow with any blast percentage. In this 
instance, marrow evaluation should be repeated weekly until response 
determination can be made through at least Day 49. 
 
10.6.9 Bone Marrow Classification: 
M1 is  5% blasts 
M2 is 5 to 25% blasts 
M3 is > 25% blasts 
 
10.7 
Response Criteria for Patients with ALL 
 
10.7.1 Complete Response (CR) 
Complete response (CR) is defined as an M1 marrow (< 5% blasts) with no 
evidence of circulating blasts or extramedullary disease and with peripheral count 
recovery, defined as absolute neutrophil count (ANC) ≥ 500/µL and platelet count 
≥ to 50,000/µL without transfusion for 7 days.  
 
10.7.2 Complete Response with Incomplete Count Recovery (CRi) 
Complete response with incomplete recovery of peripheral blood counts (CRi) is 
defined as an M1 marrow (< 5% blasts) with no evidence of circulating blasts or 
extramedullary disease and with an ANC < 500/µL and/or platelet count < 
50,000/µL. 
 
10.7.3 Partial Response (PR) 
Complete disappearance of circulating blasts and achievement of M2 marrow 
status if M3 originally, without new sites of extramedullary disease, and with 

  
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recovery of absolute neutrophil count (ANC ≥ 500/µL). Complete response in the 
marrow without resolution of extramedullary sites is a PR. 
 
10.7.4 Stable Disease (SD) 
Patient does not satisfy the criteria for PD, or has recovery of ANC ≥ 500/µL and 
fails to qualify for CR, CRi, or PR. 
 
10.7.5 Progressive Disease (PD) 
An increase of at least 25% in the absolute number of bone marrow leukemic cells, 
development of new sites of extramedullary disease, or other laboratory or clinical 
evidence of PD, with or without recovery of ANC or platelets. 
 
10.7.6 MRD Negative  
Patients will be considered MRD negative if their bone marrow has less than 
0.01% blasts by flow cytometric evaluation. MRD should be performed by a COG 
approved laboratory.  
 
10.8 
CNS Leukemia at Diagnosis for Patients with ALL  
 
 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin 
preparation, regardless of the number of WBCs. 
CNS 2:  In CSF, presence < 5/L WBCs and cytospin positive for blasts, or 
≥ 5/L WBCs but negative by Steinherz/Bleyer algorithm: 
CNS 2a: < 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; 
CNS 2b: ≥ 10/L RBCs; < 5/L WBCs and cytospin positive for blasts; 
CNS 2c: 
 
 
≥ 10/L RBCs; ≥ 5/L WBCs and cytospin positive for blasts but 
negative by Steinherz/Bleyer algorithm (see below). 
CNS 3: In CSF, presence of ≥ 5/µL WBCs and cytospin positive for blasts 
and/or clinical signs of CNS leukemia: 
CNS 3a: < 10/L RBCs; ≥ 5/µL WBCs and cytospin positive for blasts; 
CNS 3b: ≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer 
algorithm (see below); 
CNS 3c: 
 
 
Clinical signs of CNS leukemia (such as facial nerve palsy, 
brain/eye involvement or hypothalamic syndrome). 
 
Method of Evaluating Initial Traumatic Lumbar Punctures: 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and contains  5 WBC/L and blasts, the following algorithm should be used to 
distinguish between CNS 2 and CNS 3 disease: 
 
CSF WBC   > 2X   Blood WBC 
CSF RBC               Blood RBC 
A patient with CSF WBC  5/L blasts, whose CSF WBC/RBC is 2X greater than the blood 
WBC/RBC ratio, has CNS disease at diagnosis.  
Example: CSF WBC = 60/L; CSF RBC = 1500/L; blood WBC = 46000/L; blood RBC = 
3.0 X 106/L: 

  
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  60    = 0.04  >  2X     46,000      = 0.015 
 
  
1,500                          3.0 X 106 
 
10.9 
CNS Leukemia at Diagnosis for Patients with AML  
 
Negative In cerebral spinal fluid (CSF), absence of blasts on cytospin 
preparation, regardless of the number of WBCs. 
Positive In CSF, presence blasts on cytospin, regardless of the number of 
WBCs. 
 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event (AE) 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. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, AEs must be submitted 
according to the timeframes in the AE reporting table assigned to the protocol, using the 
CTEP Adverse Event Reporting System (CTEP-AERS). 
 
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. 
 
11.3 
Specific Examples for Expedited Reporting  
 
11.3.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 

  
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possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting table in this protocol.  
 
11.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it occurs 
at any time following treatment since these are considered serious AEs. 
 
11.3.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: Newborn death occurring during the first 28 days after 
birth.  
o 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 term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of “General disorder and 
administration site conditions”. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.3.4 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 metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
All secondary malignancies that occur following treatment with an agent must be 
reported via CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 

  
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Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.3.5 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. 
 
11.3.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: 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 (310) 640-9193. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.3.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should 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 is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.3.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero”. Any 
Pregnancy loss should 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. 
 
11.3.6.3 Death Neonatal  
Neonatal death, defined in CTCAE 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. 
 
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the “General disorders and administration” SOC 
when the death is the result of a patient pregnancy or pregnancy in 
partners of men on study.  
 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men on study as a Grade 5 event since CTEP-

  
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AERS recognizes any Grade 5 event as a patient death.  
 
11.4 
Reporting Requirements for Specialized AEs  
 
11.4.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.4.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.4.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5 
Exceptions to Expedited Reporting 
 
11.5.1 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting table for this protocol. 

  
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11.6 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting and are 
located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report must be submitted electronically to the NCI via CTEP-AERS at: 
https://eapps-ctep.nci.nih.gov/ctepaers.  
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be 
submitted within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect, 
or is an IME, which based upon the medical judgment of the investigator may 
jeopardize the patient and require intervention to prevent a serious AE, must be 
reported via CTEP-AERS if the event occurs following investigational agent 
administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE 
requires expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  

  
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Any medical documentation supporting an expedited report (e.g., H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax 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. 
 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to sponsor (NCI)  ANY SAEs, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64).  
An AE is considered serious if it results in ANY of the following outcomes:  
1) 
Death  
2) 
A life-threatening AE  
3) 
An AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
 ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life 
 functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
 
ALL SAEs that meet the above criteria MUST be immediately reported to the Sponsor via CTEP-
AERS within the timeframes detailed in the table below.   
 
 
Grade 1-3 Timeframes 
 
Grade 4-5 Timeframes 
 
24-Hour notification, 7 calendar days 
 
24-Hour notification, 5 calendar days 
NOTE: Protocol-specific exceptions to expedited reporting of SAEs are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
 
Expedited AE reporting timelines are defined as:  
o 
“24-Hour notification; 5 Calendar Days” - The SAE must initially be reported via CTEP-AERS 
within 24 hours of learning of the SAE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o 
“24-Hour notification, 7 Calendar Days” - The SAE must initially be reported via CTEP-AERS 

  
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within 24 hours of learning of the SAE, followed by a complete expedited report within 7 
calendar days of the initial 24-hour report.   
  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-Hour notifications are required for all SAEs followed by a complete report 
• 
Within 5 calendar days for Grade 4-5 SAEs 
• 
Within 7 calendar days for Grade 1-3 SAEs  
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE 
reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
 
Effective Date: August 30, 2024 
 
11.9 
Protocol Specific Additional Instructions and Reporting Exceptions 
• 
Grades 1 – 4 myelosuppression (anemia, neutropenia, thrombocytopenia, 
leukopenia, lymphopenia) do not require expedited reporting unless it is 
associated with hospitalization.  
 
11.10 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway  
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy with a Commercial Agent or Within 30 Days1 
 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, 
regardless of attribution. Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent that can be attributed (possibly, probably, or definitely) to 
the agent and is not due to cancer recurrence must be reported via CTEP-AERS. 
 
11.11 Routine Reporting of Adverse Events 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 

  
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Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher Adverse Events. 
 
12.0 
 STUDY REPORTING AND MONITORING 
 
The Case Report Forms and the submission schedule are posted on the COG website with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
 
13.0 
 SURGICAL GUIDELINES 
 
13.1 
Guidelines 
a. Biopsies may be by needle or as an open procedure. 
 
b. During the resection of the tumor, biopsy tract must be included and kept in continuity with 
the tumor at all times. 
 
c. For the purpose of this study, a tumor is considered to be resectable if it is anticipated that 
a complete resection (for tumors other than IFS or CMN; see Section 13.2.1) or marginal 
resection (for IFS and CMN; see Section 13.2.2) can be achieved without functional loss, 
neurologic compromise, or significant cosmetic impairment that is not acceptable to the 
patient/family or surgeon. In particular, tumors that would require amputation of an arm or 
leg, resection of a major nerve, or for which resection is anticipated to result in major 
neurologic deficits are NOT considered resectable for the purpose of this protocol. Patients 

  
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who do not meet this definition should continue larotrectinib per protocol until their tumor 
becomes resectable or for a maximum of 26 cycles of therapy (see Section 4.1.3). 
 
13.2 
Definition of Margins  
 
13.2.1 Incomplete Resection (Incisional Resection; R2): Tumor resection that leaves 
gross (macroscopic) residual tumor behind.  
 
13.2.2 Marginal Resection (Gross Total Resection with Positive Microscopic Margins; 
R1):  
a. 
Tumor resection that leaves no residual macroscopic tumor behind, but 
there is microscopic tumor present at the margins of the specimen OR 
b. 
Biopsies of grossly uninvolved areas of the tumor bed that contain tumor 
cells microscopically. 
 
13.2.3 Complete Resection (Gross Total Resection with Negative Margins; R0): removal 
of tumor entirely with microscopic absence of tumor on the inked margins.  
 
13.2.4 If rupture of the tumor occurs during the resection and tumor is spilled, the 
resection should be considered to be marginal (if gross tumor removal is 
accomplished) or incomplete (if gross tumor is left behind). 
 
 
 

  
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Rubin JB,Segal RA: Growth, survival and migration: the Trk to cancer. Cancer Treat Res 115:1-
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Amatu A, Sartore-Bianchi A,Siena S: NTRK gene fusions as novel targets of cancer therapy across 
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Bourgeois JM, Knezevich SR, Mathers JA, et al.: Molecular detection of the ETV6-NTRK3 gene 
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Knezevich SR, Garnett MJ, Pysher TJ, et al.: ETV6-NTRK3 gene fusions and trisomy 11 establish 
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Martin-Zanca D, Hughes SH,Barbacid M: A human oncogene formed by the fusion of truncated 
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Pavlick D, Schrock AB, Malicki D, et al.: Identification of NTRK fusions in pediatric mesenchymal 
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Prasad ML, Vyas M, Horne MJ, et al.: NTRK fusion oncogenes in pediatric papillary thyroid 
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Sheng WQ, Hisaoka M, Okamoto S, et al.: Congenital-infantile fibrosarcoma. A clinicopathologic 
study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-
embedded tissues. Am J Clin Pathol 115:348-55, 2001 
13. 
Stransky N, Cerami E, Schalm S, et al.: The landscape of kinase fusions in cancer. Nat Commun 
5:4846, 2014 
14. 
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 46:444-50, 2014 
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Coffin CM, Jaszcz W, O'Shea PA, et al.: So-called congenital-infantile fibrosarcoma: does it exist 
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Coffin CM,Alaggio R: Fibroblastic and myofibroblastic tumors in children and adolescents. Pediatr 
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Coffin CM,Dehner LP: Soft tissue tumors in first year of life: a report of 190 cases. Pediatr Pathol 
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Orbach D, Rey A, Oberlin O, et al.: Soft tissue sarcoma or malignant mesenchymal tumors in the 
first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant 
Mesenchymal Tumor Committee. J Clin Oncol 23:4363-71, 2005 
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Knezevich SR, McFadden DE, Tao W, et al.: A novel ETV6-NTRK3 gene fusion in congenital 
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Wong V, Pavlick D, Brennan T, et al.: Evaluation of a Congenital Infantile Fibrosarcoma by 
Comprehensive Genomic Profiling Reveals an LMNA-NTRK1 Gene Fusion Responsive to 
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report]. Arch Pediatr 18:28-32, 2011 
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van Grotel M, Blanco E, Sebire NJ, et al.: Distant metastatic spread of molecularly proven infantile 
fibrosarcoma of the chest in a 2-month-old girl: case report and review of literature. J Pediatr 
Hematol Oncol 36:231-3, 2014 
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Orbach D, Brennan B, De Paoli A, et al.: Conservative strategy in infantile fibrosarcoma is possible: 
The European paediatric Soft tissue sarcoma Study Group experience. Eur J Cancer 57:1-9, 2016 
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Orbach D, Rey A, Cecchetto G, et al.: Infantile fibrosarcoma: management based on the European 
experience. J Clin Oncol 28:318-23, 2010 
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Bolande RP, Brough AJ,Izant RJ, Jr.: Congenital mesoblastic nephroma of infancy. A report of 
eight cases and the relationship to Wilms' tumor. Pediatrics 40:272-8, 1967 
26. 
van den Heuvel-Eibrink MM, Grundy P, Graf N, et al.: Characteristics and survival of 750 children 
diagnosed with a renal tumor in the first seven months of life: A collaborative study by the 
SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups. Pediatr Blood Cancer 
50:1130-4, 2008 
27. 
Gooskens SL, Houwing ME, Vujanic GM, et al.: Congenital mesoblastic nephroma 50 years after 
its recognition: A narrative review. Pediatr Blood Cancer, 2017 
28. 
Tognon C, Knezevich SR, Huntsman D, et al.: Expression of the ETV6-NTRK3 gene fusion as a 
primary event in human secretory breast carcinoma. Cancer Cell 2:367-76, 2002 
29. 
Skálová A, Vanecek T, Sima R, et al.: Mammary analogue secretory carcinoma of salivary glands, 
containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am 
J Surg Pathol 34:599-608, 2010 
30. 
Wiesner T, He J, Yelensky R, et al.: Kinase fusions are frequent in Spitz tumours and spitzoid 
melanomas. Nat Commun 5:3116, 2014 
31. 
Hunger SP,Mullighan CG: Acute Lymphoblastic Leukemia in Children. N Engl J Med 373:1541-
52, 2015 
32. 
Roberts KG, Li Y, Payne-Turner D, et al.: Targetable kinase-activating lesions in Ph-like acute 
lymphoblastic leukemia. N Engl J Med 371:1005-15, 2014 
33. 
Nguyen K, Devidas M, Cheng SC, et al.: Factors influencing survival after relapse from acute 
lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22:2142-50, 2008 
34. 
Taylor J, Marcelus C, Pavlick D, et al.: Characterization of Ntrk fusions and Therapeutic Response 
to Ntrk Inhibition in Hematologic Malignancies. Presented at the ASH Annual Meeting, Atlanta, 
GA, 2017 
35. 
Kralik JM, Kranewitter W, Boesmueller H, et al.: Characterization of a newly identified ETV6-
NTRK3 fusion transcript in acute myeloid leukemia. Diagn Pathol 6:19, 2011 
36. 
Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers 
in Adults and Children. N Engl J Med 378:731-739, 2018 
37. 
Reid T: Reintroduction of imatinib in GIST. J Gastrointest Cancer 44:385-92, 2013 
38. 
Turpin B, Albert CM, Mascarenhas L, et al.: A pediatric phase 1 study of larotrectinib, a highly 
selective inhibitor of the tropomyosin receptor kinase (TRK) family: an updated analysis. Presented 
at the AACR, Atlanta, GA, 2017 
39. 
Drilon A, Nagasubramanian R, Blake JF, et al.: A Next-Generation TRK Kinase Inhibitor 
Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-
Positive Solid Tumors. Cancer Discov 7:963-972, 2017 
40. 
Klega K, Imamovic-Tuco A, Ha G, et al.: Detection of Somatic Structural Variants Enables 
Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors. 
JCO Precis Oncol 2018, 2018 
41. 
Shulman DS, Klega K, Imamovic-Tuco A, et al.: Detection of circulating tumour DNA is 
associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's 
Oncology Group. Br J Cancer 119:615-621, 2018 

  
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42. 
Tessarollo L, Tsoulfas P, Donovan MJ, et al.: Targeted deletion of all isoforms of the trkC gene 
suggests the use of alternate receptors by its ligand neurotrophin-3 in neuronal development and 
implicates trkC in normal cardiogenesis. Proc Natl Acad Sci U S A 94:14776-81, 1997 
43. 
Sanchez-Ortiz E, Yui D, Song D, et al.: TrkA gene ablation in basal forebrain results in dysfunction 
of the cholinergic circuitry. J Neurosci 32:4065-79, 2012 
44. 
Johnson EM, Craig ET,Yeh HH: TrkB is necessary for pruning at the climbing fibre–Purkinje cell 
synapse in the developing murine cerebellum. J Physiol 582:629-46, 2007 
45. 
Yeo GS, Connie Hung CC, Rochford J, et al.: A de novo mutation affecting human TrkB associated 
with severe obesity and developmental delay. Nat Neurosci 7:1187-9, 2004 
46. 
Indo Y: Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory 
and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in 
TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton 
Res 12 Suppl 1:I20-32, 2002 
47. 
Laetsch TW, Voss S, Ludwig K, et al.: Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma 
and Other Pediatric NTRK Fusion-Positive Solid Tumors (Children's Oncology Group 
ADVL1823). J Clin Oncol:Jco2401854, 2024 
48. 
Schwartz GJ,Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J 
Pediatr 106:522-6, 1985 
49. 
Abo RP, Ducar M, Garcia EP, et al.: BreaKmer: detection of structural variation in targeted 
massively parallel sequencing data using kmers. Nucleic Acids Res 43:e19, 2015 
50. 
Shukla NN, Patel JA, Magnan H, et al.: Plasma DNA-based molecular diagnosis, prognostication, 
and monitoring of patients with EWSR1 fusion-positive sarcomas. JCO Precis Oncol 2017, 2017 
51. 
Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
52. 
Cheson B,et al: Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for 
Therapeutic Trials in Acute Myeloid Leukemia. JCO 21:4642-4649, 2003 
53. 
VITRAKVI® (larotrectinib) [package insert]. Stamford, CT: Loxo Oncology, Inc., 2018 
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Gioia GA, Isquith PK, Guy SC, et al.: Behavior Rating Inventoy of Executive Function. PAR, 2000 
 

  
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified investigators. National 
Cancer Institute (NCI) policy requires all individuals contributing to any NCI-sponsored trials to register 
with their qualifications and credentials to renew their registration annually. To register, all individuals must 
obtain Cancer Therapy Evaluation Program (CTEP) credentials necessary to access secure NCI Clinical 
Oncology Research Enterprise (CORE) systems. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository (RCR). The RCR is a 
self-service online person registration application with electronic signature and document submission 
capability. 
 
RCR utilizes four person registration types that are applicable to this study. 
• Investigator (IVR) — MD, DO, or international equivalent; 
• Non-Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
• Associate Plus (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; and 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials. 
  
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI 
Biosketch 
(education, 
training, 
employment, license, and certification) 
 
 
 
 
GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Selection as the treating, credit, or consenting person in OPEN; 
• 
Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
• 
Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting or treating investigator in OPEN, or as the CI on the DTL must be rostered at the 
enrolling site with a participating organization.   

  
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Refer to the NCI RCR page on the CTEP website for additional information. For questions, please 
contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
 
CTSU Registration Procedures 
 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on the person and site roster assignment housed in the Roster Maintenance application and 
in most cases viewable and manageable via the Roster Update Management System (RUMS) on 
the Cancer Trials Support Unit (CTSU) members’ website. 
 
This study is supported by the NCI CTSU. 
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted to institutions and their associated investigators and staff on a participating roster. To 
view/download site registration forms:  
• 
Log in to the CTSU members’ website (https://www.ctsu.org); 
• 
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, Protocol Related Documents, and use the Document Type filter 
and select Site Registration to download and complete the forms provided. (Note: For 
sites under the CIRB, IRB data will load automatically to the CTSU.) 
 
Protocol-Specific Requirements For ADVL1823 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted) 
• 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must be 
aligned to an RTI provider. To manage provider associations, access the Provider Association page 
from 
the 
Regulatory 
section 
on 
the 
CTSU 
members’ 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation.aspx. Sites must be linked to at least one 
Imaging and Radiation Oncology Core (IROC) provider to participate on trials with an RTI 
component. Enrolling sites are responsible for ensuring that the appropriate agreements and IRB 
approvals are in place with their RTI provider. Only an individual with a primary role on a treating 
site roster can update the provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, view the Person Roster Browser under 
the RUMS section on the CTSU members’ website. 
 

  
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Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
 
 
 
 
 
 

  
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Checking Your Site’s Registration Status 
 
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol Status, 
and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Data Submission / Data Reporting 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
o Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
o Rave Read Only or Rave SLA role must have at a minimum an Associates (A) 
registration type. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons with 
Rave roles assigned on the appropriate roster will be sent a study invitation email from iMedidata. 
No action will be required; each study invitation will be automatically accepted and study access 
to the study in Rave will be automatically granted.  Site staff will not be able to access the study in 
Rave until all required Medidata and study-specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the eLearning 
link in the Tasks pane located in the upper right corner of the iMedidata screen. If an eLearning is 
required for a study and has not yet been taken, the link to the eLearning will appear under the 
study name in the Studies pane located in the center of the iMedidata screen; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be granted, and a 
Rave EDC link will replace the eLearning link under the study name. 
 
 
 

  
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APPENDIX II:  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1823 
(for children from 7 through 12 years of age) 
 
A study of larotrectinib in patients with a cancer that has a TRK fusion 
 
 
1. We are asking you to take part in a research study because you have 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. We will do this by trying 
a new medicine to treat your cancer.  
 
2. People who are part of this study will be treated with a cancer-fighting medicine called 
larotrectinib. You will also have regular tests and exams done more often while you are in this 
study. The doctors want to see if larotrectinib will make people with your type of cancer get 
better. We don’t know if larotrectinib will work well to get rid of your cancer. That is why we are 
doing this study.  
 
3. 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 
larotrectinib may cause your cancer to shrink or go away but we don’t know for sure if there is 
any benefit of being part of this study. 
 
4. 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 larotrectinib. Other things may happen to you that we don’t yet know about. 
 
5. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
6. 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. These samples would be taken when other standard 
blood tests are being performed, so there would be no extra procedures. You can still take part in 
this study even if you don't allow us to collect the extra blood samples for research. If you have 
leukemia, we will also collect a watery fluid that flows through your brain and spinal cord called 
cerebrospinal fluid. These samples will be taken when other standard procedures are being 
performed, so there will be no extra procedures for us to collect the cerebrospinal fluid.    
 
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY ADVL1823 
(for teens from 13 through 17 years of age) 
 
A study of larotrectinib in patients with a cancer that has a TRK fusion 
 
 
1. We have been talking with you about your cancer. After doing tests, we have found that you have a 
type of cancer that has a mutation called a TRK fusion.  
 
2. We are asking you to take part in a research study because you have cancer with a TRK fusion. 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 cancers with TRK fusions.   
 
3. People who are part of this study will be given a cancer-fighting medicine called larotrectinib. 
Larotrectinib works to fight against TRK fusions. You will be given larotrectinib by mouth twice 
daily for a 28-day period. This entire 28-day period is called a cycle. You may continue to receive 
larotrectinib for up to about 2 years (26 cycles) as long as you do not have bad effects from it and 
your cancer does not get any worse. If your cancer gets better, you may undergo surgery to remove 
your tumor and/or be told to stop taking larotrectinib but you will continue to be monitored.  
 
4. You will also have regular tests and exams done more often while you are in this study. The doctors 
want to see if larotrectinib will make people with your type of cancer get better. We don’t know if 
larotrectinib will work well to get rid of your cancer. That is why we are doing this study.  
 
5. Sometimes good things can happen to people when they are in a research study.  These good things 
are called “benefits.”  We hope that a benefit to you of being part of this study is that larotrectinib 
may cause your cancer to shrink or go away but we don’t know for sure if there is any benefit of 
being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you may have problems or side effects from 
larotrectinib. Other things may happen to you that we don’t yet know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your doctor 
can tell you about. Make sure to ask your doctors any questions that you have.  
 
8. 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. These samples would be taken when other standard blood 
tests are being performed, so there would be no extra procedures. You can still be treated on this 
study even if you don't allow us to collect the extra blood samples for research. If you have leukemia, 
we will also collect a watery fluid that flows through your brain and spinal cord called cerebrospinal 
fluid. These samples will be taken when other standard procedures are being performed, so there will 
be no extra procedures for us to collect the cerebrospinal fluid. 
 
 
     

  
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APPENDIX III:  TISSUE STUDIES FORM 
 
COG Pt ID # _______________ 
ACC # ______________ Date:________       
(Please do not write patient names on this form or on samples) 
 
Sample Labeling: 
Samples should be labeled with the following information: 
Protocol number:    ADVL1823 
Institution:        _________________ 
Patient ID #:     _________________ 
Accession #:     _________________  
Cycle #:            _________________ (Write “N/A” for archival tissue) 
Sample Date:    _________________ 
Site of Acquired Tissue:  __________________ 
 
Tissue obtained at (check one option below): 
Archived    Relapse     Time of local control       Time of bone marrow evaluation 
 
Tissue sample is from a: 
    Resection     or       Biopsy 
Shipment of Tumor Tissue: 
Archival tumor tissue submission is required and must be sent following patient enrollment. Additionally, tumor tissue 
must be sent following resection at time of local control, following bone marrow evaluation for patients with bone 
marrow involvement, and/or following optional biopsy post disease progression. Archived tissue samples should be 
in the form of 1 H&E stained slide from all available formalin-fixed paraffin embedded (FFPE) tissue blocks and 15 
unstained slides from the most representative block or the block itself. Samples should be accompanied by a copy of 
the pathology report. Fine needle aspirate samples or other cytology samples are not acceptable and tumor samples 
obtained from bone metastases are generally not considered acceptable. 
 
All blocks or slides must be labeled with the patient’s study registration number (COG Patient ID #), the study I.D. 
(ADVL1823), and the sample collection date. Data should be recorded on this Tissue Studies Form, which must 
accompany the sample(s) to the address provided in Section 7.3.1.4.  
 
1. If sending paraffin block (PREFERRED): 
a. 
Place appropriate sample ID label on back of cassette 
b. Place labeled cassette in a Zipper lock bag  
c. 
Paraffin blocks are shipped to the lab at ambient temperature. It is acceptable to send blocks 
refrigerated if sending blocks and slides together. 
 
2. If sending slides: 
If slides will be cut from tissue block, recommended thickness of tissue sections for slides is 4 microns. 
Positively charged slides are required (Superfrost Plus is recommended). After cutting, the slides should be 
kept in refrigerator (2-5°C). 
a. 
Place slides in the plastic slide holder and place sample ID label provided on the slide holder 
b. Place the slide holder in the Zipper lock bag and eliminate as much air (and therefore moisture) as 
possible prior to sealing the Zip-lock bag 
c. 
Slides are shipped to the lab at refrigerated temperature on a cold gel pack. It is acceptable to send 
blocks refrigerated if sending blocks and slides together. 
 
One copy of this form should be uploaded into RAVE.   
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
Signature: _________________________________________          Date:________________________________ 
                (site personnel responsible for collection of samples) 

  
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APPENDIX IV:  CIRCULATING TUMOR DNA 
 
COG Pt ID # _______________ 
 
 
 
 
                       Date: 
_____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg   
 
 
 
 
 
       Body Surface Area: ________m2 
 
Larotrectinib Dose Level: ________ mg/m2 BID  
 
 
Larotrectinib Daily Dose: __________ mg BID 
 
Blood samples will be collected in consenting patients in Streck Cell-Free DNA BCT tubes at the following time 
points: prior to Cycle 1, Day 15 of Cycle 1 of larotrectinib therapy, Day 1 of Cycle 2 of larotrectinib therapy, at the 
end of Cycle 6 of larotrectinib therapy (prior to Cycle 7 or local control), at the end of study treatment, and at the time 
of progression.  
 
Peripheral blood samples for circulating tumor DNA should be obtained as follows:  
• 
For patients > 10 kg, collect 20 mL (10 mL per tube x 2 tubes) 
• 
For patients > 5 kg but < 10kg, collect 10 mL (1 tube) 
• 
For patients < 5 kg, collect 5 mL in 1 tube   
 
Record the exact date and time the sample is drawn.  
 
Blood 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time 
Sample Collected 
1 
Pre-Cycle 1, Day 1 
 
 
|__|__| : |__|__| 
2 
Cycle 1, Day 15 
Prior to AM dose 
 
|__|__| : |__|__| 
Larotrectinib AM Dose on Cycle 1, Day 15        Date:___/___/___                Time Dose Given: |__|__| : |__|__|      
   3 
Cycle 2, Day 1 
Prior to AM dose 
 
|__|__| : |__|__| 
Larotrectinib AM Dose on Cycle 2, Day 1        Date:___/___/___                Time Dose Given: |__|__| : |__|__|       
4 
End of Cycle 6 
Prior to Cycle 7, Day 1 AM 
dose OR prior to local control 
 
|__|__| : |__|__| 
Larotrectinib AM Dose on Cycle 7, Day 1        Date:___/___/___                Time Dose Given: |__|__| : |__|__|     
5 
End of study 
treatment 
 
 
|__|__| : |__|__| 
6 
At the time of 
progression1 
 
 
|__|__| : |__|__| 
 
 
1 If applicable 
 
 
One copy of this ctDNA Form should be uploaded into RAVE. A second copy should be sent with the samples to the 
address listed in Section 7.3.2.4. See Section 7.3.2.3 for detailed guidelines for packaging and shipping PK samples. 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
Signature: _________________________________________                
        Date:___________________ 
 
    (site personnel responsible for collection of samples) 

  
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APPENDIX V: LAROTRECTINIB DRUG INTERACTIONS  
 
Some drugs, food, and supplements may interact with larotrectinib.  Examples include: 
Drugs that may interact with larotrectinib* 
• Antibiotics  
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifapentin, rifampin, telithromycin 
• Antifungals  
• Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, voriconazole 
• Anti-rejection medications 
• Cyclosporine, tacrolimus, sirolimus 
• Antiretrovirals and antivirals  
• Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir, 
tenofovir, tipranavir 
• Anti-seizure medications  
• Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, carvedilol, diltiazem, dronedarone, propafenone, quinidine, ranolazine,  
verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, eltrombopag, fosnetupitant, 
ivacaftor, mifepristone, modafinil, nefazodone, netupitant  
 
Food and supplements that may interact with larotrectinib** 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Sometimes these drugs are used with larotrectinib on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to your 
doctor before starting any new medications, over-the-counter medicines or herbal supplements and 
before making a significant change in your diet. 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX VI: CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references.  
 
 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers 
abemaciclib 
acalabrutinib5 
alectinib 
alfentanil4,5  
amiodarone4 
apixaban 
aprepitant/fosaprepitant 
aripiprazole 
axitinib 
benzodiazepines5 
bortezomib 
bosutinib5 
brexpiprazole 
brigatinib 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers  
carbamazepine 
ceritinib 
citalopram 
clobazam 
cobimetinib5 
cobicistat 
codeine 
colchicine5 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
daflazacort2 
dexamethasone2 
dihydroergotamine 
docetaxel 
domperidone 
doxorubicin 
dronedarone5 
elagolix 
elbasvir/grazoprevir 
adagrasib 
atazanavir 
ceritinib 
clarithromycin 
cobicistat 
darunavir 
grapefruit3 
grapefruit juice3 
idelalisib 
itraconazole 
ketoconazole 
levoketoconazole 
lonafarnib 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
nirmatrelvir/ritonavir 
paritaprevir/ritonavir/ 
ombitasvir +/- dasabuvir 
posaconazole 
ritonavir 
tipranavir/ritonavir 
tucatinib 
voriconazole 
aprepitant 
avacopan 
berotralstat 
crizotinib 
diltiazem 
dronedarone 
duvelisib 
erythromycin 
fedratinib 
fluconazole 
fosamprenavir 
fosnetupitant 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
lenacapavir 
letermovir 
mifepristone 
netupitant 
nilotinib 
nirogacestat 
ribociclib 
verapamil 
apalutamide 
barbiturates 
carbamazepine 
encorafenib 
enzalutamide 
fosphenytoin 
lumacaftor/ 
ivacaftor 
mitotane 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bexarotene 
bosentan 
cenobamate 
dabrafenib 
efavirenz 
eslicarbazepine 
etravirine 
lorlatinib 
mitapivat 
modafinil 
nafcillin 
pexidartinib 
repotrectinib 
rifabutin 
rifapentin 
sotorasib 
 
 
 

  
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eletriptan5 
eliglustat5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
irinotecan  
isavuconazole5 
itraconazole 
ivabradine 
ivacaftor 
ketoconazole 
lapatinib 
lidocaine 
linagliptin 
lorlatinib 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midostaurin5 
naldemedine 
naloxegol5 
nelfinavir 
neratinib 
netupitant 
nevirapine 
nilotinib 
nirogacestat 
olaparib 
osimertinib 
oxycodone 
paclitaxel 
palbociclib 
panobinostat 
pazopanib 
pimozide5 
ponatinib 
quetiapine5 
quinidine4  
regorafenib 
ribociclib 

  
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rilpivirine5 
risperidone 
rivaroxaban5 
rolapitant 
romidepsin 
ruxolitinib 
selumetinib 
sildenafil5 
simeprevir 
sirolimus4,5 
sonidegib 
sorafenib 
sotorasib 
statins  
sunitinib 
suvorexant 
tacrolimus4,5  
tamoxifen 
tasimelteon 
temsirolimus 
teniposide 
ticagrelor5 
tipranavir5 
tofacitinib 
tolvaptan5 
tramadol 
trazodone 
vandetanib 
vardenafil5 
vemurafenib 
venetoclax5 
vilazodone 
vinca alkaloids 
vorapaxar 
voriconazole 
zaleplon 
ziprasidone 
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 _____ 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 VII-A: MEDICATION DIARY (LAROTRECTINIB CAPSULE FORMULATION) 
 
COG Patient ID:___________   ACC # : _____     Institution :__________________ BSA:_____ m2 
 
Please do not write patient names on this form. 
 
Instructions: Store your capsules at room temperature and away from areas of high heat and humidity. 
 
Complete each day with the time and dose given for larotrectinib. If a dose is accidentally skipped, leave that section blank. 
Make note of other drugs and supplements taken under the Comments section below. Larotrectinib capsules should not 
be opened and must be swallowed whole. You should take each dose of larotrectinib approximately 12 hours apart, at about 
the same time each day. If you vomit after taking a dose, DO NOT retake the dose. This should be noted in the comments 
section. If you forget a dose and remember it within 4 hours of the time the dose was due, you should take the dose at that 
time. Otherwise, you should skip the forgotten dose. Either way, the next dose should be taken at the usual time. If a dose 
is accidentally skipped leave that section blank. Add the dates to the calendar below and return the completed diary and the 
empty bottle or any leftover capsules to the study clinic at each visit (weekly during Cycle 1, and then after each treatment 
cycle). 
 
EXAMPLE 
Day 
Date 
Time 
# of larotrectinib capsules prescribed to 
take 
Comments  
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
25 mg 
100 mg 
AM#_3__ 
PM#_3__ 
AM#___ 
PM#___ 
# of larotrectinib tablets taken  
25 mg 
100 mg 
Day 1 
09/20/18 
8:30 
AM 
3 
 
He felt nauseated an hour after taking 
the drug but did not vomit. 
8:30 
PM 
3 
 
 
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|     
                              End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2/dose                                                   
Day 
Date 
Time 
# of larotrectinib capsules prescribed to 
take 
Comments 
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
25 mg 
100 mg 
      AM #___ 
      PM #___ 
      AM #___ 
      PM #___ 
# of larotrectinib capsules taken 
25 mg 
100 mg 
Day 1 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 2 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 3 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 4 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 5 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 6 
 
 
AM 
 
 
 
 
PM 
 
 
 

  
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Day 7 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 8 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 9 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 10 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 11 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 12 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 13 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 14 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 15 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 16 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 17 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 18 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 19 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 20 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 21 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 22 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 23 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 24 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 25 
 
 
AM 
 
 
 
 
PM 
 
 
 
Day 26 
 
 
AM  
 
 
 
 
PM 
 
 
 
Day 27 
 
 
AM  
 
 
 
 
PM 
 
 
 

  
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Day 28 
 
 
AM  
 
 
 
 
PM 
 
 
 

  
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APPENDIX VII-B: MEDICATION DIARY (LAROTRECTINIB LIQUID FORMULATION) 
 
COG Patient ID:___________   ACC # : _____     Institution :__________________ BSA:_____ m2 
 
Please do not write patient names on this form. 
 
Instructions: Store the larotrectinib liquid formulation in the refrigerator. 
 
Complete each day with the time and dose given for larotrectinib. If a dose is accidentally skipped, leave that section blank. 
Make note of other drugs and supplements taken in the Comments section below. You should take each dose of 
larotrectinib approximately 12 hours apart, at about the same time each day. If you vomit after taking a dose, DO NOT 
retake the dose. This should be noted in the comments section.  If you forget a dose and remember it within 4 hours of the 
time the dose was due, you should take the dose at that time. Otherwise, you should skip the forgotten dose. Either way, the 
next dose should be taken at the usual time. If a dose is accidentally skipped leave that section blank.  Add the dates to the 
calendar below and return the completed diary and the empty liquid formulation bottle(s) or any leftover liquid formulation 
to the study clinic at each visit (weekly during Cycle 1, and then after each treatment cycle). 
 
EXAMPLE 
Day 
Date 
Time 
AM Dose: Take ___2__ mL 
PM Dose: Take ___2__ mL 
Comments  
(Describe any missed or extra doses, 
vomiting and/or bothersome effects.) 
Amount of larotrectinib liquid 
formulation taken (mL) 
Day 1 
09/20/18 
8:30 
AM 
2 
He felt nauseated an hour after taking 
the drug but did not vomit. 
8:30 
PM 
2 
 
 
Cycle #: _____    Start Date: |__/__|__/__|__/__|     
                              End Date: |__/__|__/__|__/__|              Dose Level:            mg/m2/dose                                                   
Day 
Date 
Time 
AM Dose: Take ______ mL 
PM Dose: Take ______ mL 
Comments 
(Describe any missed or extra doses, vomiting 
and/or bothersome effects.) 
Amount of larotrectinib 
liquid formulation taken 
(mL) 
Day 1 
 
 
AM  
 
 
 
PM 
 
 
Day 2 
 
 
AM  
 
 
 
PM 
 
 
Day 3 
 
 
AM  
 
 
 
PM 
 
 
Day 4 
 
 
AM  
 
 
 
PM 
 
 
Day 5 
 
 
AM 
 
 
 
PM 
 
 
Day 6 
 
 
AM 
 
 
 
PM 
 
 
Day 7 
 
 
AM 
 
 
 
PM 
 
 
Day 8 
 
 
AM 
 
 
 
PM 
 
 

  
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Day 9 
 
 
AM 
 
 
 
PM 
 
 
Day 
10 
 
 
AM 
 
 
 
PM 
 
 
Day 
11 
 
 
AM 
 
 
 
PM 
 
 
Day 
12 
 
 
AM 
 
 
 
PM 
 
 
Day 
13 
 
 
AM 
 
 
 
PM 
 
 
Day 
14 
 
 
AM 
 
 
 
PM 
 
 
Day 
15 
 
 
AM 
 
 
 
PM 
 
 
Day 
16 
 
 
AM 
 
 
 
PM 
 
 
Day 
17 
 
 
AM 
 
 
 
PM 
 
 
Day 
18 
 
 
AM 
 
 
 
PM 
 
 
Day 
19 
 
 
AM  
 
 
 
PM 
 
 
Day 
20 
 
 
AM 
 
 
 
PM 
 
 
Day 
21 
 
 
AM  
 
 
 
PM 
 
 
Day 
22 
 
 
AM  
 
 
 
PM 
 
 
Day 
23 
 
 
AM 
 
 
 
PM 
 
 
Day 
24 
 
 
AM  
 
 
 
PM 
 
 
Day 
25 
 
 
AM 
 
 
 
PM 
 
 
Day 
26 
 
 
AM  
 
 
 
PM 
 
 
Day 
27 
 
 
AM  
 
 
 
PM 
 
 
Day 
28 
 
 
AM  
 
 
 
PM 
 
 
 
 
 

  
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Instructions for drawing up larotrectinib oral solution into a syringe: 
Information and images adapted from VITRAKVI® (larotrectinib) package insert.53  
 
Important information about measuring larotrectinib oral solution:  
• Always use the oral syringes provided with larotrectinib to make sure that you correctly measure the 
prescribed dose.  
• When you receive larotrectinib oral solution, you will get 1 or more glass bottles of larotrectinib oral 
solution and a bottle adapter.  
• You will receive oral syringes that are marked to help you correctly measure the prescribed dose of 
larotrectinib oral solution. Each oral syringe may be used for up to a 7-day period and then must be 
discarded. Do not use a household teaspoon to measure the dose. 
 
Supplies needed for administering larotrectinib (See Figure A): 
• 
Bottle of larotrectinib 
• 
Oral syringe 
• 
Bottle adapter 
• 
Gloves 
   
 
Step 1: Put on gloves.  Place the larotrectinib bottle on a flat work surface. Open the bottle by pushing down 
firmly on the child-resistant cap and turning it in the direction of the arrow (counter-clockwise). See Figure 
B. Do not throw away the child-resistant cap. 

  
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Step 2: Insert the bottle adapter by pressing it into the bottle neck and make sure it is secure. See Figure C. 
Do not remove the bottle adapter. If the bottle adapter is missing, talk to your healthcare provider. 
 
 
Step 3: Remove the oral syringe from the wrapper. Throw the wrapper away in your household trash. The 
barrel of the oral syringe has markings in milliliters (mL). Look at the markings on the barrel of the oral 
syringe and find the mL marking that matches the larotrectinib oral solution dose in mL prescribed by your 
healthcare provider. See Figure D. 

  
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Step 4: With the bottle on your flat work surface, use 1 hand to hold the bottle upright. Using your other 
hand, push the air out of the oral syringe by pushing the plunger down. Then, insert the tip of the oral 
syringe into the bottle adapter at the top of the bottle. See Figure E. The tip of the oral syringe should fit 
snugly into the hole of the bottle adapter. 
 
 
Step 5: Use 1 hand to hold the oral syringe in place. With the other hand, turn the bottle upside down. Pull 
back on the plunger until the top of the plunger lines up with the marking on the barrel of the oral syringe 
that matches the dose of larotrectinib oral solution prescribed by your healthcare provider. See Figure F. 
Your dose may be different than the dose shown in Figure F. 

  
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Step 6: Check for air bubbles in the oral syringe. If you see air bubbles, push up gently on the plunger to 
push any large air bubbles back into the bottle. Then, pull back on the plunger to the prescribed dose. See 
Figure G. 
 
 

  
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Step 7: Turn the bottle upright again and place it on your work surface. Remove the oral syringe from the 
bottle adapter by gently pulling up on the syringe barrel. See Figure H. Do not push on the plunger during 
this step. The bottle adapter should stay attached to the bottle. 
 
 
Step 8: Place the tip of the oral syringe into the child’s mouth against the inside of the cheek. Slowly squirt 
larotrectinib oral solution into the mouth by pressing down on the plunger and allow the child to swallow. 
See Figure I. If the child has an NG or G-tube you may administer larotrectinib via the tube instead of into 
the mouth if instructed by your healthcare provider. The child should be kept in an upright position for a 
few minutes right after giving a dose of larotrectinib.  
 
 
Step 9: Replace the child-resistant cap on the bottle of larotrectinib oral solution. Do not remove the bottle 
adapter. Close the bottle by turning the bottle cap in the direction of the arrow (clockwise). See Figure J. 

  
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Cleaning instructions for oral syringe:  
Follow the instructions below for cleaning the oral syringe (Step 10 through Step 16). After 7 days of use, 
throw away the oral syringe in your household trash. Use a new one for the next 7 days. 
 
Step 10: Remove plunger from the barrel of the oral syringe. See Figure K. 
 
 
Step 11: Rinse the barrel and plunger in warm running water to help ensure that all of the medicine has 
been removed from the oral syringe. See Figure L. Do not boil the oral syringe. 

  
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Step 12: Re-insert the plunger into the barrel of the oral syringe. See Figure M. 
 
 
Step 13: Draw warm water several times into the oral syringe and squirt out again until all of the medicine 
has been removed from the oral syringe. See Figure N. 

  
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Step 14: Disassemble the oral syringe, and rinse the barrel and plunger again with warm water. See Figure 
O. 
 
 
Step 15: Shake off excess water or wipe off the outside, and the place the barrel and plunger on a clean, dry 
paper towel to dry. See Figure P.  Remove gloves and place in regular household trash. 

  
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Step 16: Assemble the oral syringe and store in a clean place until the next use.  
Replace the oral syringe after 7 days of use, or if:  
• there is any damage to the barrel, plunger, or tip  
• the dosage marking is no longer clearly recognizable   
• it becomes difficult to move the plunger 
 
 
 

  
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APPENDIX VIII: CSF AND PLASMA PHARMACOKINETIC STUDY FORM 
 
COG Pt ID # _______________ 
 
 
 
 
                       Date: 
_____________
 
Please do not write patient names on this form or on samples. 
 
Patient Weight: ______kg   
 
 
 
 
 
       Body Surface Area: ________m2 
 
Larotrectinib Dose Level: ________ mg/m2 BID  
 
 
Larotrectinib Daily Dose: __________ mg BID 
 
For all patients with leukemia, a CSF and plasma sample will be collected after Cycle 1, during the first disease 
evaluation after starting protocol therapy. The plasma sample will be obtained as close as possible to the same time as 
the CSF sample. In patients who are undergoing lumbar puncture (LP) for intrathecal chemotherapy administration, a 
CSF and plasma sample will also be collected at the time of lumbar puncture. The plasma sample will be obtained as 
close as possible to the same time as the CSF sample.  Samples will be collected during Cycle 1 on the following days: 
Day 8, Day 15, and Day 22. There is no required time window from the most recent larotrectinib dose, but the dose 
and time of administration must be recorded.  
 
Record the exact time both samples are drawn along with the exact time and dose of the most recent dose of 
larotrectinib that was given prior to the lumbar puncture.   
 
Sample 
No. 
Time Point 
Scheduled Collection Time 
Actual Date 
Sample 
Collected  
Actual Time CSF 
Collected  
(24-hr clock) 
Actual Time 
Plasma Collected  
(24-hr clock) 
Most recent larotrectinib dose prior to LP        Date:___/___/___               Time Dose Given: |__|__| : |__|__| 
Actual larotrectinib dose administered _______ mg = ______ mg/m2        
1* 
Cycle 1, Day 8 
At time of lumbar puncture 
 
|__|__| : |__|__| 
|__|__| : |__|__| 
Most recent larotrectinib dose prior to LP        Date:___/___/___              Time Dose Given: |__|__| : |__|__| 
Actual larotrectinib dose administered _______ mg = ______ mg/m2        
2* 
Cycle 1, Day 15 
At time of lumbar puncture 
 
|__|__| : |__|__| 
|__|__| : |__|__| 
Most recent larotrectinib dose prior to LP        Date:___/___/___                Time Dose Given: |__|__| : |__|__| 
Actual larotrectinib dose administered _______ mg = ______ mg/m2        
3* 
Cycle 1, Day 22 
At time of lumbar puncture 
 
|__|__| : |__|__| 
|__|__| : |__|__| 
Most recent larotrectinib dose prior to LP        Date:___/___/___                Time Dose Given: |__|__| : |__|__| 
Actual larotrectinib dose administered _______ mg = ______ mg/m2        
4 
End of Cycle 1 
At time of lumbar puncture 
 
|__|__| : |__|__| 
|__|__| : |__|__| 
 
 
* Only for leukemia patients receiving intrathecal therapy.  
 
 
 
One copy of this CSF and Plasma Pharmacokinetic Study Form should be uploaded into RAVE. A second copy should 
be sent with the samples to the address listed in Section 7.3.3.4. See Section 7.3.3.3 for detailed guidelines for 
packaging and shipping CSF and plasma PK samples. 
 
 
Notes_______________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________
____________________________________________________________________________________________

  
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____________________________________________________________________________________________
____________________________________________________________________________________________ 
 
 
If this form will be used as a source document, the site personnel who collected the samples must sign and date this 
form below: 
 
Signature: _________________________________________                
        Date:___________________ 
 
    (site personnel responsible for collection of samples) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX IX: PERFORMANCE STATUS SCALES/SCORES 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX X-A: Larotrectinib Dosing Nomogram (CAPSULE 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 a BSA ≥ 0.66 m2 may take either the capsule or liquid formulation. Patients < 0.66 m2 
must receive the liquid formulation (See Appendix X-B for dosing preparation of the larotrectinib 
liquid formulation. 
 
Larotrectinib Dosing Table 
 
BSA (m2) 
Starting Dose 100 
mg/m2/ dose PO BID 
Dose Reduction 1 
Dose Reduction 2 
Dose Reduction 3 
0.66-0.87 
75 mg BID 
50 mg BID 
34 mg/dose BID  
Use liquid formulation 
18 mg/dose BID  
Use liquid formulation 
≥ 0.88 
100 mg BID 
75 mg BID 
50 mg BID 
25 mg BID 
   
Patients with BSA ≥ 0.66 m2 may be switched to the liquid formulation at the same dose level if their 
ability to swallow capsules changes during the treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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APPENDIX X-B: 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 X-A 
for dosing nomogram for larotrectinib capsule formulation).  
 
Up to three dose reductions of larotrectinib will be allowed for dose limiting toxicities as outlined in 
Section 5.0:  
• 
1st dose reduction: 75 mg/m2/dose BID (maximum of 75 mg/dose BID) 
• 
2nd dose reduction: 50 mg/m2/dose BID (maximum of 50 mg/dose BID) 
• 
3rd dose reduction: 25 mg/m2/dose BID (maximum of 25 mg/dose BID) 
 
The concentration of 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 (100 mL per bottle).  
 
A site-supplied press-in bottle adapter is required for use with an oral syringe for dosing purposes.  
 
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 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 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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APPENDIX XI: QOL AND NEUROCOGNITIVE ASSESSMENTS 
 
A standardized battery of parent-report measures has been developed to provide a brief assessment of the 
child’s executive, adaptive, and social/emotional/behavioral functioning as well as overall quality of life. The 
battery was designed to strike a balance between achieving research goals while also minimizing the burden 
on children with cancer and their families. The battery of measures will take approximately 45 minutes to 
complete, and all measures will be administered at four distinct time points: within 4 weeks after enrollment, 
6 months ( 4 weeks) after enrollment, 12 months ( 4 weeks) after enrollment, 24 months ( 4 weeks) after 
enrollment, and 4-5 years after enrollment. The measures that are administered at each time point depend on 
the child’s age at the time of the assessment (see Table 1). General information about each of the measures in 
the battery is provided below. Please refer to Attachment 1 for information about administration order of these 
measures. Please see Attachment 2 for information about how to respond to critical items for the measures 
included in the assessment battery.  
 
At least one parent or guardian must have receptive and expressive language skills in English to complete the 
parent-reported neurocognitive, behavioral, and QoL assessments. Patients who do not meet this criteria will 
not complete the neurocognitive, behavioral and QoL assessments.  
 
 
Table 1. COG Standardized Neuropsychological and Behavioral Battery (parent reports) 
 
                                                     Child’s Age (Years : Months) 
 
 
< 2:0 
2:0 
↓ 
5:11 
6:0 
↓ 
older 
Attention and Behavioral/Social Function 
BASC-3 (20 min) 
 
X 
X 
Executive Function 
BRIEF-P (5 min) 
 
X 
 
BRIEF-2 (5min) 
 
 
X 
Adaptive Function 
ABAS-III (15 min) 
X 
X 
X 
Quality of Life 
PedsQL 4.0 (Generic Module only) 
 
X 
X 
 
Index of Test Abbreviations 
ABAS-III 
Adaptive Behavior Assessment System – 3rd Edition 
BASC-3 
Behavior Assessment System for Children – 3rd Edition 
BRIEF-2 
Behavior Rating Inventory of Executive Function Scales, Second Edition 
BRIEF-P 
Behavior Rating Inventory of Executive Function – Preschool Version 
PedsQL 4.0 
Pediatric Quality of Life Inventory Version 4.0 (Generic Module) 
 
Parent-Report Measures  
 
Adaptive Behavior Assessment System – 3rd Edition (ABAS-III) 
The parent-report form of the ABAS-III will be used for the assessment of adaptive skills in individuals 
from birth to 18 years of age (patients ≥18 years of age will complete a self-report form). Separate scale 
scores are available for 11 skills areas, as well as for 3 adaptive domains (Conceptual, Social and Practical) 
and a General Adaptive Composite (GAC). The internal consistency ranges from .91 to .99 for the adaptive 
domains and the GAC.  

  
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Behavior Assessment System for Children – 3rd Edition (BASC-3) 
The BASC-3 describes the behaviors, thoughts, and emotions of children and adolescents. The parent rating 
scale will be utilized for individuals who are at least 2 years and less than 18 years of age. Patients who are 
> 18 years of age will complete a self-report form and no parent-report form will be used. This measure 
yields composite and scale scores in the domains of externalizing, internalizing, school, and other problems 
as well as adaptive skills and behavioral symptoms. PLEASE NOTE: General Combined sex norms (i.e., 
not Clinical or sex-specific norms) should be used when scoring the BASC-3. 
 
Behavior Rating Inventory of Executive Functioning (BRIEF-2; BRIEF-P) is a parent-completed measure 
of executive function behaviors in the home environment. There are two versions available: one for 
preschoolers (BRIEF-P) and one for older children and adolescents (BRIEF-2, Second Edition). Executive 
functions are defined as “a collection of processes that are responsible for guiding, directing, and managing 
cognitive, emotional and behavioral functions, particularly during active, novel problem solving”.54 The 
Parent Form of the BRIEF-2 contains 63 items within nine domains that measure different aspects of 
executive functioning. These nine Scales form three broader indexes of executive function, Behavior 
Regulation and Emotion Regulation, and Cognitive Regulation, as well as an overall score, The Global 
Executive Composite. Internal consistency of the Parent Form Scales ranges from .80 to .98. The BRIEF 
also has well-established content and construct validity. 
 
Pediatric Quality of Life Inventory Version 4 (PedsQL 4.0) 
The PedsQL 4.0 is a modular approach to measuring health-related quality of life in healthy children and 
adolescents as well as in those with acute and chronic health conditions. The Generic Version consists of 
23 items, and yields domain scores for Physical, Emotional, Social, and School Functioning as well as 
summary scores for Total Quality of Life, Physical Health, and Psychosocial Health. Parents will complete 
the age-appropriate parent-report form for all patients under age 18.  
 
Data Handling 
The assessment measures will be provided to all sites who have a patient enrolled. The appropriate packet of 
measures will be mailed to the site CRA prior to each assessment window. After completion, the questionnaire 
measures (labeled with the patient’s COG ID) should be sent to Krystal Robinson, PsyD (see Study 
Committee) for scoring. Hard copies of the raw data (completed questionnaire) will be retained at each 
institution and must be secured according to research standards. 
 
 
 
 

  
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ATTACHMENT 1: ADMINISTRATION ORDER FOR NEUROPSYCHOLOGICAL AND BEHAVIOR BATTERY 
 
The measures vary by age group and should be completed in the order presented below. 
 
Age at Testing 
Parent Report 
Birth  
through 
1 year, 11 months 
1. ABAS-III: Parent/Primary Caregiver Form (Ages 0-5) 
2 years, 0 months 
through 
5 years, 11 months 
1. PedsQL 4.0 Generic Version 
2. BASC-3: Parent Rating Scales-Preschool (Ages 2-5) 
3. BRIEF-Preschool Version 
4. ABAS-III: Parent/Primary Caregiver Form (Ages 0-5) 
6 years, 0 months 
and older 
1. PedsQL 4.0 Generic Version 
2. BASC-3: Parent Rating Scales-Child (Ages 6-11) or Parent Rating Scales-
Adolescent (Age 12-21) 
3. BRIEF-2 (Second Edition)  
4. ABAS-III: Parent Form (Ages 5-21) 
 
 

  
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ATTACHMENT 2:  CRITICAL ITEMS  
 
The Behavior Assessment System for Children – 3rd edition (BASC-3) includes questions related to 
suicidal ideation, known as “critical items.” The purpose of highlighting these items is to be sure that the 
individual administering the battery checks specific items at the end of a testing session. If a critical item is 
endorsed, it is IMPERATIVE that the physician/social worker/psychologist/neuropsychologist is informed 
immediately and that he/she determines whether the child’s parents and/or physician will be contacted. If 
any indication of a potential problem is detected, parents will receive individual consultation with the 
physician/social worker/psychologist/neuropsychologist on site who will explain the meaning of the scores 
and refer to a qualified professional for a more thorough Follow-up evaluation.  
 
Summary of critical items on the BASC-3 
• 
Ages 6 to 11 years: Parent-report 
o Item #92: Says “I want to die” or “I wish I were dead” 
o Item #138: Says “I want to kill myself” 
 
• 
Ages 12 to 21 years: Parent-report 
o Item #60: Says “I want to kill myself” 
o Item #90: Says “I want to die” or “I wish I were dead” 
 
 

  
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APPENDIX XII: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
> ULN - ≤ 1.5 x ULN 
Grade 2: 
> 1.5 x ULN – 3.0 x ULN 
Grade 3: 
> 3.0 x ULN – 10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT 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 SGOT 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