A Comparison of Clinical Outcomes in Infantile Fibrosarcoma (IFS) Patients Treated With Larotrectinib in the Phase I/II SCOUT Study Versus (an) External Historical Cohort(s)
Conditions: Locally Advanced or Metastatic Infantile Fibrosarcoma Harboring an NTRK Gene Fusion, Infantile Fibrosarcoma
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol 
Official Title: 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase 
I/II SCOUT study versus (an) external historical cohort(s) 
NCT Number: 
NCT05236257 
Document Date: 
27 JUL 2021 
 

Reference Number: RD-SOP-1214 
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Observational Study Information 
Acronym/Title 
EPI VITRAKVI: A comparison of clinical outcomes in 
Infantile 
Fibrosarcoma 
(IFS) 
patients 
treated 
with 
larotrectinib in the phase I/II SCOUT study versus (an) 
external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JULY 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / 
Phase IV 
Medicinal product 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care, external historical control 
Study Initiator and Funder 
Bayer HealthCare SAS 
Research question and objectives The Haute Autorité de Santé (HAS), French National 
Authority for Health, gave a positive opinion for the 
reimbursement of larotrectinib for the treatment of pediatric 
patients with IFS or another Soft Tissue Sarcoma (STS), 
harboring a Neurotrophic Tyrosine Receptor Kinase (NTRK) 
gene fusion, which is locally advanced or metastatic, and 
refractory or in relapse. The HAS granted a moderate clinical 
benefit (service médical rendu [SMR]) with no improvement 
in clinical benefit (amélioration du service médical rendu 
[ASMR V]). This positive opinion is conditional and will be 
reassessed upon the provision of comparative data of 
larotrectinib treatment versus standard of care at least versus 
an external control arm, in particular in IFS. This study is 
designed to address this request. 
Primary objective: 
The primary objective of the present study is to compare the 
time to medical treatment failure (defined as: next systemic 
treatment or mutilating surgery or radiation therapy or death 
due to any cause) between larotrectinib and standard of care 
in IFS patients using externally-controlled comparison 
performed with phase I/II SCOUT study and eligible external 
historical cohort(s). 
Secondary objectives: 
The secondary objectives are to compare: 
 Treatment outcomes (next systemic treatment, 
mutilating surgery, radiation therapy, death due to 
any cause), 
 Treatment discontinuation rates due to toxicity. 
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Countries of study 
Countries involved in SCOUT study (13 countries worldwide 
including France) and eligible external historical cohort(s) 
Authors 
 
Bayer HealthCare SAS, 
220 Avenue de la Recherche, 59120 Loos, France 
 
 
Bayer SAS, 
10 Place de Belgique, 92257 La Garenne-Colombes, France 
 
 
Bayer US LLC, 
100 Bayer Boulevard, Whippany, 07981 NJ, USA 
 
 
The study will be conducted in compliance with the protocol 
and any applicable regulatory requirements. 
 
 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. 
Hence, the appearance of product names without these symbols does not imply that these names are 
not protected. 
 
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1. 
Table of contents 
 
1. 
Table of contents ................................................................................................................ 3 
2. 
List of abbreviations .......................................................................................................... 5 
3. 
Responsible parties ............................................................................................................ 8 
3.1 
Study initiator and funder ................................................................................................. 8 
3.2 
External partners/Scientific Committee ............................................................................ 9 
4. 
Abstract ............................................................................................................................. 10 
5. 
Amendments ..................................................................................................................... 23 
6. 
Milestones ......................................................................................................................... 23 
7. 
Rationale and background .............................................................................................. 23 
7.1 
NTRK gene family and NTRK gene fusion-associated cancers ...................................... 23 
7.2 
IFS and current standard of care ..................................................................................... 24 
7.3 
STS and current standard of care .................................................................................... 25 
7.4 
Toxicities associated with chemotherapy and radiotherapy ........................................... 26 
7.5 
Larotrectinib ................................................................................................................... 27 
7.5.1 
Larotrectinib clinical development and efficacy ......................................................... 27 
7.5.2 
Larotrectinib safety profile .......................................................................................... 29 
7.6 
Rationale for the conduct of this observational study .................................................... 30 
7.7 
Rationale for the use of an external historical control .................................................... 30 
7.8 
Rationale for the choice of the primary endpoint ........................................................... 31 
8. 
Research questions and objectives ................................................................................. 32 
8.1 
Primary objective ............................................................................................................ 32 
8.2 
Secondary objectives ...................................................................................................... 33 
9. 
Research methods ............................................................................................................ 33 
9.1 
Study design ................................................................................................................... 33 
9.1.1 
Primary endpoint ......................................................................................................... 33 
9.1.2 
Secondary endpoints ................................................................................................... 33 
9.1.3 
Exploratory endpoints ................................................................................................. 33 
9.2 
Setting ............................................................................................................................. 34 
9.2.1 
Study population ......................................................................................................... 34 
9.2.2 
Study time frame ......................................................................................................... 34 
9.2.3 
Selection criteria .......................................................................................................... 34 
9.2.3.1 
Selection criteria for the sources of the external historical control cohort(s) .......... 34 
9.2.3.2 
Selection criteria for patients ................................................................................... 36 
9.2.4 
Representativeness ...................................................................................................... 37 
9.3 
Variables ......................................................................................................................... 38 
9.3.1 
Variables to determine the primary endpoints ............................................................ 38 
9.3.2 
Variables to determine the secondary endpoints ......................................................... 38 
9.3.3 
Variables to determine the exploratory endpoints ....................................................... 39 
9.3.4 
Potential confounders .................................................................................................. 39 
9.4 
Data sources .................................................................................................................... 40 
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9.5 
Study size ........................................................................................................................ 40 
9.6 
Data management ........................................................................................................... 41 
9.6.1 
Data access rights and confidentiality ......................................................................... 41 
9.6.2 
Document and data archiving ...................................................................................... 41 
9.7 
Data analysis ................................................................................................................... 41 
9.7.1 
Index Date and endpoints ............................................................................................ 41 
9.7.2 
Adjustment methodology ............................................................................................ 42 
9.7.3 
IPTW method .............................................................................................................. 43 
9.7.4 
Outcome model ........................................................................................................... 43 
9.7.5 
Sample size and power considerations ........................................................................ 44 
9.7.6 
Sensitivity analysis ...................................................................................................... 45 
9.7.7 
Complementary analyses ............................................................................................. 46 
9.7.8 
Bias analysis for primary endpoint .............................................................................. 47 
9.8 
Quality control ................................................................................................................ 48 
9.9 
Limitations of the research methods ............................................................................... 48 
9.10 Other aspects ................................................................................................................... 49 
10. Protection of human patients .......................................................................................... 49 
11. Management and reporting of adverse events/adverse reactions ................................ 50 
12. Plans for disseminating and communicating study results .......................................... 50 
13. References ......................................................................................................................... 51 
Annex 1: List of stand-alone documents ............................................................................... 56 
Annex 2: Additional information........................................................................................... 57 
Annex 3: Signature pages ....................................................................................................... 61 
 
 
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2. 
List of abbreviations 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AKT 
Protein Kinase B 
ALT 
Alanine Aminotransferase 
ANSM 
Agence Nationale de Sécurité du Médicament et des Produits de Santé (French National 
Agency for Drug and Health Product Safety) 
ASMR 
Amélioration du Service Médical Rendu (Added medical value) 
AST 
Aspartate Aminotransferase 
ATE 
Average Treatment Effect 
ATT 
Average Treatment in the Treated 
ATU 
Autorisation Temporaire d’Utilisation (Temporary Authorization for Use) 
BDNF 
Brain-Derived Neurotrophic Factor 
BTBD1 
BTB Domain Containing 1 
CESREES 
Comité Ethique et Scientifique pour les Recherches, les Etudes et les Evaluations dans 
le domaine de la Santé (French Ethic and Scientific Committee for the Researches, 
Studies and Evaluations in the Health Domain) 
CI 
Confidence Interval 
CMN 
Congenital Mesoblastic Nephroma 
CNIL 
Commission Nationale de l’Informatique et des Libertés (French National Committee of 
Information Technology and Civil Liberty) 
CNS 
Central Nervous System 
COG 
Children Oncology Group 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CWS 
Cooperative Weichteilsarkom Studiengruppe 
DCR 
Disease Control Rate 
DoR 
Duration of Response 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EpSSG 
European pediatric Soft tissue sarcoma Study Group 
ESCAT 
ESMO Scale of Clinical Actionability for molecular Targets 
ESMO 
European Society for Medical Oncology 
ETV6 
ETS Variant Transcription Factor 6 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GPP 
Good Publication Practice 
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HAS 
Haute Autorité de Santé (French National Authority for Health) 
HDH 
Health Data Hub 
HEOR 
Health Economics and Outcomes Research 
HR 
Hazard Reduction 
ICH 
International Conference on Harmonization 
ID 
Ifosfamide-Doxorubicin 
IEC 
Independent Ethics Committee 
IFS 
Infantile Fibrosarcoma 
IHC 
Immunohistochemistry 
IPTW 
Inverse Probability of Treatment Weighting 
IRB 
Institutional Review Board 
IRR 
Incidence Rate Ratio (underlying hazard ratio) 
IRS 
Intergroup Rhabdomysosarcoma Study 
IVA 
Ifosfamide-Vincristine-Actinomycin D 
IVADo 
Ifosfamide-Vincristine-Actinomycin D-Doxorubicin 
MA 
Marketing Authorization 
MAH 
Marketing Authorization Holder 
MAPK 
Mitogen-Activated Protein Kinase 
N/A 
Not Applicable 
NGF 
Nerve Growth Factor 
NGS 
Next Generation Sequencing 
NT 
Neurotrophin 
NTRK 
Neurotrophic Tyrosine Receptor Kinase 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PFS 
Progression-free survival 
PH 
Proportional Hazard 
PICO 
Patient, Intervention, Comparison, Outcome 
PR 
Partial Response 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMS 
Rhabdomyosarcoma 
RR 
Risk Ratio 
RTK 
Receptors Tyrosine Kinase 
RT-PCR 
Reverse Transcription-Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SEER 
Surveillance of Epidemiology and End Results 
SLR 
Systemic Literature Review 
SMR 
Service Médical Rendu (Medical value quotation) 
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STROBE 
The Strengthening the Reporting of Observational Studies in Epidemiology 
STS 
Soft Tissue Sarcoma 
TEAE 
Treatment Emergent Adverse Event 
TPM3 
Tropomyosin 3 
TRK 
Tropomyosin Receptor Kinase 
TRKi 
TRK Inhibitor 
VA 
Vincristine-Actinomycin D 
VAC 
Vincristine-Actinomycin D-Cyclophosphamide 
VAC/VI 
Vincristine-Actinomycin D-Cyclophosmamide/Vincristine-Irinotecan 
VAdriaC 
Vincristine-Doxorubicin (Adriamycine)-Cyclophosphamide 
VDC/IE 
Vincristine-Doxorubicin-Cyclophosphamide/Ifosfamide-Etoposide 
VOD 
Veno-Occlusive Disease 
 
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3. 
Responsible parties 
3.1 
Study initiator and funder 
 
Role: 
 
Name: 
 
E-mail: 
 
 
 
Role: 
 
Name: 
 
E-mail: 
 
 
 
Role: 
 
Name: 
 
E-mail: 
 
 
 
Role: 
 
Name: 
 
E-mail: 
 
 
 
Role: 
 
Name: 
 
E-mail: 
 
 
 
Role: 
 
 
Name: 
 
E-mail 
 
 
 
Role: 
 
Name: 
 
E-mail: 
 
Contact details of the responsible parties at Bayer HealthCare SAS, data controller of the study, are 
available upon request. 
Data privacy aspects of the study are managed by the data protection officer of the study initiator who 
can be reached at the following contact details: 
Bayer SAS 
Délégué à la Protection des Données – DPO 
Direction Juridique 
16 Rue Jean-Marie Leclair 
69009 Lyon 
DPO-BayerFrance@bayer.com 
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3.2 
External partners/Scientific Committee 
The Principal Investigator of this observational study is Dr. Daniel Orbach, MD, Pediatric Oncologist 
of Institut Curie, SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents 
and Young Adults with Cancer, Paris, France). 
A Scientific Committee was constituted for this study. Its role is to help to define and validate the 
methodologies and the modalities of the data analyses, to review and validate content of the study 
protocol, the study-related documents, the study results and the study report. The Scientific Committee 
can be solicited during the study course to obtain an independent evaluation and/or advices as needed. 
The Scientific Committee will participate in the communication/dissemination of the results and is 
composed of: 
 Dr. Daniel Orbach, MD, Pediatric Oncologist of Institut Curie, SIREDO Oncology Center 
(Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), 
 Dr. 
 MD, PhD, 
 of Institut Curie, Biometry Unit. 
The writing of the study protocol, the statistical analyses and the writing of the study report are 
subcontracted to a Contract Research Organization (CRO) (Keyrus Life Science [previously Keyrus 
Biopharma]). 
Two Systematic Literature Reviews (SLRs) will be performed to identify: (1) appropriate non-biased 
data sources to constitute the external control arm and (2) the important prognostic factors to be taken 
into account in adjusted analysis. The 2 SLRs are subcontracted to IQVIA Operations France. SLR 
protocol and results will be kept as stand-alone documents. 
Contact details of the Principal Investigator, members of the Scientific Committee, and the CROs are 
kept as stand-alone documents (see Table 2, Annex 1) which are available upon request. 
Administrative changes of responsible persons and/or the composition of the committee will be 
documented by updating the respective lists but will not require formal protocol amendments. 
 
 
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4. 
Abstract 
Acronym/Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the 
phase I/II SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study Initiator and Funder 
Bayer HealthCare SAS 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase 
IV 
Authors 
 
Bayer HealthCare SAS, 
220 Avenue de la Recherche, 59120 Loos, France 
 
 
Bayer SAS, 
10 Place de Belgique, 92257 La Garenne-Colombes, France 
 
 
Bayer US LLC, 
100 Bayer Boulevard, Whippany, 07981 NJ, USA 
Rationale and background 
Although very rare (less than 1% of all childhood cancers), IFS 
is the most common Soft Tissue Sarcoma (STS) in infants under 
one year of age, commonly located in extremities. IFS tumors 
are typically characterized by a fusion transcript constituted of 
Neurotrophic Tyrosine Receptor Kinase (NTRK) and ETS 
Variant Transcription Factor 6 (ETV6) (ETV6-NTRK). ETV6-
NTRK3 transcript was detected in 87.2% of IFS patients, which 
makes this specific gene fusion nearly pathognomonic for IFS 
(Orbach 2016). 
Conservative surgery remains the primary treatment for patients 
with IFS. When upfront resection is not feasible, treatment must 
be chosen to minimize acute and chronic/long term toxicities, 
due to the very young age of patients. Chemotherapy is generally 
indicated as first-line treatment and usually shows a good 
response, notably the Vincristine-Actinomycin-D (VA) regimen 
which if the preferred first line option, or other regimens 
including 
Vincristine-Actinomycin-D-Cyclophosphamide 
(VAC) 
and 
Vincristine-doxorubicin 
(Adriamycine)-
Cyclophosphamide (VAdriaC) in case of insufficient response to 
VA (Loh 2002; Orbach 2016; Orbach 2020; Weiss 2014). 
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However, central venous administration is challenging to 
manage in such young patients. Because of the risk of sequelae, 
extensive and mutilating surgery, as well as radiotherapy, should 
only be performed after failure of salvage therapies but were 
discouraged and not recommended in these young patients 
(Orbach 2010; Orbach 2016). In case of failure of chemotherapy, 
alkylating agents and anthracyclines can be prescribed. 
However, because of their acute and chronic/long-term 
toxicities, their use is limited, raising a need for alternative 
medical treatments with less toxicity. 
The clinical development program of the first-in-class selective 
Tropomyosin Receptor Kinase inhibitor (TRKi) larotrectinib, 
including the pediatric Phase I/II SCOUT study1, to date has 
shown that the tumor response observed under treatment with the 
drug, is pronounced and durable even if no comparator is used 
in the ongoing clinical studies. Larotrectinib presents high 
potency and high specificity for TRKA, TRKB and TRKC 
receptors inhibition and has the benefit to be provided in 2 
formulations: a liquid oral formulation mainly for the pediatric 
population and capsules with 2 different doses mainly for adults. 
In addition, it is generally well tolerated. 
In September 2019, larotrectinib was granted a conditional 
Marketing Authorization (MA) in Europe for the treatment of 
adult and pediatric patients with solid tumors that display a 
NTRK gene fusion: 
• 
who have a disease that is locally advanced, metastatic or 
where surgical resection is likely to result in severe morbidity, 
and 
• 
who have no satisfactory treatment options. 
In France, a dossier was submitted to the National Authority for 
Health (Haute Autorité de Santé [HAS]) in October 2019 to 
obtain the reimbursement of larotrectinib in the country in line 
with the population described in the MA. 
In July 2020, the HAS’s final appraisal was a positive opinion 
for the reimbursement of larotrectinib only in pediatric patients 
with IFS or another STS harboring a NTRK gene fusion, which 
is locally advanced or metastatic, and refractory or in relapse. 
The HAS granted a moderate clinical benefit (service médical 
rendu – SMR) with no improvement in clinical benefit 
(amélioration du service médical rendu – ASMR V) mainly due 
to the lack of comparative evidence. In this context, the positive 
opinion is conditional and will be reassessed upon the provision 
                                                 
1 SCOUT study, a Phase I/II study of the oral TRK inhibitor larotrectinib in pediatric patients with advanced solid or 
primary central nervous system tumors – international clinical study. 
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of comparative data of larotrectinib treatment versus standard of 
care at least versus an external control arm, in particular in IFS. 
This study is designed to address this request. 
Performing a comparison of the available data from the ongoing 
SCOUT study with data from an external historical cohort 
reflecting standard of care, constitutes a relevant approach to 
assess the efficacy of larotrectinib and to contextualize its 
therapeutic benefit over current therapies which may be 
associated with detrimental outcomes. Given the rarity of the 
condition and ethics consideration, the use of an external control 
arm allows for the timely generation of comparative data. 
Research 
question 
and 
objectives 
The aim of this study is to assess the therapeutic benefit of 
larotrectinib over the current standard of care in pediatric 
patients with locally advanced or metastatic IFS. 
 
Primary objective: 
The primary objective of the present study is to compare the time 
to medical treatment failure (defined as: next systemic treatment 
or mutilating surgery or radiation therapy or death due to any 
cause) between larotrectinib and standard of care in IFS patients 
using externally-controlled comparison performed with phase 
I/II SCOUT study and eligible external historical cohort(s). 
 
Secondary objectives: 
The secondary objectives are to compare: 
 Treatment 
outcomes 
(next 
systemic 
treatment, 
mutilating surgery, radiation therapy, death due to any 
cause), 
 Treatment discontinuation rates due to toxicity. 
Study design 
This study will be a retrospective observational externally-
controlled study. Data of patients with IFS in the eligible 
external historical cohort(s) will serve as control for the 
comparison with data of patients with IFS who have been 
enrolled in the SCOUT study. Data which will be used for the 
analyses will come from: 
 SCOUT study: 
o At least 27 sites across 13 countries, including France. 
 External cohort(s) meeting inclusion and exclusion criteria 
described below (see Population section), including at least 
the Institut Curie database. 
 
 
 
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Primary endpoint: 
 Time to medical treatment failure: defined as the time 
(months) from the start of treatment to the date of the 
following events, whichever comes first: subsequent 
systemic treatment, radiation therapy, mutilating surgery or 
death due to any cause. 
 
Secondary endpoints: 
 Time to subsequent systemic treatment. 
 Time to mutilating surgery including limb amputation. 
 Time to radiation therapy. 
 Time 
to 
complete 
surgical 
resection 
(excluding 
amputation). 
 Overall Survival (OS): defined as the time (months) from 
the start of treatment to the date of death due to any cause. 
Patients alive or lost to follow-up at the time of analysis 
will be censored at their last date of follow-up. 
 Incidence of patients with treatment discontinuation due to 
treatment-related adverse events (AEs). 
 
Exploratory endpoints: 
 Progression-free survival (PFS): defined as the time 
(months) from the start of treatment to the date of first 
observed disease progression (radiological or clinical, 
whichever is earlier) or death due to any cause, if death 
occurs before progression is documented. Patients alive 
without documented progression at the time of analysis 
will be censored at the date of last tumor assessment. 
 Overall response rate (ORR): defined as the proportion of 
patients with a best overall response of complete response 
(CR) or partial response (PR) assessed by investigators. 
 Disease Control Rate (DCR): defined as the proportion of 
patients with a best overall response of CR, PR, or Stable 
Disease (SD). 
Population 
Selection criteria for the sources of the external historical control 
cohort(s) 
The choice of the control cohort(s) constituting the comparator 
arm of the study is not arbitrary. The non-arbitrary choice of the 
data sources to constitute the control cohort will be ensured by a 
comprehensive review of the existing relevant databases in 
France and internationally (notably based on a Systematic 
Literature Review [SLR]). Data sources will be selected upon 
the following eligibility and feasibility criteria: 
 
 
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Inclusion criteria: 
 Cohorts with prospective enrollment and with retrospective 
and prospective data collection from 2000 to present, 
 Cohorts containing at least clinical data allowing to assess 
the efficacy of the treatment and the main prognostic factors 
as follows: 
o Diagnosis and stage of the disease (locally advanced or 
metastatic), 
o Type of treatments (chemotherapy, radiotherapy, 
surgery: mutilating yes/no) and date of the initiation or 
of the procedure, 
o Death and date, 
o Localization of the tumor (axis versus limb), 
o Size of the tumor (< 5 cm versus > 5 cm). 
Exclusion criteria: 
 Databases not containing patients with locally advanced or 
metastatic IFS, 
 Medico-administrative databases or absence of data 
allowing the assessment of the efficacy of the treatment and 
main prognostic factors, or high rate of missing data (>10% 
on outcome and >25% on covariates), 
 Cohorts with retrospective enrollment and case report, 
 Cohorts with prospective enrollment for which all patients 
were included before 2000. 
Based on a preliminary search of databases and the selection 
criteria described above, in addition to the database of the Institut 
Curie which is the only database confirmed, the following data 
sources are theoretically eligible to be used to constitute (an) 
external control cohort(s) for the present study: 
 Databases found in the literature (preliminary search that 
will be completed by the SLR): 
 Database of the European pediatric Soft tissue 
Sarcoma Study Group (EpSSG, a consortium housed 
in the University of Padua, Italy, European data), 
 Database 
of 
the 
Cooperative 
Weichteilsarkom 
Studiengruppe (CWS, Germany). 
 Commercial databases with electronic medical data: 
 No eligible databases were found. 
The SLR that will be performed might identify additional 
eligible cohorts. The availability, the access, and the feasibility 
of use of the different eligible databases identified will be then 
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investigated. Further details will be described in the final study 
report. 
 
*** 
Selection criteria for the patients 
The study population will comprise all patients in the SCOUT 
study and the eligible external historical cohort(s) with a 
diagnosis of locally advanced or metastatic IFS, regardless of 
their refractory or relapsed status, i.e. including treatment-naive 
patients to avoid further reducing the sample size. 
 
The choice of the study population has mainly been driven by 
feasibility/sample size considerations, in order to be able to 
perform a comparison based on a minimal number of patients. 
 
Inclusion criteria: 
The inclusion criteria listed below are in line with those of the 
SCOUT study in terms of patients and disease characteristics: 
 Age ≤ 21 years old. 
 Locally advanced or metastatic IFS. 
 Patients with available information on clinical, radiological 
characteristics of their tumor, therapies administered and 
outcomes. 
 Patients receiving larotrectinib in the SCOUT trial. 
 Patients receiving at least one chemotherapy-based 
regimen2 in the external historical control cohort(s). 
 No opposition from the patients and/or representatives for 
data use. 
 
Exclusion criteria: 
 Patients treated with TRKi in the external historical control 
cohort(s). 
 Patients with documented absence of NTRK gene fusion. 
 Patients participating in an investigational program with 
interventions outside of routine clinical practice. 
Variables 
To determine the different endpoints, the variables described 
below will be collected from the Case Report Forms (CRFs) of 
the patients eligible for the present observational study of the 
SCOUT study and from the databases of the external historical 
control cohort(s). 
 
 
                                                 
2 In order to preserve the sample size, patients will be included regardless of the type of chemotherapy they have received. 
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Variables to determine the primary endpoint: 
For the time to medical treatment failure endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for the external 
historical control cohort(s), and whichever comes first: 
o Start date of a post-treatment3 systemic anti-cancer 
therapy, if any, or, 
o Start date of a post-treatment3 radiation therapy, if 
any, or, 
o Date of a post-treatment3 mutilating surgery, if any, or, 
o Date of death due to any cause, if applicable. 
 
Variables to determine the secondary endpoints: 
For the time to subsequent systemic treatment endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for the external 
historical control cohort(s), and, 
 Start date of a post-treatment3 systemic anti-cancer therapy, 
if any. 
For the time to mutilating surgery including limb amputation 
endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for the external 
historical control cohort(s), and, 
 Date of a post-treatment3 mutilating surgery including limb 
amputation, if any. 
For the time to radiation therapy endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for the external 
historical control cohort(s), and, 
 Start date of a post-treatment3 radiation therapy, if any. 
For the time to complete surgical resection (excluding 
amputation) endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for the external 
historical control cohort(s), and, 
 Date of a post-treatment3 complete surgical resection 
(excluding amputation), if any. 
                                                 
3 After the start of larotrectinib treatment for the SCOUT study or after the start of chemotherapy (first line) for the external 
historical control cohort(s). 
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For the OS endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for the external 
historical control cohort(s), and, 
 Date of death due to any cause, if applicable, or, 
 Last date of patient follow-up for patients alive and lost to 
follow-up, if applicable. 
For the Incidence of patients with treatment discontinuation due 
to treatment-related AEs endpoint: 
 Record of treatment4 discontinuation due to treatment-
related AEs, if applicable. 
 
Variables to determine the exploratory endpoints: 
For the PFS endpoint: 
 Start date of larotrectinib treatment for the SCOUT study 
and start date of chemotherapy (first line) for locally-
advanced/metastatic disease for the external historical 
control cohort(s), and, 
 Date of first post-treatment5 disease progression/relapse 
assessed by radiological or clinical examination by 
investigator, if any, or, 
 Date of death due to any cause, if applicable, or, 
 Censored at last date of tumor assessment. A complete list 
of censoring rules will be provided in the statistical analysis 
plan (SAP). 
For the ORR and DCR endpoints: 
 Patient response to treatment4 (CR, PR and SD) assessed 
by investigator. 
 
Potential confounders: 
The following baseline variables will be considered when 
balancing the two cohorts: patients with IFS enrolled in SCOUT 
and the external historical control cohort(s). 
 Patients and disease characteristics: 
o Sex, 
o Age, 
o Disease history: 
 Date of initial diagnosis, 
                                                 
4 Larotrectinib treatment for the SCOUT study and chemotherapy (first line) for the external historical control cohort(s). 
5 After the start of larotrectinib treatment for the SCOUT study or after the start of chemotherapy (first line) for the external 
historical control cohort(s). 
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 Anatomical disease site(s) at diagnosis, 
 Stage of disease at diagnosis (local versus locally 
advanced versus metastatic), 
 Primary tumor size (< 5 cm or > 5 cm), 
 Date of advanced disease stage evolution (locally 
advanced, metastatic), 
 Time from locally advanced/metastatic disease 
diagnostic to initiation of larotrectinib (SCOUT) or 
first line of chemotherapy (external historical 
control cohort(s)), 
 Intergroup Rhabdomyosarcoma Study (IRS) group, 
 Anatomical site(s) of metastases, if any. 
 Collection of treatment-related information: 
o Prior/current surgical treatment(s) for cancer: 
 Anatomical site(s), 
 Date(s) of surgery, 
 Best resection (R0, R1, R2), 
 Nature of intervention(s) (e.g. amputation or other 
disfiguring procedures), 
 Surgery 
for 
a 
curative 
intent 
(excluding 
amputation) because of the use of systemic 
treatment. 
o Prior/current radiation treatment(s) for cancer: 
 Anatomical sites, 
 Date(s) of radiation therapy. 
o Systemic treatment(s), including: 
 Treatment regimen, 
 Date of initiation, 
 Date of radiological or clinical progression, 
 Reasons for discontinuation, as appropriate. 
Data sources 
 SCOUT database (Bayer-sponsored study), 
 The Institut Curie database and the other eligible external 
historical control cohort(s) identified after SLR. 
Study size 
All patients meeting the selection criteria will be included in the 
study. Statistical power will be computed retrospectively 
according to the available sample size. 
Data analysis 
Statistical analyses 
A comparison of patients in the larotrectinib group with patients 
from the external historical control cohort(s) who received 
systemic therapy (chemotherapy-based regimen) will be 
conducted by Bayer, at least with the Institut Curie database. In 
the event that other external historical control cohorts are eligible 
and accessible, the databases will be pooled if feasible. 
 
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Index Date and Endpoints 
The comparison of the two cohorts will be considered for the 
primary composite endpoint: 
 Time-to-treatment-failure (earliest of next systemic 
therapy, radiotherapy, mutilating surgery or death due to 
any cause). 
In addition, all secondary and exploratory endpoints detailed 
above will be analyzed: 
 Time to subsequent systemic treatment, 
 Time to mutilating surgery or limb amputation, 
 Time to radiation therapy, 
 Time to complete surgical resection (excluding 
amputation), 
 OS, 
 PFS, 
 Incidence of treatment discontinuation due to treatment-
related AEs, 
 ORR, 
 DCR. 
The analysis will include patients on both first and second line 
(or higher) therapy, though the index date will be initiation of 
first line chemotherapy for the external historical control 
cohort(s). For SCOUT patients, the index date will be defined as 
the start date of larotrectinib, regardless of the line of treatment. 
Therefore, the index date will represent first or second line in 
larotrectinib patients, and first line in control subjects. Given the 
expected small sample size, this will avoid discarding events on 
key endpoints above, while the initial imbalance on lines of 
therapy between treatment groups will be corrected in the 
statistical modeling, as detailed later in this document. Given 
approximately 70% of SCOUT patients received larotrectinib as 
second line of treatment, while in the external historical control 
cohort(s) all patients will have received chemotherapy in first 
line of treatment, the proposed primary analysis is expected to 
provide a rather conservative estimate of treatment effect. 
 
Patient matching methodology 
Patients who received larotrectinib in the SCOUT trial will likely 
differ in various underlying characteristics from those who are 
recorded in the historical control cohort(s). These characteristics 
are listed above as potential confounders (see Variables section). 
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The analyses will need to be adjusted for these patient 
characteristics to avoid biased results. 
The Inverse Probability of Treatment Weighting [IPTW] 
propensity method will be employed to reduce the effects of 
measured confounding variables in the interpretation of the 
treatment effect (larotrectinib versus control group). A 
propensity score can be seen as an overall “balancing score”, that 
is calculated for each patient based on his or her measured 
underlying characteristics. 
 
IPTW Diagnostics and Sensitivity Analyses 
For all baseline covariates included in the propensity score 
model, standardized differences between larotrectinib and 
comparator groups will be computed. A graph will show the 
absolute standardized difference for each of the covariates, 
comparing larotrectinib and comparator, for both the unweighted 
and weighted samples. A standardized difference of 10% is 
commonly considered the threshold below which demonstrates 
reasonable balance between the two groups. 
Sensitivity analyses include trimming the IPTW weights and 
truncating large weights. Trimming at 5% level amounts to 
dropping the individuals with the most extreme PS values in both 
the treatment and control groups, as they may lack a match in the 
other group. Weight truncation reduces any ‘large’ weight down 
to a maximum weight. 
 
Outcome model 
Time-to-event variables 
The primary endpoint, time to medical treatment failure, and 
other time-to-event endpoints detailed above will be investigated 
by plotting Kaplan-Meier survival curves for the original 
unweighted samples. Also included on the survival graphs will 
be adjusted Kaplan-Meier curves for the two groups that 
incorporate the IPTW balancing weights. Summary statistics 
using the Kaplan-Meier method will be reported for both the 
unweighted and weighted samples. 
Additionally, a hazard ratio will be computed using a weighted 
Cox Proportional Hazards model, regressing survival time on an 
indicator variable denoting treatment status (larotrectinib / 
external historical control) and incorporating the IPTW weights. 
Hazard ratios will also be reported for the unweighted samples. 
 
 
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Response variables 
The response endpoints, ORR and DCR, will be summarized for 
both groups in both the original and weighted samples. 
Incidence of treatment discontinuation due to treatment-related 
AEs will be summarized descriptively in the original unweighted 
sampled only. 
 
Bias Analysis for Primary Endpoint 
A bias analysis will investigate the effect of an unmeasured 
covariate for the primary endpoint, time to medical treatment 
failure. 
 
Sample Size and Power considerations 
Given the expected small sample size and the rarity of the events 
observed in the SCOUT trial, it is very unlikely that the required 
number of events will occur: the study is only powered to detect 
a very large treatment effect, e.g. with a risk reduction of 75% 
(Hazard Reduction [HR]=0.25) we cannot exceed 49% power 
(this assumes 35 IFS subjects and very low probabilities of 
failure in SCOUT [0.04] and the external historical control 
cohort [0.19]). As the study is underpowered, a formal 
hypothesis cannot be formulated, and the results should only be 
interpreted as exploratory. 
The matching methodology described above will attempt to 
balance the two groups of patients. However, considering that all 
SCOUT patients had either relapsed or were refractory to 
previous treatment (or at risk of mutilating surgery), which might 
not be the case in the external historical control cohort(s), the 
SCOUT population might be more severe. Therefore, the results 
of the comparison in the original unweighted sample are unlikely 
to be biased in favor of larotrectinib. 
 
Sensitivity Analyses 
An exploratory analysis will define the index date as: the start of 
larotrectinib, regardless of line of therapy; or for the external 
historical control cohort(s) the start date of chemotherapy. 
However, control patients who take a second line of therapy will 
have their index date set at the start of second line, in order to 
provide a closer comparison with the larotrectinib group prior to 
any adjustment using IPTW. 
As the majority of larotrectinib patients will be receiving 2nd line 
therapy, the analysis attempts to maximize consistency between 
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treatment groups in terms of line of therapy while committing to 
the inclusion of all available patients. 
Sensitivity analyses will be detailed in the SAP. Subgroup 
analyses will also be performed for: 
 Patients treated with second line or more systemic 
therapy (with index date set at start of second line for 
both groups). 
 
Complementary Analyses 
The following complementary analyses will be conducted on the 
primary, secondary and exploratory endpoints: 
 Patients with IFS or other STS with NTRK gene fusion. 
 
Number of events and censored patients will be reported for all 
time-to-event endpoints referenced above, and Kaplan-Meier 
plots of the survival curves will be produced showing median 
survival and 95% CI, and also survival probabilities at 12 and 24 
months. 
Frequency tables (n, %) will be produced for discrete endpoints, 
such as ORR, DCR and incidence rate of treatment 
discontinuation due to treatment-related AEs. 
Milestones 
 Approval of the Observational Study protocol: Q2 2021 
 Submission to Health Data Hub (HDH): Q3 2021 
 Comité Ethique et Scientifique pour les Recherches, les 
Etudes et les Evaluations dans le domaine de la Santé 
(CESREES) opinion: Q3 2021 
 Commission Nationale de l’Informatique et des Libertés 
(CNIL) authorization (decision within 2 months – can 
be renewed 2 months): Best case: Q4 2021/Worst case: 
Q1 2022 
 Start of analyses: Best case: Q4 2021/Worst case: Q1 
2022 
 End of analyses – Minimum 2 months of analyses – Best 
case: Q1 2022/Worst case: Q2 2022 
 Observational Study report – Minimum 2 months of 
writing – Best case: Q2 2022/Worst case: Q3 2022 
Note: these milestones are only valid for the comparison with the Institut 
Curie database. The use of any additional databases constituting the external 
historical control cohort(s) can have an impact on the calendar since it will 
require to set-up a data transfer agreement between Bayer and the data source 
owner(s). 
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5. 
Amendments 
None. 
6. 
Milestones 
Table 1 presents planned milestones for the project. These milestones are based on a timely review 
and approval of the project. Administrative changes to milestones due to delays in study preparation, 
data release and analysis do not require amendments to the protocol. Revised study timelines and 
milestones which do not constitute a need for a formal protocol amendment are kept as stand-alone 
document (Table 2, Annex 1) that is available upon request. 
 
Table 1: Milestones 
Milestone 
Planned date 
Approval of the Observational Study Protocol 
Q2 2021 
Submission to HDH 
Q3 2021 
CESREES opinion 
Q3 2021 
CNIL authorization (decision within 2 months – 
can be renewed 2 months) 
Best case: Q4 2021/Worst case: Q1 2022 
Start of analyses 
Best case: Q4 2021/Worst case: Q1 2022 
End of analyses (minimum 2 months of analyses) 
Best case: Q1 2022/Worst case: Q2 2022 
Observational Study Report (minimum 2 months 
of writing) 
Best case: Q2 2022/Worst case: Q3 2022 
CESREES: Comité éthique et Scientifique pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé; 
CNIL: Commission Nationale de l’Informatique et des Libertés; HDH: Health Data Hub. 
 
Note: these milestones are only valid for the comparison with the Institut Curie database. The use of 
any additional databases constituting the external historical control cohort(s) can have an impact on 
the calendar since it will require to set-up a data transfer agreement between Bayer and the data source 
owner(s). 
7. 
Rationale and background 
7.1 
NTRK gene family and NTRK gene fusion-associated cancers 
Neurotrophin (NT) receptors also known as Tropomyosin Receptor Kinase (TRK) are a family of 
transmembrane receptors tyrosine kinases (RTKs) which specifically bind to neurotrophic factors and 
with important physiological roles in neurodevelopment (Nakagawara 2001). The 3 main TRK 
receptors are TRKA, TRKB, and TRKC encoded by the NTRK genes NTRK1, NTRK2 and NTRK3, 
respectively. The main ligands of these receptors are Nerve Growth Factor (NGF), Brain-Derived 
Neurotrophic Factor (BDNF), and Neurotrophin-3 (NT-3). 
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The first NTRK oncogene that was identified as a fusion with the tropomyosin gene in a colorectal 
cancer, follows the well-established paradigm of other oncogenic fusions by driving the growth of 
tumors via constitutive activation of its tyrosine kinase activity, thereby inducing cell proliferation 
and initiating cancer-related downstream signaling pathways (Knezevich SR, McFadden DE, Tao W, 
Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 
1998b; 18(2):184-187. 
Kremer, LC, van Dalen EC, Offringa M, Ottenkamp J, Voûte PA. Anthracycline-induced clinical heart 
failure in a cohort of 607 children: long-term follow-up study. J. Clin. Oncol. 2001. 19, 191-196. 
Le Borgne F, Giraudeau B, Querard AH, Giral M, Foucher Y. Comparisons of the performance of 
different statistical tests for time-to-event analysis with confounding factors: practical illustrations in 
kidney transplantation. Stat Med. 2016; 35(7):1103-1116. 
Loh ML, Ahn P, Perez-Atayde AR, Gebhardt MC, Shamberger RC, Grier HE. Treatment of infantile 
fibrosarcoma with chemotherapy and surgery: results from the Dana-Farber Cancer Institute and 
Children's Hospital, Boston. J Pediatr Hematol Oncol. 2002; 24(9):722-726. 
Manck E. Institut Curie. Epidemiology of sarcomas: who is affected ? 2017. https://institut-
curie.org/dossier-pedagogique/epidemiology-sarcomas-who-affected. 
Martin-Zanca 1986; Vaishnavi 2013). 
The role of NTRK genes in pediatric cancer was initially reported in 1998, with the identification of 
the fusion between ETS variant gene 6 (ETV6) and NTRK3 (ETV6-NTRK3), as the predominant 
genetic feature of both Infantile Fibrosarcoma (IFS) and cellular Congenital Mesoblastic Nephroma 
(CMN) (Knezevich 1998). In a recent study, ETV6-NTRK3 transcript was detected in 87.2% of the 
IFS patients tested in the study (Orbach 2016), which makes this specific gene fusion nearly 
pathognomonic for IFS. However, it is important to note that the NTRK gene fusions are not specific 
to IFS. Other studies have implicated the ETV6-NTRK3 gene fusion as one of a number of kinase 
alterations in children with Philadelphia chromosome positive (Ph+)-like acute lymphoblastic 
lymphoma (Roberts 2014). NTRK gene fusions have been incriminated in pediatric astrocytoma, 
pontine glioma, as well as other Central Nervous System (CNS) primary tumors (Wu 2014). In 
addition, in vivo testing of human Tropomyosin 3 (TPM3)-NTRK1 or BTB Domain Containing 1 
(BTBD1)-NTRK3 transduced into the mouse brain induced high-grade gliomas which showed high 
levels of phosphorylated protein kinase B (AKT) and Mitogen-Activated Protein Kinase (MAPK) 
(Wu 2014). 
The analysis of the transcriptomes of nearly 7,000 tumors also identified NTRK gene fusions in various 
adult cancers including thyroid cancer, glioblastoma multiforme, lung adenocarcinoma, colon 
adenocarcinoma, head and neck squamous cell carcinoma, as well as Soft Tissue Sarcoma (STS) 
(Stransky 2014). NTRK gene fusions are rare. It is estimated that such fusions are present in less than 
1% of solid tumors (Stransky 2014). For example, in lung cancers, it represents 0.23% of the cancers 
(Farago 2018). However, this gene fusion is not tested in routine for all tumors. Therefore, the 
epidemiological data are likely not accurate. 
The identification of NTRK gene fusions has recently come into focus due to the availability of 
targeted treatment modalities (TRK inhibitors [TRKi]). NTRK gene fusions can be detected indirectly 
or directly by multiple methods (Prasad  2016; Brenca 2016; Hechtman 2017), including: 
- 
Next Generation Sequencing (NGS), 
- 
Fluorescence In Situ Hybridization (FISH), 
- 
Reverse Transcription-Polymerase Chain Reaction (RT-PCR), 
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- 
Immunohistochemistry (IHC). 
7.2 
IFS and current standard of care 
IFS is a rare tumor, representing less than 1% of childhood cancers. IFS is a subtype of STS that 
primarily affects children below 2 years old. An incidence peak has been reported before the first year 
of age, diagnosed at birth or in the neonatal period. NTRK gene fusion is considered pathognomonic 
for IFS (Orbach 2016). Surveillance of Epidemiology and End Results (SEER) data suggest an 
incidence of 5 per one million infants born (Ries 1999). IFS accounts for 5-10% of all sarcoma 
diagnoses in children less than 1 year of age (Orbach 2005; Orbach 2010). IFS most commonly arises 
in the extremity (almost 50% of cases) and often presents with rapid initial growth sometimes followed 
by a more indolent course. Metastatic spread is uncommon (1-13%) (Loh 2002; Mertens AC, Yutaka 
Yasui, Liu Y, Stovall M, Hutchinson R, Ginsberg J, Sklar C, Robison LL. Pulmonary Complications 
in Survivors of Childhood and Adolescent Cancer A Report from the Childhood Cancer Survivor 
Study. Cancer. 2002; volume 95, number 11. 
Miettinen 2019; Orbach 2010; Orbach 2016). Overall, IFS has a good prognosis and life expectancy 
is rarely impacted. A retrospective study analyzing clinical features and results of treatment of 56 
infants under the age of 2 years between 1979 and 2005 from 6 European studies reported a 5-year 
overall survival rate of 89% (Orbach 2010). The objective is to provide these patients with treatment 
inducing minimal sequelae. At diagnosis, primary tumors are considered to be unresectable in 48-62% 
of the cases and, therefore, require a multidisciplinary strategy with preoperative cytoreductive 
treatment and local therapy including conservative surgery (Demetri 2020; Orbach 2016; Orbach 
2020; Weiss 2014). Because of the very young age of patients, special attention must be paid to 
minimizing both the acute and chronic toxicities of therapy, including delivering drugs with minimal 
long-term consequences. 
Chemotherapy plays a major role in the treatment strategy for unresectable tumors. The Vincristine-
Actinomycin-D (VA) regimen is the preferred first line option and has shown good response rates in 
IFS. For those patients with insufficient response to VA, other effective regimens include Vincristine-
Actinomycin-D-Cyclophosphamide 
(VAC) 
and 
Vincristine-doxorubicin 
(Adriamycine)-
Cyclophosphamide (VAdriaC) (Loh 2002; Orbach 2016; Orbach 2020; Weiss 2014). 
Almost 17% of patients with IFS have experienced significant negative long-term effects with 
conventional therapies. In addition, 5-10% of treated patients died, mostly as a consequence of a tumor 
which was refractory to multiple lines of therapy (Loh 2002; Orbach 2016; Orbach 2020). 
Chemotherapy drug administration is challenging to manage in such young patients (because of the 
need for central venous catheter insertion, risk of systemic infections, weekly hospital visits for 
chemotherapy administration, potential acute toxic side effects such as Veno-Occlusive Disease 
[VOD] or neuropathy). VA is preferred over VAC chemotherapy (cyclophosphamide) or 
anthracycline-containing regimens which were previously used in 53-87% of IFS patients, as it does 
not have gonadal, mutagenic or cardiac long-term toxicities (Sadurska 2015). Because of their acute 
and long-term toxicities, the use of alkylating agents and anthracyclines is limited. 
7.3 
STS and current standard of care 
Although the main analysis focuses on IFS patients, this section is provided in order to contextualize 
the complementary analyses focusing on the wider STS population (including IFS and other NTRK 
fusion positive STS). 
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STSs are a heterogeneous group of relatively rare mesenchymal tumors, representing 1% to 2% of all 
cancers, with 4,000 to 5,000 new cases per year reported in France. The tumors develop mainly in 
adults around the age of 50, but may occur at any age: 10% of patients are children and adolescents 
(Manck 2017). STSs represent about 8% of all pediatric cancers, with about 120 cases per year 
reported in France (Regnault 2017). Two main types of STSs have been characterized: 
rhabdomyosarcomas (RMS) and non-RMS STSs. RMS are more frequent in young children while 
non-RMS STSs are more frequent in adolescents. These tumors can be localized or metastatic (St. 
Jude Children’s Research Hospital 2018)St. Jude . 
The 5-year relative survival rate for STS is 65% for all SEER stages combined; 81%, 56%, and 15% 
for localized, regional and distant tumors, respectively (American Cancer Society 2021). 
Treatment of these tumors has not dramatically changed over the last two decades. It relies on 
knowledge of their natural history and tumor biology as this information is used to categorize STSs 
according to their risk. Pre-treatment clinical staging aims to categorize the tumors according to their 
site, size, local invasion, regional lymph node involvement and distant metastasis (Orbach 2005; 
Orbach 2016). 
The aim of any standard STS treatment should be to achieve adequate local and systemic tumor control 
while minimizing the long-term sequelae. Chemotherapy, surgery and irradiation are used in the 
treatment of STS. Although surgery is the main treatment in localized low-risk tumors, good outcomes 
are not achieved without adjuvant radiation and chemotherapy aiming to reduce the risk of relapse 
and improve overall survival. In addition, upfront chemotherapy reduces the aggressiveness of the 
required surgery, especially in younger children with growing bodies, and helps preserve organ 
function in a number of cases (Orbach 2005; Orbach 2016). 
Chemotherapy is an essential component of the multimodal treatment of RMS. The standard regimen 
in non-metastatic RMS in Europe, is a combination of Ifosfamide, Vincristine and Actinomycin-D 
(IVA) associated with Doxorubicine (IVADo) in case of metastases (Bisogno 2018). For intermediate- 
and high-risk patients, successive Children’s Oncology Group (COG) trials have failed to improve the 
survival outcome by incorporating novel agents, such as etoposide (Vincristine-Doxorubicin-
Cyclophosphamide alternating with Ifosfamide-Etoposide combination [VDC/IE]), and irinotecan 
(Vincristine-Actinomycin D-Cyclophosphamide alternating with Vincristine-Irinotecan [VAC/VI]), 
with the aim of reducing the cumulative cyclophosphamide dose (Ruymann 2003). In non-RMS, 
chemotherapy provides a poorer response than in RMS. In such tumor group, the therapeutic regimen 
typically comprises Ifosfamide/Doxorubicin (ID) (Ferrari 2015). 
7.4 
Toxicities associated with chemotherapy and radiotherapy 
Chemotherapy is associated with toxicities. The onset of these side effects can be acute or chronic, 
having the potential of severe disabling, life-threatening or fatal illness, such as cardiovascular disease, 
kidney failure, or even a second malignancy (Sadurska 2015; Oberlin 2009). 
Among the most significant complications of pediatric cancer treatment is the occurrence of cardiac 
morbidity, occurring in up to 57% of survivors treated with anthracycline chemotherapy 
(Ramjaun 2015RamjaunRamjaunRamjaun). 
Moreover, 
chemotherapy 
combined 
with 
the 
administration of other cardiotoxic agents increases toxic effect of anthracyclines on the 
cardiovascular system (Sadurska 2015). A high cumulative dose of anthracycline is the greatest risk 
factor for cardiotoxicity, although, it has also become evident that there is no ‘safe’ dose of 
anthracyclines; patients have experienced cardiac damage even at doses < 240 mg/m2 (Lipshultz 2013; 
Lipshultz 2014). In addition, the prevalence of myocardial impairment due to anthracycline increases 
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with a longer follow-up (Lipshultz 2013). In fact, childhood cancer survivors exposed to 250 mg/m2 
of anthracyclines prior to age 5 have an ongoing risk of developing sustained echocardiographic 
abnormalities for up to 25 years following treatment (Ramjaun 2015). After cancer recurrence and 
secondary malignancies, the leading cause of morbidity and mortality in survivors of childhood cancer 
is cardiovascular-related disease (Lipshultz 2014). 
Alkylating agent toxicities and especially those related to cyclophosphamide exposure are multiple. 
Their related gonadotoxicity has been widely described in the literature (Ridola 2009). Beside acute 
toxicities such as hematopoietic or gastrointestinal, it is to be noted that alkylating agents are 
associated with direct damage to the gonads and a significant risk of infertility (Oberlin 2009). Long-
term male gonadal damage following cyclophosphamide-containing regimens has been shown to be 
dose-dependent with up to 70% or 80% of patients being affected by abnormal Follicle Stimulating 
Hormone (FSH) levels after treatment with a cumulative dose of the drug exceeding 9 g/m² 
(Ridola 2009). Elevated serum FSH is consistently associated with an abnormal sperm count. 
However, normal FSH was not found to be predictive of a normal semen analysis. Furthermore, 
cyclophosphamide exposure prior to the onset of puberty did not appear to protect males from 
subsequent gonadal damage (Kenney 2001). 
A study aiming at comparing gonadal toxicity of ifosfamide versus cyclophosphamide during 
childhood showed that ifosfamide was associated with a lower risk of gonadal damage than 
cyclophosphamide and that the risk of abnormal FSH increased with the cumulative dose of 
cyclophosphamide (Ridola 2009). In addition, ifosfamide may cause renal failure and an increased 
risk of second malignancies (tubular and glomerular) (Oberlin 2009). 
Although radiation therapy is very effective to control tumor growth and prolong overall survival, it 
has adverse effects on healthy tissue within the field of radiation. In addition, the combination with 
chemotherapy increases normal-tissue toxicity and therefore leads to even further reduction of the 
tolerable maximum dose. While acute radiation toxicity is marked by acute cell death, the processes 
in chronic toxicity are generally characterized by fibrogenesis and extracellular matrix deposition 
(Klaus 2021; Palmer 2021). A publication focusing on the risk assessment of radio-chemotherapy in 
106 pediatric STS highlighted acute and delayed toxicity in the form of hematological, gastrointestinal 
toxicity and alopecia that occurred in all patients. In addition, hepatic, genitourinary toxicities, 
cardiotoxicity, neurotoxicity and skin complications could be seen in 13.2%, 11.3%, 1.9% and 4.7% 
and 28.3% of patients respectively. Mucositis was noticed in 42.5% of patients, and for 15.1% of them 
it was due to radiotherapy, which also caused dysphagia and dysphonia, impaired taste sensation and 
transient conjunctivitis in 4.7%, 1.9% and 6.6% of patients respectively (Abaza 2015). Additionally, 
46.7% of post-pubertal patients were found to be azoospermic more than 5 years after the end of 
treatment. Respectively, 3.8% and 6.6% of patients developed ototoxicity and skin fibroses due to 
local irradiations (Abaza 2015). Furthermore, hypo- or hyperthyroidism and growth retardation was 
encountered in 7.5% and 6.6% of patients, respectively. Regarding late onset of toxicity, 5.7% of 
patients developed secondary malignancy, 7 years after the end of therapy (Abaza 2015). 
Toxicity due to radiotherapy is usually irreversible and may worsen over time. The latency, or time to 
onset of late toxicity, is thought to be inversely related to radiation dose, whereas its progression 
directly depends on radiation dose (Palmer 2020). 
Toxicities associated with chemotherapy and radiotherapy are summarized in Table 3, Table 4 and 
Table 5 (Annex 2). 
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7.5 
Larotrectinib 
7.5.1 
Larotrectinib clinical development and efficacy 
Larotrectinib is a first-in-class selective TRKi with high potency (IC50 = 5-11 nM in cellular assays) 
and high specificity for TRKA, TRKB and TRKC receptors (≥ 100-fold selectivity versus 229 other 
kinases). 
Larotrectinib has the benefit to be orally bioavailable and to be provided in 2 formulations: a liquid 
oral formulation mainly for the pediatric population and hard gelatin capsules formulated in 2 doses 
(25 mg or 100 mg) mainly for adults. 
Larotrectinib has been tested on patients with advanced solid tumors harboring NTRK gene fusion in 
3 clinical trials: 
 Phase I clinical trial conducted in adults (NCT02122913, “A study to test the safety of the 
investigational drug larotrectinib in adults that may treat cancer” [active, non-recruiting]), 
 Phase I/II clinical trial conducted in the pediatric population (up to 21 years old): SCOUT 
study (NCT02637687, “A Phase I/II study of the oral TRK inhibitor larotrectinib in pediatric 
patients with advanced solid or primary central nervous system tumors [international clinical 
study; recruiting]), 
 Phase II conducted in adults and adolescents (from 12 years old): NAVIGATE study 
(NCT02576431, “A study to test the effect of the drug larotrectinib in adults and children with 
NTRK-fusion positive solid tumors [recruiting])6. 
A first pooled analysis from these 3 clinical trials was performed with a primary data cut-off date of 
17 July 2017 (Drilon 2018). The decision to pool efficacy data from patients with a NTRK fusion-
positive tumor across all three studies was made early in the development program on the basis of the 
rarity of NTRK fusions, the inherent heterogeneity of cancer types, and global regulatory advice. The 
best overall response rate (ORR) derived from the time point responses using the Response Evaluation 
Criteria in Solid Tumors (RECIST) as determined for the first 55 patients with NTRK gene fusion by 
an independent radiology review committee (central assessment) was 75% (95% CI, 61-85%), with 
13% of CR, 62% of PR and 13% of SD. By investigator assessment, the ORR was 80% (95% CI, 67-
90%). 
A second pooled analysis was performed on 159 patients with NTRK gene fusion from the same 3 
clinical trials at data cut-off date of February 19, 2019 (Hong 2020) second analysis confirmed the 
results of the first one, with a best ORR of 79% (95% CI, 72-85), 16% of CR, 63% of PR and 12% of 
SD (investigator assessment), regardless of the type of tumors, the population (adult or pediatric) and 
the type of gene fusion involved. The median Duration of Response (DoR) was 35.2 months, the 
median progression-free survival (PFS) was 28.3 months and the median overall survival (OS) was 
44.4 months. In the IFS population (n=28), 27 patients had an objective response (ORR 96%, 95% CI 
82–100). The median duration of response was not estimable. 
Moreover, the interim clinical study report of the SCOUT study, at data cut-off date of July 15, 2019, 
reported 88 patients of whom 38 patients were in the Phase I portion of the study (24 in escalation and 
14 in expansion) and 50 patients were in Phase II. The full analysis set included all 88 treated patients. 
At the time of this interim analysis, all 79 NTRK gene fusion patients and all 9 of the non-NTRK gene 
fusion patients were evaluable for response. Within the NTRK gene fusion subgroup (consisting 
                                                 
6 Following a protocol amendment of the NAVIGATE study, the study now only includes patients older than 18 years. 
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predominantly of IFS and STS), 54 of the 79 patients with measurable disease had a confirmed 
objective response, yielding an ORR of 77% (95% CI: 66, 86) based on Investigator assessment. This 
included 21 CRs and 37 PRs (including 4 pending confirmation of a PR). Within the non-NTRK gene 
fusion subgroup, no responses were observed. 
In the IFS population (n=34), the ORR was 94% (95% CI 80, 99). Among the patients with IFS, 
included in SCOUT at data cut-off of July, 2019, 21 patients had no other curative options besides 
disfiguring surgery or amputation before larotrectinib initiation. At the time of analysis, all of these 
patients showed responses, with 4 complete surgical responses, 7 complete responses and 9 partial 
responses recorded. None of these patients required an amputation or disfiguring surgery and no death 
was reported at the time of analysis. 
As a conclusion, in these various analysis, larotrectinib has demonstrated clinically meaningful 
antitumor activity in pediatric patients with locally advanced or metastatic solid tumors with NTRK 
gene fusions, including IFS, that had previously progressed and had little or no effective treatment 
alternatives and facing limb amputation or disfiguring surgery. 
According to the European Society for Medical Oncology (ESMO) Scale of Clinical Actionability for 
molecular Targets (ESCAT), larotrectinib was classified as “tier I-C”, which is attributed “when 
clinical trials in multiple tumor types, or basket clinical trials, have demonstrated a clinically 
meaningful benefit for the target-drug pair with similar magnitude of benefit across the different tumor 
types” (Mateo 2018). 
In the United States, FDA approved larotrectinib (Vitrakvi) in November 2018 with an accelerated 
approval in the following indication: 
Vitrakvi is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid 
tumors that: 
 have a neurotrophic 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. 
In France, a Temporary Authorization of Use (Autorisation Temporaire d’utilisation [ATU]) was 
granted by the National Agency for Drug and Health Products Safety (Agence Nationale de Sécurité 
du Medicament et des Produits de Santé [ANSM]) in March 2019. 
In September 2019, larotrectinib was granted a conditional MA in Europe, for the treatment of adult 
and pediatric patients with solid tumors that display a NTRK gene fusion: 
 who have a disease that is locally advanced, metastatic or where surgical resection is likely to 
result in severe morbidity, and 
 who have no satisfactory treatment options. 
7.5.2 
Larotrectinib safety profile 
At the cut-off date of July 2019, 88 pediatric patients ranging in age from less than 1 month to 19.9 
years had been enrolled in the SCOUT trial and treated with larotrectinib. 85/88 patients experienced 
at least one Treatment Emergent Adverse Event [TEAE]. The TEAEs were usually mild. The most 
commonly occurring TEAEs by preferred term (PT) were pyrexia (47%), vomiting (44%), alanine 
aminotransferase (ALT) increase (40%), cough (39%), diarrhea (38%), aspartate aminotransferase 
(AST) increase (34%), neutrophil count decrease (30%), constipation (25%), upper respiratory tract 
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infection (25%), fatigue (22%), and nausea (20%). Sixty-two (62) patients (70%) experienced at least 
one TEAE attributed to larotrectinib. Forty-seven (47) patients experienced a TEAE that was Grade 3 
or 4 (53%), although these were considered related to larotrectinib in only 17 patients (19%). The 
related Grade 3 or 4 TEAEs, occurring in more than one patient each by PT, were neutrophil count 
decrease (8 patients), weight increase (2 patients) and ALT increase (2 patients). Twenty-seven (27) 
patients experienced a TEAE that was considered serious (31%) with 6 considered related to the drug 
(7%). Two (2) patients (2%) experienced a TEAE with fatal outcome but none were related to 
larotrectinib. 
Moreover, an expanded safety population analysis of 260 patients enrolled and treated in the phase I 
study in adults, the phase I/II pediatric (SCOUT), or the phase II adolescent and adult trial 
(NAVIGATE), was performed (data cut-off February 2019, Hong 2020). No new safety signals were 
identified from this analysis. This was also the case in the subset of pediatric patients with TRK fusion-
positive tumors (n=52). To date, the known safety profile has not changed over time. The long-term 
toxicity and developmental effects of larotrectinib in pediatric patients are being investigated in the 
SCOUT trial and also via the observational post-authorization safety study. With at least 60 months 
of follow-up from larotrectinib initiation in pediatric patients, this non-interventional study will 
generate additional safety and effectiveness data in a broader population (300 patients, with a 
minimum of 30 pediatric patients) in a real-world setting, including long-term effects of larotrectinib 
on growth (height and weight), neurological outcomes, developmental milestones, and sexual 
development. 
Larotrectinib offers a novel, well-tolerated and often highly effective treatment for infants with TRK 
fusion IFS. Moreover, the oral solution of larotrectinib allows for an easy administration in very young 
patients. 
7.6 
Rationale for the conduct of this observational study 
The clinical development program of larotrectinib to date has shown that the tumor response observed 
with the drug is pronounced and durable even if no comparator is used in the ongoing clinical studies, 
including the pediatric Phase I/II study (SCOUT). 
In France, a dossier was submitted to the National Authority for Health (Haute Autorité de Santé – 
HAS) in October 2019 to obtain the reimbursement of larotrectinib in the country, in line with the 
population described in the MA. 
In July 2020, the HAS’s final appraisal was a positive opinion for the reimbursement of larotrectinib 
only in the pediatric patients with IFS or another STS harboring a NTRK gene fusion, which is locally 
advanced or metastatic, and refractory or in relapse, for moderate clinical benefit (SMR) with no 
improvement in clinical benefit (ASMR V) mainly due to the lack of comparative evidence. Among 
other requests, the HAS requested post-inscription clinical data to be provided. In this context, the 
reimbursement remains conditional and will be reassessed based on the provision of comparative data 
of larotrectinib versus standard of care at least versus an external control arm, in particular in IFS. 
This study is designed to address this request but also to possibly use the data to provide comparison 
with historical data as agreed in the pediatric investigation plan with EMA. 
7.7 
Rationale for the use of an external historical control 
Performing a comparison of the available data in the larotrectinib ongoing pediatric phase I/II study 
(SCOUT) with that of (an) external historical cohort(s) reflecting standard of care, constitutes a 
relevant approach to assess the efficacy of larotrectinib and to contextualize its therapeutic benefit 
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over current therapies which may be associated with detrimental outcomes. Given the rarity of the 
condition and ethics consideration, the use of an external control arm allows for the timely generation 
of comparative data. 
To our knowledge, the database of the Institut Curie is the only database that is confirmed today to be 
eligible and accessible to be an external historical cohort for the present study (see eligibility criteria 
in Section 9.2.3.1). The Institut Curie database is the largest database available in France (including 
patients treated in Institut Curie and also treated in other hospitals) which describes French pediatric 
patients harboring TRK fusion cancer (especially IFS) that is able to provide patient-level data for the 
constitution of a historical control group. The patients constituting the Institut Curie database were all 
diagnosed with a NTRK gene fusion by RNAseq. 
For nearly 25 years, the Somatic Genetics Unit of the Institut Curie has been involved in the 
establishment of molecular diagnoses and the classification of pediatric sarcomas and tumors with the 
objective to optimize patient care. This institute is a leader and can be considered as a reference in the 
field in France and in Europe. The care of the patients included in the Institut Curie database 
corresponds to the standard of care of the patients with the targeted indication. 
Additional databases meeting the eligibility and feasibility criteria identified following a 
comprehensive search of databases (Systematic Literature Review [SLR]) will be used as external 
historical control cohorts (see details in Section 9.2.3.1). 
7.8 
Rationale for the choice of the primary endpoint 
In oncology clinical trials, OS, defined as the time from randomization until death due to any cause, 
is generally considered as the most convincing measure for drug efficacy and benefit and represents 
the gold standard primary endpoint for these trials (FDA 2018). 
In the present observational study, the time to medical treatment failure (defined as the time from the 
start of treatment to the date of the following events, whichever comes first: subsequent systemic 
treatment, radiation therapy, mutilating surgery or death due to any cause), was chosen to be the 
primary endpoint. 
The choice of the time to medical treatment failure as primary endpoint over OS was motivated by the 
results of recent studies (Orbach 2020) confirming the excellent OS of patients with IFS. A 
retrospective analysis performed in 2020 of all published data from patients with IFS of the European 
pediatric Soft tissue Sarcoma Study Group (EpSSG) and Cooperative Weichteilsarkom Studiengruppe 
(CWS) databases revealed that among the 172 European patients treated, 162 (94.2%) were alive at 
the end of the study follow-up. Among the 10 patients who died, 9 patients died because of the disease 
and one because of toxicity (Orbach 2020). Based on these observations, OS does not therefore 
represent the most relevant criterion to assess the therapeutic benefit of a treatment for IFS patients. 
The challenges for IFS patients are the management of their morbidities and the long-term effects 
associated to the type of therapies used, which includes the resection of their tumor without anatomic 
and functional damage, as well as the administration of adapted therapies (alkylants, anthracyclines, 
radiotherapy) by minimizing acute and chronic toxicities, including minimal long-term consequences. 
The retrospective analysis performed by Orbach et al. (Orbach 2020), showed that among the 172 
patients included in the study, 65 patients (40% of all survivors) were treated with surgery alone and 
64 (39%) with surgery combined with chemotherapy. Radiotherapy was delivered to 5 patients (3% 
of survivors), and 28 patients (17%) exclusively received chemotherapy. Among the 129 patients who 
were treated with surgery, 91% had conservative surgery (118 patients). Twenty patients (12%) 
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survived with major functional deficits or had mutilating surgery. In this series, almost 17% of patients 
may have experienced significant negative long-term effects with conventional therapies (20 patients 
treated with mutilating surgery and 5 with radiotherapy). In addition, 10 patients died mostly as a 
consequence of a tumor which was refractory to multiple lines of therapy. Altogether, these 
observations evidence that conventional conservative strategies demonstrate efficacy in IFS, even for 
the extensive tumors, but they are associated with acute and chronic side effects (Orbach 2020, see 
Section 7.4). 
To increase the robustness of the comparison for the primary analysis, events that are considered the 
most relevant in view of the multidisciplinary management of these tumor types will be selected. 
Chemotherapy is an essential component of the multimodality treatment with multiple lines 
considered in case of suboptimal outcomes, while surgery and radiation therapy acting as a local 
control may be associated with significant morbidities, with, in the worst case, failing to preserve the 
affected organ, particularly in the extremities. Three European studies analyzing the total burden of 
therapy for patients with IFS treated with conventional treatments showed that radiotherapy was used 
in 2.9% of patients, mutilating surgery was performed in 6.9% of patients and 5.2% of patients died 
of disease. Moreover, in main recent large series published in IFS, mutilating surgery, radiotherapy, 
alkylating chemotherapy and anthracycline agents were performed or used in 6-13%, 2-20%, 20-87% 
and 0-13% of cases, respectively (Orbach 2020). 
The systemic treatment administered to the patient population targeted in this observational study is 
expected to either allow a complete response or to qualify the patient for non-mutilating complete 
surgical resection. Based on the experience of the experts of the field, tumor responses after 
conventional chemotherapy generally occur slowly over several months, whereas larotrectinib may 
lead to an early response (median time to response 1.8 months, with clinical improvement noted within 
days to weeks), which may be more important when there are life-threatening symptoms including 
tumor bleeding or organ compression. In cases of refractory tumors, life-threatening complications, 
or of metastatic tumors, TRKi should be immediately considered (Orbach 2020). 
Events that constitute the primary endpoint (subsequent systemic treatment, radiation therapy, 
mutilating surgery or death due to any cause) were chosen based on the following rationales: 
 They are all considered as markers of treatment failure from a clinical perspective and it is 
clinically relevant to avoid the occurrence of any of these events, because of associated 
morbidities and long-term toxicities: 
o Use of a subsequent treatment is considered when treatment response is not pronounced 
enough to qualify a patient for non-mutilating surgical resection or upon progression, 
o Radiation therapy is considered when systemic treatment fails as it can cause significant 
morbidity, 
o Mutilating surgery (at the investigator’s discretion in SCOUT and external historical control 
cohorts): clinicians aim at avoiding mutilating surgery, it is the very last option in case of 
previous treatment failure to prevent evolution to the metastatic stage and associated risk of 
shortened survival, 
o Death. 
 Measuring methods for those events in the SCOUT and external historical control cohort(s) seem 
more reliable than the evaluation of the PFS or tumor response, which are dependent upon local 
methods of reading radiological images. 
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 Due to the small patient population, the comparison with (an) external historical control cohort(s) 
and the anticipated rarity of events of clinical interest, the choice of a composite endpoint sounds 
the most appropriate approach. 
8. 
Research questions and objectives 
8.1 
Primary objective 
The aim of the study is to assess the therapeutic benefit of larotrectinib over the current standard of 
care in patients with locally advanced or metastatic IFS. 
The primary objective of the present study is to compare the time to medical treatment failure (defined 
as: next systemic treatment or mutilating surgery or radiation therapy or death due to any cause) 
between larotrectinib and standard of care in IFS patients using externally-controlled comparison 
performed with phase I/II SCOUT study and eligible external historical cohort(s). 
8.2 
Secondary objectives 
The secondary objectives in this study include the comparison of: 
 Treatment outcomes (next systemic treatment, mutilating surgery, radiation therapy, death 
due to any cause), 
 Treatment discontinuation rates due to toxicity. 
9. 
Research methods 
9.1 
Study design 
This study is a retrospective observational externally-controlled study. Data of patients with IFS in 
the eligible external historical cohort(s) will serve as control for the comparison with data of patients 
with IFS who have been enrolled in the SCOUT study. Data which will be used for the analyses will 
come from: 
 SCOUT study: 
o At least 27 sites across 13 countries, including France. 
 Eligible external historical control cohort(s) (see inclusion and exclusion criteria of databases 
in Section 9.2.3.1), including at least the Institut Curie database. 
9.1.1 
Primary endpoint 
The primary endpoint of the study is the time to medical treatment failure: defined as the time 
(months) from the start of treatment to the date of the following events, whichever comes first: 
subsequent systemic treatment, radiation therapy, mutilating surgery or death due to any cause. 
The rationale for the choice of this variable as primary endpoint, notably over OS variables is detailed 
in Section 7.8. 
9.1.2 
Secondary endpoints 
The secondary endpoints of the study are: 
 Time to subsequent systemic treatment. 
 Time to mutilating surgery including limb amputation. 
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 Time to radiation therapy. 
 Time to complete surgical resection (excluding amputation). 
 OS, defined as the time (months) from the start of treatment to the date of death due to any cause. 
Patients alive or lost to follow-up at the time of analysis will be censored at their last date of 
follow-up. 
 Incidence of patients with treatment discontinuation due to treatment-related adverse events 
(AEs). 
9.1.3 
Exploratory endpoints 
The following exploratory endpoints will also be investigated: 
 Progression-free survival (PFS): defined as the time (months) from the start of treatment to the 
date of first observed disease progression (radiological or clinical, whichever is earlier; assessed 
by the treating physician in the external historical control cohort(s)) or death due to any cause, 
if death occurs before progression is documented. Patients without documented progression at 
the time of analysis will be censored at the date of last tumor assessment. 
 Overall response rate (ORR): defined as the proportion of patients with a best overall response 
of complete response (CR) or partial response (PR), as assessed by investigators. 
 Disease Control Rate (DCR): defined as the proportion of patients with a best overall response 
of CR, PR, or Stable Disease (SD). 
9.2 
Setting 
9.2.1 
Study population 
The study population will comprise all patients of the SCOUT study and of the external historical 
control cohort(s) (including at least the Institut Curie database) with a diagnosis of locally advanced 
or metastatic IFS. Inclusion and exclusion criteria for patients are described in Section 9.2.3.2. 
9.2.2 
Study time frame 
This study, being a retrospective observational study, does not require diagnostic or therapeutic 
procedures nor the respect of a specific calendar for patient visits. 
The detailed planned dates of the different milestones of the study are presented in Section 6 in Table 
1. 
9.2.3 
Selection criteria 
9.2.3.1 
Selection criteria for the sources of the external historical control cohort(s) 
The choice of the external control cohort(s) to be included in the comparator arm is not arbitrary. In 
order to ensure a non-biased selection and to maximize as possible the sample size and power of the 
comparator group, the following actions were or will be undertaken: 
 A comprehensive assessment of the existing databases in France and internationally will be 
performed from the following sources: 
 Databases found in the literature, 
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 Databases from clinical studies sponsored by Bayer or known by Bayer, notably 
through its interactions with experts in the field, 
 Commercial databases with electronic medical data. 
 A SLR will be conducted to ensure completeness of the identification of all databases that 
could be used as external historical control cohorts. This SLR will be based on a protocol of 
research including the following Patient, Intervention, Comparison, Outcome (PICO) criteria: 
o Population: IFS, 
o Intervention: N/A, 
o Comparison: N/A, 
o Type of studies: all interventional and observational studies except case reports, 
o Period: from 2000 to present, 
o Scope: international. 
The SLR protocol and report will be annexed to the final study report. 
The selection of data sources will be performed upon the following eligibility and feasibility criteria, 
with the following justifications: 
 Inclusion criteria: 
 Cohorts with prospective enrollment and with retrospective and prospective data 
collection from 2000 to present. 
This criterion was defined based on the following rationales: 
o The strong evolution of histological diagnostic in the 2000’s, 
o The risk of classification bias if databases prior to 2000’s were considered (e.g., 
with our current knowledge and the current classification, nowadays, some 
patients would not be diagnosed with IFS but with spindle cells 
rhabdomyosarcoma [Orbach 2020]), 
o The development and the use of biomolecular diagnostic since the 2000’s: IFS 
diagnosis is no more considered in absence of NTRK gene fusion, 
o The absence of significant evolution in the IFS diagnosis and therapeutic 
approaches from 2000 to present: Chemotherapy (VA regimen) has been the 
standard of care for this indication for several decades (reference: HAS opinion 
on larotrectinib). 
 Cohorts containing at least clinical data allowing to assess the efficacy of the treatment 
and the main prognostic factors as follows: 
o Diagnosis and stage of the disease (locally advanced or metastatic), 
o Type of treatments (chemotherapy, radiotherapy, surgery: mutilating yes/no) 
and date of the initiation or of the procedure, 
o Death and date, 
o Localization of the tumor (axis versus limb), 
o Size of the tumor (< 5 cm versus > 5 cm). 
 Exclusion criteria: 
 Databases not containing patients with locally advanced or metastatic IFS, 
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 Medico-administrative databases or absence of data allowing the assessment of the 
efficacy of the treatment and main prognostic factors, or high rate of missing data 
(>10% on outcome and >25% on covariates), 
o The use of these databases, especially medico-administrative databases, is not 
feasible because of missing data and the limited information available on the 
clinical, biological, diagnostic and treatment data, notably for rare diseases like 
IFS. These limitations would be an issue for the prognostic, outcomes and 
selection criteria of patients. 
 Cohorts with retrospective enrollment and case report, 
o Cohorts with retrospective enrollment or case report are subject to a greater risk 
of selection bias than those with prospective enrollment and with retrospective 
and prospective data collection, given that all patients who should have been 
considered to be included might have not been included a posteriori. 
 Cohorts with prospective enrollment for which all patients were included before 2000, 
o There is a risk of classification bias for cohorts constituted before 2000 because 
of the evolution of the histological and molecular diagnosis of IFS (see details 
in the inclusion criteria). 
Based on a preliminary search of databases and the selection criteria described above, in addition to 
the database of the Institut Curie which is the only database confirmed, the following data sources are 
theoretically eligible to be used to constitute (an) external historical control cohort(s) for the present 
study: 
 Databases found in the literature (preliminary search that will be completed by the SLR): 
 Database from the European pediatric Soft tissue Sarcoma Study Group (EpSSG, a 
consortium housed in the University of Padua, Italy, European data), 
 Database from the Cooperative Weichteilsarkom Studiengruppe (CWS, Germany). 
 Commercial databases with electronic medical data: 
 No eligible databases were found. 
The comprehensive review of the literature (SLR) that will be performed might identify additional 
eligible cohorts. The availability, the access, and the feasibility of use of the different eligible 
databases identified will be then investigated. Further details will be described in the final study report. 
9.2.3.2 
Selection criteria for patients 
 Inclusion criteria: 
The inclusion criteria listed below are in line with those of the SCOUT study in terms of 
patients and disease characteristics: 
- 
Age ≤ 21 years old. 
- 
Locally advanced or metastatic IFS. 
- 
Patients with available information on clinical, radiological characteristics of their tumor, 
therapies administered and outcomes. 
- 
Patients receiving larotrectinib in the SCOUT trial. 
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- 
Patients receiving at least chemotherapy-based regimen in the external historical control 
cohort(s). 
- 
No opposition from the patients and/or representatives for data use. 
 Exclusion criteria: 
- 
Patients treated with TRKi in the external historical control cohort(s). 
- 
Patients with documented absence of NTRK gene fusion: 
o Formal identification of NTRK gene fusion has not been retained as an inclusion 
criteria as the information might be missing from the databases used to constitute the 
external historical control cohort(s). Given the rarity of the condition and the 
anticipated small sample size, the study will authorize the inclusion of patients with 
unknown NTRK gene fusion status to maximize sample size while there is a limited 
risk of introducing a bias, as NTRK fusion is almost pathognomonic in IFS (Orbach 
2016). 
- 
Patients participating in an investigational program with interventions outside of routine 
clinical practice. 
 Population sampling strategy: 
The study population will comprise all IFS patients in the SCOUT study and the eligible external 
historical cohort(s) (including at least the Institut Curie database) with a diagnosis of locally advanced 
or metastatic IFS regardless of their refractory or relapsed status, i.e. including treatment-naive 
patients to avoid further reducing the sample size. 
The choice of the study population has mainly been driven by feasibility/sample size considerations, 
in order to be able to perform a comparison based on a minimal number of patients. 
In addition, the IFS population will also include patients with advanced or metastatic CMN since the 
histopathological characteristics of these tumors are very close to those of IFS, as mentioned in the 
WHO sarcomas classification (Kallen and Hornick 2020). Moreover, the presence of the same fusion 
transcript as in IFS is identified in the cellular form of CMN (Thebaud 2012). 
9.2.4 
Representativeness 
Larotrectinib as monotherapy is indicated for the treatment of adult and pediatric patients with solid 
tumors that display a NTRK gene fusion, 
 who have a disease that is locally advanced, metastatic or where surgical resection is likely to 
result in severe morbidity, and 
 who have no satisfactory treatment options. 
The positive opinion of the HAS for the conditional reimbursement of larotrectinib was given only 
for the pediatric patients with a diagnosis of locally advanced or metastatic IFS or another STS 
harboring an NTRK gene fusion, refractory or in relapse. Therefore, the data that will be used for the 
analyses of this observational study are data from IFS patients who are in line with the scope of the 
conditional reimbursement of larotrectinib, broaden to IFS regardless of their refractory or relapsed 
status, i.e. including treatment-naive patients, in order to limit the further reduction of the sample size. 
Data will be extracted from the following sources: 
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 The SCOUT study, which is an international clinical trial conducted in 27 centers in 13 
countries including France, started in December 2015, 
 The Institut Curie database and the eligible databases identified through a SLR with an 
international scope according to the selection criteria described in Section 9.2.3.1. The choice 
of using cohorts with prospective enrollment and with retrospective and prospective data 
collection from 2000 to present will avoid the risk of selection bias that could have occurred 
if cohorts with retrospective enrollment would have been included and the risk of classification 
bias if cohorts constituted before 2000 would have been included, notably because of the 
evolution of histological and molecular diagnosis of IFS in the 2000’s. Therefore, the control 
cohort(s) that will be identified using this systematic approach with an international scope and 
the chosen selection criteria can be considered representative. 
Even though the sample size is small (which is inherent to the very low incidence of the targeted 
indications), these sources can be considered as reliable and representative of the population targeted 
in the present observational study, given the time windows and the sources from which the data will 
be extracted (e.g. the Institut Curie database regroups data from French centers from all over the 
regions of France). 
9.3 
Variables 
9.3.1 
Variables to determine the primary endpoints 
To determine the primary endpoint (time to medical treatment failure), the following variables will be 
collected from the Case Report Forms (CRFs) of the eligible patients for the present observational 
study from the SCOUT study and from the database(s) of the eligible external control cohort(s): 
 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and whichever comes first: 
 Start date of a post-treatment7 systemic anti-cancer therapy, if any, or, 
 Start date of a post-treatment6 radiation therapy, if any, or, 
 Date of a post-treatment6 mutilating surgery, if any, or, 
 Date of death due to any cause, if applicable. 
9.3.2 
Variables to determine the secondary endpoints 
To determine the secondary endpoints, the following variables will be collected from the CRFs of the 
SCOUT study and from the external control database(s) eligible for the present observational study: 
For the time to subsequent systemic treatment endpoint: 
 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and, 
 Start date of a post-treatment7 systemic anti-cancer therapy, if any. 
For the time to mutilating surgery including limb amputation endpoint: 
                                                 
7 After the start of larotrectinib treatment for the SCOUT study or after the start of chemotherapy (first or second line) for 
the external historical control cohort(s). 
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 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and, 
 Date of a post-treatment7 mutilating surgery including limb amputation, if any. 
For the time to radiation therapy endpoint: 
 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and, 
 Start date of a post-treatment8 radiation therapy, if any. 
For the time to complete surgical resection (excluding amputation) endpoint: 
 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and, 
 Date of a post-treatment7 complete surgical resection (excluding amputation), if any. 
 
 
                                                 
8 After the start of larotrectinib treatment for the SCOUT study or after the start of chemotherapy (first line) for the external 
historical control cohort(s). 
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For the OS endpoint: 
 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and, 
 Date of death due to any cause, if applicable, or, 
 Last date of patient follow-up for patients alive and lost to follow-up, if applicable. 
For the Incidence of patients with treatment discontinuation due to treatment-related AEs endpoint: 
 Record of treatment9 discontinuation due to treatment-related AEs, if applicable. 
9.3.3 
Variables to determine the exploratory endpoints 
To determine the exploratory endpoints, the following variables will be collected from the CRFs of 
the SCOUT study and the external historical control cohort(s) of the patients eligible for the present 
observational study: 
For the PFS endpoint: 
 Start date of larotrectinib treatment for the SCOUT study and start date of chemotherapy (first 
line) for the external historical control cohort(s), and, 
 Date of first post-treatment7 disease progression/relapse assessed by radiological or clinical 
examination, if any, or, 
 Date of death due to any cause, if applicable, or, 
 Last tumor assessment date for patients alive without documented progression. 
For the ORR and DCR endpoints: 
 Patient response to treatment8 (CR, PR and SD) assessed by investigator. 
9.3.4 
Potential confounders 
The following baseline variables will be considered when balancing the two cohorts: IFS patients 
enrolled in SCOUT study and the external historical control cohort(s). 
 Patients and disease characteristics: 
o Sex, 
o Age, 
o Disease history: 
 Date of initial diagnosis, 
 Anatomical disease site(s) at diagnosis, 
 Stage of disease at diagnosis (local versus locally advanced versus metastatic), 
 Primary tumor size (< 5 cm or > 5 cm), 
 Date of advanced disease stage evolution (locally advanced, metastatic), 
 Time from locally advanced/metastatic disease diagnostic to initiation of larotrectinib 
(SCOUT) or first line of chemotherapy (external historical control cohort(s)), 
 Intergroup Rhabdomyosarcoma Study (IRS) group, 
 Anatomical site(s) of metastases, if any. 
 Collection of treatment-related information: 
o Prior/current surgical treatment(s) for cancer: 
 Anatomical site(s), 
                                                 
9 Larotrectinib treatment for the SCOUT study and chemotherapy (first line) for the external historical control cohort(s). 
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 Date(s) of surgery, 
 Best resection (R0, R1, R2), 
 Nature of intervention(s) (e.g. amputation or other disfiguring procedures), 
 Surgery for a curative intent (excluding amputation) because of the use of systemic 
treatment. 
o Prior/current radiation treatment(s) for cancer: 
 Anatomical sites, 
 Date(s) of radiation therapy. 
o Systemic treatment(s), including: 
 Treatment regimen, 
 Date of initiation, 
 Date of radiological or clinical progression, 
 Reasons for discontinuation, as appropriate. 
A SLR will be conducted to identify and quantify prognostic factors which could impact the study 
primary endpoint. This SLR is based on a protocol of research including the following PICO criteria: 
 
Population: IFS locally advanced or metastatic. 
 
Intervention: no restriction. 
 
Comparison: no restriction. 
 
Outcomes: prognostic factors. 
 
Type of studies: no restriction except case reports. 
 
Period: no limit of time. 
 
Scope: international. 
The SLR protocol and report will be annexed to the final study report. 
9.4 
Data sources 
Data used in this study will come from the following different sources: 
 From the international phase I/II clinical trial called ‘SCOUT’ conducted in a pediatric 
population (up to 21 years old) with advanced solid or primary CNS tumors. 
For the SCOUT study, data are collected via electronic CRFs (eCRFs) completed by the 
investigators during the study conduct in each site. 
 From the Institut Curie database and the other eligible external historical control cohort(s), 
data are collected from the respective databases. The definitive choice of the external historical 
control cohort(s) will be done after a comprehensive assessment of the existing French and 
international databases and SLR. The characteristics of the control cohorts that will be 
identified as eligible will be described in the final study report. 
9.5 
Study size 
All patients meeting the selection criteria will be included in the study. Statistical power will be 
computed retrospectively according to the available sample size. 
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9.6 
Data management 
9.6.1 
Data access rights and confidentiality 
For the larotrectinib arm of the study, data that will be used for the analyses of this observational study 
are secondary data that were originally pseudonymized during the conduct of the SCOUT study. Each 
patient was identified by a unique central patient identification code, which was only used for the 
purpose of this study. The patient’s treating physician or authorized site personnel are the only persons 
able to identify the patient, based on the patient’s identification code. Uncoded patient data (which 
allows to directly identify a person) as well as the list allowing to do the link between the patient and 
the unique central patient identification code are only and securely stored at study sites. 
For the eligible control cohorts, grant access to Bayer to patient-level raw data will be requested to 
the corresponding databases. A data transfer agreement will be agreed between Bayer and the 
databases owners to set up requirements in terms of data transfer, transfer and storage. The transfer of 
external data to Bayer will be performed via CLIXX (Clinical Information Exchange Platform for 
External Partners). The purpose of this secured platform is to facilitate the exchange of personal data 
between Bayer and external partners. After successful download, the data will be removed from 
CLIXX and deposited into TOSCA, which is a globalized tool, developed internally, which combines 
a central location for clinical data, standards and program repository, and a SAS programming 
environment for storing, programming managing and analyzing data. Bayer data center is located in 
Leverkusen, Germany. 
In compliance with the laws and regulations in application and in particular with the General Data 
Protection Regulation (GDPR, EU 2016/679 of 27 April 2016), the persons having a direct access to 
the source data will take the necessary precautions to ensure the confidentiality of the information 
relative to the experimental medicinal products, to the clinical studies, and to the individuals who 
participated to the studies. These persons will be bound by professional secrecy. 
9.6.2 
Document and data archiving 
Data will be accessible when CNIL authorization is obtained until the end of statistical analysis. The 
data will be then stored during a 2-year period after finalization of the publication. Any data as well 
as programs from statistical programming performed to generate results will be archived within the 
programming system for at least 25 years. 
Bayer will ensure that all relevant documents related to this observational study will be archived after 
the end or discontinuation of the study for at least 25 years. 
9.7 
Data analysis 
A comparison of patients in the larotrectinib group with patients from the external historical control 
cohort(s) who received systemic therapy (chemotherapy-based regimen) will be conducted by Bayer, 
at least with the Institut Curie database. In the event that other external historical control cohorts are 
eligible and accessible, the databases will be pooled if feasible. 
The data and statistical analyses that will be performed are summarized in the following sections. 
Further details will be described in the statistical analysis plan (SAP), including methods for handling 
missing data. 
9.7.1 
Index Date and endpoints 
The comparison of the two cohorts will be considered for the primary composite endpoint: 
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 Time-to-treatment-failure (earliest of next systemic therapy, radiotherapy, mutilating surgery 
or death due to any cause). 
In addition, all secondary and exploratory endpoints detailed in Section 9.1.2 and Section 9.1.3 will 
be analyzed: 
 Time to subsequent systemic treatment, 
 Time to mutilating surgery or limb amputation, 
 Time to radiation therapy, 
 Time to complete surgical resection (excluding amputation), 
 OS, 
 PFS, 
 Incidence of treatment discontinuation due to treatment-related AEs, 
 ORR, 
 DCR. 
The analysis will include patients on both first and second line (or higher) therapy. For SCOUT 
patients, the index date will be defined as the start date of larotrectinib. For patients of the external 
historical control cohort(s), the index date will be the start date of the first line of chemotherapy. The 
initial imbalance on lines of therapy between treatment groups will be corrected in the statistical 
modeling, in particular the variable defined by time from locally advanced/metastatic disease to index 
date will be a key variable in the propensity score model. Given approximately 70% of SCOUT 
patients received larotrectinib as second line of treatment, while in the external historical control 
cohort(s) all patients will have received chemotherapy in first line of treatment, the proposed primary 
analysis is expected to provide a rather conservative estimate of treatment effect. 
9.7.2 
Adjustment methodology 
Patients who received larotrectinib in the SCOUT trial will likely differ in various underlying 
characteristics from those who are recorded in the external historical control cohort(s). These 
characteristics are listed above as potential confounders (See Section 9.3.4). The analyses will need 
to be adjusted for these patient characteristics to avoid biased results. 
An adjustment methodology using a propensity score will be employed to reduce the effects of 
measured confounding variables in the interpretation of the treatment effect (larotrectinib versus 
historical group). A propensity score can be seen as an overall “balancing score”, that is calculated for 
each patient based on his or her measured underlying characteristics. 
The propensity score will be obtained from a logistic regression model with dependent variable: 
larotrectinib group (yes/no). Covariates will be taken from the list of potential baseline confounders 
above (see Section 9.3.4). The predicted probabilities of receiving larotrectinib from this logistic 
regression model will form the propensity scores for each patient. 
The most widely used propensity score is 1:1 matching, which involves selecting treated and control 
patients without replacement to form matched pairs. However, this typically requires a larger group 
of control patients than within the treated group, so that each treated patient can find a satisfactory 
matching control. 
Because cases of IFS are exceedingly rare, resulting in small sample sizes, we favor IPTW as it is easy 
to implement and retains data from all patients (it does not discard the unmatched patients), which 
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makes it closer to the global population (Austin 2014; Thoemmes 2016; Cenzer 2020). In addition, 
the IPTW method allows one to estimate the average treatment effect (ATE). In this sense, it can mimic 
a randomized trial, which is designed to provide an unbiased estimation of the ATE (Austin 2014). In 
contrast, a conventional matching approach (e.g. matching pairs of treated and control subjects on the 
logit of the propensity score) is restricted to estimating the average treatment effect in the treated 
(ATT). ATT would only be expected to equal ATE in a randomized control trial setting. The IPTW 
method makes it possible to reduce bias by correcting each patient’s contribution by a weight equal 
to the reciprocal of the probability of receiving the treatment that was actually received. For 
larotrectinib patients, this is the reciprocal of the propensity score, while for comparator patients this 
is the reciprocal of one minus the propensity score. These weights are stabilized by multiplying by the 
marginal probability of treatment that was actually received, which avoids very large weights being 
assigned to larotrectinib patients with a very low propensity score or to comparator patients with a 
propensity score close to 1. Austin and Stuart recommend keeping “design” and “analysis” separate, 
and not using the outcome data in the propensity score process. Therefore, the balancing and analysis 
steps will be two completely distinct tasks (Austin and Stuart 2015). 
9.7.3 
IPTW method 
The choice of covariates for the propensity score model will be finalized at a later date. IPTW analysis 
will be adopted for all time-to-event endpoints, and also for response endpoints (ORR, DCR). If 
possible, all available covariates will be included in the propensity score model. A SLR will be 
conducted to identify and quantify the known prognostic factors (see details in Section 9.3.4). If 
possible, the analyses will be adjusted based on all those prognostic factors. Every effort will be made 
to decrease bias by including covariates that are associated with outcome, or are true confounders 
(associated with both exposure and outcome), as demonstrated by Piracchio et al. (Pirracchio 2012) 
in simulations involving small sample sizes (Cenzer 2020). 
For all baseline covariates included in the propensity score model, standardized differences between 
larotrectinib and comparator groups will be computed. A graph will show the absolute standardized 
difference for each of the covariates, comparing larotrectinib and comparator, for both the unweighted 
and weighted samples. A standardized difference of 10% is commonly considered the threshold below 
which demonstrates reasonable balance between the two groups. Greater imbalance may be more 
acceptable for covariates that are weakly prognostic than for covariates that are strongly prognostic 
(Austin and Stuart 2015). The list of covariates with strong prognostic impact will be refined based 
on a SLR. 
For continuous covariates, side-by-side boxplots comparing the distribution of the covariate between 
the two groups will be presented for both unweighted and weighted samples. After weighting, the 
boxplots for larotrectinib and comparator should appear similar. 
The distribution of the propensity score will be graphed for both larotrectinib and control groups. 
Ideally, there will be no extreme propensity scores and good overlap of treatment and control. If there 
are markedly different propensity score distributions between the two groups, then it may be more 
challenging to provide valid treatment group comparisons. 
9.7.4 
Outcome model 
Time-to-event variables 
The primary endpoint, time to medical treatment failure, and other time-to-event endpoints detailed 
above will be investigated by plotting Kaplan-Meier survival curves for the original unweighted 
samples. Superimposed on these survival plots (e.g. with dashed lines) will be adjusted Kaplan-Meier 
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curves for the two groups that incorporate the IPTW balancing weights. Therefore, the dashed lines 
will represent the survival curves after balancing the larotrectinib and external cohort databases. 
Median estimates of survival and survival probabilities at meaningful timepoints determined by the 
data, e.g. 6 and 12 months, will be displayed using Kaplan-Meier method for both original unweighted 
and weighted samples. 95% confidence intervals will also be reported. 
Statistical tables will report the log-rank test, comparing larotrectinib and comparator groups. Per Xie 
and Liu, an analogous log-rank test for the weighted sample will also be computed. Additionally, a 
hazard ratio will be computed using a weighted Cox Proportional Hazards model, regressing survival 
time on an indicator variable denoting treatment status (larotrectinib/comparator) and incorporating 
the IPTW weights. To construct the confidence interval of the hazard ratio, the bootstrap-based 
variance estimator will provide approximately correct estimates of standard errors as it takes into 
account the fact that the IPTW weights are only estimates from the available data. For each of 
bootstrap samples (e.g. 200 samples) drawn from the data, weights will be drawn from the propensity 
score model and the log-hazard ratio will be calculated from the weighted Cox model. The standard 
deviation of the estimated log-hazard ratios (i.e., the estimated regression coefficient for the treatment 
status indicator) across the 200 bootstrap samples will be used as the bootstrap estimate of the standard 
error of the estimated regression coefficient obtained in the original data set. Ninety-five percent 
confidence intervals of the hazard ratio can be constructed as: 
𝜷̂ ∓𝟏. 𝟗𝟔× SE(𝜷̂) 
where 𝜷̂ denotes the estimated treatment effect in the original weighted sample, and SE(𝜷̂) denotes 
the estimated standard error of the treatment effect using bootstrapping. 
Hazard ratios will also be reported for the unweighted samples. 
 
Response variables 
The response endpoints, Overall Response Rate (ORR) and Disease Control Rate (DCR), will be 
summarized for both groups in both the original and weighted samples. 
The binary response outcome is regressed on group indicator (larotrectinib, comparator) using a 
logistic regression model, incorporating the IPTW weights. Standard errors are calculated using a 
robust sandwich estimator. The odds ratios comparing larotrectinib to comparator, with 95% 
confidence interval, will be provided for both ORR and DCR. Odds ratios will also be reported for the 
unweighted samples. 
Incidence of treatment discontinuation due to treatment-related AEs will be summarized descriptively 
in the original unweighted sampled only. 
9.7.5 
Sample size and power considerations 
The number of patients available is quite small, and no formal hypothesis and power calculations are 
considered for this study. 
We can calculate the power for the comparison of two groups under a Cox Proportional Hazards 
Model, with the following applicable formula (Rosner 2006): 
Power = Φ (
√km|IRR-1|
k × IRR+1 − z1-α/2) 
where m = expected total number of events over both groups 
               = 𝑛1𝑝𝐸+ 𝑛2𝑝𝐶 
𝑛1, 𝑛2 = number of participants in experimental (E) and control (C) groups 
𝑘= 𝑛1/𝑛2 (ratio of participants in E versus C groups) 
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𝑝𝐶 = probability of failure in group C over time period of study 
𝑝𝐸 = probability of failure in group E over time period of study 
IRR = underlying hazard ratio 
z1-α/2 is the 100(1-α/2)-th percentile of the standard normal distribution 
Φ is the CDF of N(0,1) 
We assume 35 IFS subjects and probabilities of failure equal to 0.04 and 0.19 in SCOUT and the 
external historical control cohort(s), respectively. Even with a strong treatment effect (hazard 
ratio=0.25), the power can only reach 49%, as further additions to the control cohort lead to smaller 
increases in power as the two groups become increasingly unbalanced. Of note, an effect size of 0,5 
would already be considered as a valuable treatment effect (Fewell 2007). Therefore, having a 
powered study seems unfeasible. 
Figure 1: Representation of the study power in function of the number of patients included in 
the comparator arm (control) for different hazard ratios 
 
nE=35 (number of patients in the experimental group (treated with larotrectinib) 
pE=0.04 (probability of failure in the experimental group during the study) 
pC=0.19 (probability of failure in the control group during the study) (Orbach 2020) 
RR=0.5 to 0.2 (risk ratio) 
α=0.05 (type 1 error) 
9.7.6 
Sensitivity analysis 
As the choice of index date and statistical method may affect the results, the following sensitivity 
analysis will be conducted in order to explore the impact of methodological choices on the results. A 
consistency in the findings regarding the treatment effect between the main analysis and the sensitivity 
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analyses should instil confidence in the primary results. Inconsistencies in the results will be explored 
through further analysis. Further details will be described in the SAP. 
 Choice of index date: 
As the majority of larotrectinib patients will be receiving 2nd line therapy, this analysis attempts to 
maximize consistency between treatment groups in terms of line of therapy while committing to the 
inclusion of all available patients. For SCOUT patients, the index date will be defined as the start date 
of larotrectinib, regardless of line of therapy. In the external historical control cohort(s), the index date 
will represent start of chemotherapy. However, control patients who take a second line of therapy will 
have their index date set at the start of second line, in order to provide a close comparison with the 
larotrectinib group prior to any adjustment using IPTW. A caveat of this analysis is that it may fail to 
capture some clinically relevant events, for example control subjects receiving a second line of 
treatment. 
 Subgroup analysis: 
For the patients treated with a second line or more of systemic therapies, the index date will be defined 
as the second line of treatment in both the treatment and control groups. 
This analysis will reflect the current reimbursement scope of larotrectinib, i.e. in patients who are 
refractory or in relapse. 
 Statistical method: 
A plot of the distribution of IPTW weights by group will be used to identify very large weights. 
Trimming at 5% level will be considered, which amounts to dropping the individuals with the most 
extreme PS values in both the treatment and control groups, as they may lack a match in the other 
group. Weight truncation will also be explored that reduces any ‘large’ weight down to a maximum 
weight. Therefore, in addition to the main analyses, the following sensitivity analyses will also be 
considered: 
a. IPTW (5% trimming) 
b. IPTW (truncating large weights) 
A consistency in the findings regarding the treatment effect between the main analysis and the 
sensitivity analyses should instil confidence in the primary results. 
Additional details on the analyses performed and table shells will be provided in the SAP available as 
a stand-alone document. 
9.7.7 
Complementary analyses 
The following complementary analyses will be conducted on the primary, secondary and exploratory 
endpoints: 
 Patients with IFS or other STS with NTRK gene fusion. 
IFS is a subtype of STS and the most frequent subtype harboring NTRK gene fusion. The SCOUT trial 
included pediatric patients with locally advanced and metastatic STS – other than IFS – harboring an 
NTRK gene fusion, the databases that will be used to constitute the historical external control cohort(s) 
may also have included such patients. Therefore we propose to analyze IFS patients jointly with other 
NTRK fusion-positive STS. The eligibility criteria for the STS patients for this analysis are detailed 
below, those for the IFS patients remain unchanged (see Section 9.2.3.2). 
 Inclusion criteria: 
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The inclusion criteria listed below are in line with those of the SCOUT study in terms of 
patients and disease characteristics: 
- 
Age ≤ 21 years old. 
- 
Locally advanced or metastatic STS. 
- 
Patients with available information on clinical, radiological characteristics of their tumor, 
therapies administered and outcomes. 
- 
Patients receiving larotrectinib in the SCOUT trial. 
- 
Patients receiving at least chemotherapy-based regimen in the external historical control 
cohort(s). 
- 
No opposition from the patients and/or representatives for data use. 
 Exclusion criteria: 
- 
Patients treated with TRKi in the external historical control cohort(s). 
- 
Patients with documented absence of NTRK gene fusion. 
- 
Patients participating in an investigational program with interventions outside of routine 
clinical practice. 
Number of events and censored patients will be reported for all time-to-event endpoints referenced 
above, and Kaplan-Meier plots of the survival curves will be produced showing median survival and 
95% CI, and also survival probabilities at 12 and 24 months. 
Frequency tables (n, %) will be produced for discrete endpoints, such as ORR, DCR and incidence 
rate of treatment discontinuation due to treatment-related AEs. 
Additional details on the analyses performed and table shells will be provided in the SAP available as 
a stand-alone document. 
9.7.8 
Bias analysis for primary endpoint 
A bias analysis will investigate the effect of an unmeasured covariate for the primary endpoint, time 
to medical treatment failure. Per Austin (2014), pairs of larotrectinib and control subjects will be 
matched on the logit of the propensity score using a suitable caliper width. We define response as 
control time-to-event earlier than paired larotrectinib time-to-event, after removing pairs where the 
earlier time was censored (i.e. indeterminate response). A stratified log-rank test on the matched 
samples is equivalent to a 2-sided binomial test of the null proportion of responses, p = 0.5. If there 
exists an unmeasured confounding variable that increases the odds of larotrectinib exposure by Γ (e.g. 
10%), then we can consider two extreme scenarios where a commensurate decrease or increase in 
responses occurs after adjusting for this variable in the propensity score model. Therefore the range 
of the true significance level can be found by repeating the binomial test using p =
Γ
Γ+1     and  p =
1
Γ+1. In reality, the effect of the unmeasured covariate will lie somewhere between these 2 extremes. 
The effect of an unmeasured covariate will be reported for a range of values relating to increased odds 
of exposure. For example, with odds of 5% and 10%, we can calculate the range of true significance 
levels by applying null proportions: [0.4878, 0.5122] and [0.4762, 0.5238] respectively. 
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9.8 
Quality control 
Bayer Consumer Care AG, the sponsor of the SCOUT study, ensured adequate monitoring activities 
in accordance with applicable regulations and Good Clinical Practices (GCP, guideline for GCP 
(International Conference on Harmonization [ICH E6 (R2)]). The monitoring activities included: 
checking and assessing the progress of the study, reviewing study data collected for completeness and 
accuracy, conducting source document verifications by reviewing each patient’s CRF against source 
documents, identifying any issues and addressing resolutions, recording and reporting protocol 
deviations not previously reported to the sponsor, and confirming that Serious Adverse Events (SAEs) 
were properly reported to the sponsor and submitted to Independent Ethics Committee (IEC), as 
appropriate. 
For the Institut Curie database, after identification of cases of patients with NTRK gene fusion from 
the genomics platform database, all observations were collected in a paper CRF and were sent to the 
study sponsor for entry in the database. Data were then sent to the SIREDO service for verification of 
data entry and inconsistencies were corrected. This process was iterative until clean data were 
obtained. 
All efforts will be made to check completeness, accuracy, plausibility, and validity of the data before 
transfer of the database to Bayer for analysis. The same approach will be followed for other eligible 
external historical cohorts. 
Bayer HealthCare SAS will ensure that study information used for the analyses of this observational 
study is handled and stored to allow for accurate reporting, interpretation and verification of that 
information. The analytical dataset and statistical programs used to generate the data included in the 
final report will be kept in electronic format and available for audit and inspection. 
9.9 
Limitations of the research methods 
The limitations of the methods of study analyses are mainly associated to: 
 The anticipated rarity of events of clinical interest (IFS are diseases with very low incidence) 
and consequently the lack of statistical power to pre-specify a proper hypothesis due to the 
small patient population. To avoid further reducing the sample size, the population was 
broadened to IFS regardless of their refractory or relapsed status, i.e. including treatment-naive 
patients. The analysis will include patients on both first and second line (or higher) therapy. 
o The primary endpoint analysis is expected to provide a rather conservative estimate of 
the treatment effect. Indeed, the index date for the patients in the external cohort(s) will 
be defined as start of chemotherapy which corresponds to first line of treatment, while 
for SCOUT patients, the index date will be defined as the start date of larotrectinib 
which corresponds to a second line of treatment for about 70% of SCOUT patients. 
o To mitigate the uncertainty induced by lack of statistical power and potentially by 
methodological choices such as index date or statistical model, various sensitivity 
analyses will be considered and consistency in the findings regarding the treatment 
effect between the main analysis and the sensitivity analyses should instil confidence 
in the primary results. 
 The historical comparison with an external control arm. 
As described by Cucherat et al. (Cucherat, 2020), the comparison of results of single-arm (not 
randomized, not controlled) studies with an external control has potential limitations due to: 
o The post-hoc choice of the comparator: 
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- 
In our study, a systematic approach (SLR) will be used to ensure that the choice 
of the comparator reflects clinical practice and is not arbitrary or biased (see 
Section 9.2.3.1). 
- 
Selection criteria were defined to avoid notably the risk of selection bias (cohorts 
with prospective enrollment and with retrospective and prospective data collection 
from 2000 to present, see details in Section 9.2.3.1). 
- 
The choice of confounding variables will be validated by a SLR that will 
document the important prognostic factors in this patient population. 
o The measurement bias inherent to the comparison of data from two independent studies 
with different settings. Notably, the SCOUT study is a very well monitored clinical trial 
while the external historical control cohort(s) might regroup real word data without any 
pre-established protocol, high regulated quality monitoring or centralized protocol of 
reading. In addition, results of the analyses might be biased since patients who received 
larotrectinib in the SCOUT trial likely differ in various underlying characteristics from 
those who are recorded in the external historical control cohort(s). During data analyses, 
statistical adjustment methods will be taken to limit bias, notably taking into account the 
potential cofounding variables. Propensity score methods will be employed to reduce the 
effects of measured confounding variables in the interpretation of the treatment effect 
(larotrectinib versus control group). The IPTW method makes it possible to reduce bias 
by correcting each patient’s contribution by a weight equal to the reciprocal of the 
probability of receiving the treatment that was actually received (see Section 9.7.2 and 
Section 9.7.3). Our expectation is that there will not be large imbalance as the data for 
this study did not include a time when both treatments were available, which may have 
led to investigator bias towards one or the other treatment based on certain patient 
characteristics. Finally, a bias analysis will investigate, for the primary endpoint, the 
likelihood that a potential residual confounding bias due to an unmeasured covariate may 
have affected the result. 
9.10 Other aspects 
N/A. 
10. 
Protection of human patients 
This study is classified as “a research non-involving human beings in the health domain”. These 
studies do not actively involved human beings, and therefore do not come under the Jardé Law but 
under the data protection law (chapter IX). 
Since the processing of data does not comply with the MR-004 methodology (Deliberation n° 2018-
155 of 3 May 2018), Bayer will submit an application dossier to the HDH ensuring a role of single 
secretariat. Dossier will be transmitted for opinion to the CESREES (dedicated ethical and scientific 
committee in charge of ruling on the public interest character of researches and studies in the health 
field), and then CNIL will be consulted for its authorization. 
Bayer will seek an exemption from individual patient information from the CNIL. Indeed, given the 
international character of the SCOUT study and the different external cohorts that will be explored, 
the transmission of a specific information note to the patients would require an additional submission 
to IECs or Institutional Review Boards (IRBs) of the different locations where patients were recruited 
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prior to study start, and therefore could jeopardize the conduct of the study within the timeframe 
agreed with authorities. 
However, it should be noted that patients enrolled in SCOUT where informed via the information 
sheet and the consent form which they signed that their data could be processed for use in future 
medical or pharmaceutical researches. Additional measures will be carried out by Bayer to protect the 
rights of the patients, by making the information on the study EPI VITRAKVI publicly available on 
Bayer Trial Finder page: clinicaltrials.bayer.com. 
The person(s) responsible of the data processing will collect only the data relevant, appropriate and 
limited to the objectives of the study. The necessity of the data processing must be scientifically 
justified in the study protocol. The personal data information and its processing will be respected as 
described in the GDPR (EU 2016/679 of 27 April 2016). 
11. 
Management and reporting of adverse events/adverse reactions 
This study is a retrospective observational study using secondary data collection from a previous 
clinical trial (SCOUT study) and from eligible database(s) that will be used as external historical 
control cohort(s). Therefore, no new AEs or Adverse Drug Reactions (ADRs) are expected to be 
reported besides the ones already described during the conduct of the initial clinical trial. 
As per the EMA Guideline on Good Pharmacovigilance Practices (Module VI – Collection, 
management and submission of reports of suspected adverse reactions to medicinal products 
[Revision 2]), individual reporting of adverse reactions is not required for non-interventional study 
designs that are based on secondary use of data. Reports of adverse events/reactions will be 
summarized in the study report (EMA 2017). 
12. 
Plans for disseminating and communicating study results 
A study report will be written and transmitted to the applicable competent authorities. 
The results of this observational study are intended to be published in a peer-reviewed journal and 
possibly as abstracts/presentations at medical congresses under the oversight of the Market 
Authorization Holder (MAH). Current guidelines and recommendation on good publication practice 
will be followed (e.g. Good Publication Practice [GPP] 2 Guidelines [Graf 2009], The Strengthening 
the Reporting of Observational Studies in Epidemiology [STROBE] statement [von Elm 2008]). 
Any written or oral communication of the results of the study will have to be agreed by the study 
initiator and funder, and, if applicable, by the Scientific Committee who participated to the 
observational study. 
 
 
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13. 
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Annex 1: List of stand-alone documents 
Table 2: List of stand-alone documents 
Document Name 
Final version and date (if available)* 
Contact details of the Principal Investigator, members of the 
Scientific Committee and CROs 
v 1.0, 11 APR 2021 
SAP 
tbd 
SLR 
tbd 
* Draft versions are indicated by <draft> in brackets and date. “tbd” indicates documents that are not available at the time 
of protocol creation, but will be issued at a later stage. 
 
 
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Annex 2: Additional information 
Table 3: Long term gonadal toxicity of cyclophosphamide 
Study 
Ridola (2009) 
Kenney (2001) 
Aubier (1989) 
Patients number 
59 
17 
15 
Diagnosis 
Soft tissue sarcoma (n=11) 
Osteosarcoma (n=12) 
Ewing (n=5) 
Non hodgkin lymphoma (n=28) 
Other (n=3) 
Rhabdomyosarcoma (n=9) 
Ewing (n=4) 
Soft tissue sarcoma (n=4) 
Lymphoma (n=9) 
Rhabdomyosarcoma (n=3) 
Ewing (n=1) 
Pheochromocytoma (n=1) 
Wilm’s tumor (n=1) 
Age at diagnosis 
9.8 y [0-17.6]* 
12 y [4-19]* 
9 y [2-15]* 
Follow up intervals 
8.5 y [5-16.5]* 
12 y [5-22]* 
9 y [1-20]* 
Cyclophosphamide 
cumulative doses 
8.3 
g/m2 
[4.6-
22]* 
< 9 
n=28 
9-11,9 
n=15 
> 12 
n=16 
20.5 
g/m2 
[4.7-
31.9]* 
< 7.5 
g/m2 
n=2 
> 7.5 
g/m2 
n=15 
12 g/m2 
[2,6-29]* 
< 9 
n=2 
> 9 
n=13 
Sperm Count     Nl 
 
Oligospermia 
 
Azoospermia 
Not in the scope of the study 
2 
5 
10 
(58.8%) 
2 
0 
0 
0 
5 
10 
Gonadal 
function  Nl 
Abnormal 
 
2 
0 
 
2 
11 
FSH 
Abnormal 
 
Normal 
47.4% 
21.4% 
53.3% 
87.5% 
10 
5 
NA 
1 
10 
4 
Not in the scope of the study 
LH 
Abnormal 
 
Normal 
Not in 
the 
scope 
of the 
study 
Not in 
the 
scope 
of the 
study 
Not in 
the 
scope of 
the 
study 
Not in 
the 
scope of 
the 
study 
6 
9 
N/A 
1 
6 
8 
Not in the scope of the study 
TESTIS V Abnormal 
 
Normal 
Not in the scope of the study 
5 
10 
N/A 
N/A 
5 
10 
5 
5 
N/A 5 
0 
2 
5 
3 
* Data expressed as medians [range], Nl: normal, N/A: not available. 
 
 
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 59 of 68 
Table 4: Cardiotoxicities associated with anthracyclines 
Study 
Ramjaun (2015) 
Kremer (2001) 
McCune (2019) 
Patient 
number  
333 
Total = 607 
A-CHF = 17 
(2.8%) 
Tot: 68 
Echocardiographic systolic 
disfunction: 15 (22%) 
Male  345 
Female 262   
9 (2.6%) 
8(3.1%) 
Age at 
diagnosis 
Median 8.47 
1-4 y: 32.73% (n=109) 
> 5 y: 67.27% (n=224) 
< 2 y 
43 
2-4 y 
113 
5-9 y 
174 
10-14 y 
194 
> 14 y 
83 
1 
2.3% 
2 
1.8% 
5 
2.9% 
6 
3.1% 
3 
3.6% 
Cum Inc 2.8% 
8.6 y [1-17]* 
Time since 
end of 
treatment 
15.8 y [0.9-48]* 
Mean 6.3 y (0.01-21.74) 
12 y [1-31]* 
Doses 
mg/m2 
Median 212.9 
< 150             70 
150-300         208 
300-450         183 
450-600         108 
> 600             20 
Unknown      18 
MCD             301 
                     (14-960) 
0        0% 
1        0.5% 
5        2.7% 
7        6.5% 
3        15% 
1        5.6% 
461 (225-803) 
n=38 (55.9%): dose > 250mg/m2 
n=14 (20.6%): chest radiation 
n=3 (4.4%): cardioprotective agent 
 
Echocardiographic abnormalities 
Estimated risk of A-CHF 
 
Subclinical disfunction: 
 
Global Strain impairment+: 42/52 
(80.7%) 
Overall: 14.7% at 11.7 y 
              20%    at 20 y 
Function of follow-up 
time 
                           2y 
                           5y 
                           10y 
                           15y 
 
 
2% 
2.8% 
3.3% 
4.8% 
Probability of 
abnormal 
echo 
By age 
< 5        > 5 
By dose 
< 250 > 250 
At 10 y (%) 
13.6 
10.9 
8.3 
23.3 
At 20 y (%) 
26.7 
14.5 
19.5 
36.9 
Function of 
cumulative doses 
               300 mg/m2 
               450 mg/m2 
               600 mg/m2 
 
 
1.1% 
4.5% 
17.8% 
20 years rates 
abnormal 
echo 
  < 250 mg/m2 
  > 250 mg/m2 
> 5 years 
 
 
11% 
29% 
< 5 years 
 
 
18% 
49% 
* Data expressed as medians [range], A-CHF: congestive heart failure, Cum Inc: cumulative incidence, MCD: mean cumulative dose, CHF: congestive 
heart failure, + Global strain impairment was identified as an independent marker of future left ventricular systolic impairment. 
 
 
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 60 of 68 
Table 5: Toxicities associated with radiotherapy 
 
Acute toxicity 
Late toxicity 
 
SMN 
Cardiac 
Lung 
Selo (2010) 
 
Patients number 
(n=690) 
 
 
Salivary glands 
(n=78) 
 
Lower GI tract 
(n=153) 
 
Genito-urinary 
(n=45) 
 
Liver 
(n=61) 
 
Lung 
(n=120) 
 
Skin 
(n=632) 
 
 
Total toxicities: 
73% (506) 
 
 
22% (17) [3.8% (3)]* 
 
 
53.3% (81) [15.1% (23)]* 
 
 
22% (10) [8.9%(4)]* 
 
 
13% (12) [3.2%(2)]* 
 
 
17% (20) [4.2%(5)]* 
 
 
93% (589) [16.5% (104)]* 
Not in the scope of the study 
Paulino (2005) 
 
n=429 (multiple 
tumors) 
Median follow-up: 9.6 y 
Not in the scope of the 
study 
23 SN (5.4%) 
 
14 SMN (3%): 10 in RT 
field (71%) 
 
189 dead at time of 
analyses: 3 (1.6%) due to 
RIN and 184 (97.4%) from 
original solid tumor 
Not in the scope of the 
study 
Not in the scope of the study 
Gold (2003) 
 
n=446 (multiple 
tumors) 
Follow-up: 19.5 y [4.8-
40]* 
Not in the scope of the 
study 
n=37 (8.3%) 
In RT field: 31 (70%) 
12 died: 10 from SMN 
Overall standardized 
incidence ratio: 5.2 
Cumulative probability of 
developing a SMN at 30 
years: 13% 
Not in the scope of the 
study 
Not in the scope of the study 
Mertens (2002) 
 
n=12390 (multiple 
tumors)/siblings cohort 
n=3546 
Not in the scope of the 
study 
Not in the scope of the 
study 
Not in the scope of the 
study 
RR 
Lung fibrosis 4.3c 
Abnormal chest wall 5.0c 
Pneumonia > 3 times in 2 y 
2.2c 
Chronic cough, SOB > 1 
month 2c 
Need supplement oxygen 
1.8c 
Other respiratory problems 
2.1c 
Weiner (2006) 
 
n=30 (multiple tumors) 
Follow-up: 2.79 y 
[0-13.7]* 
Not in the scope of the 
study 
Not in the scope of the 
study 
Not in the scope of the 
study 
50% (15) abnormal PFT 
Mild, moderate and severe 
complications in 30%, 10% 
and 10% of patients 
Bolling (2008) 
 
n=37 (Ewing’s tumors) 
Follow-up: 2.1 [0-
12.6]* 
Not in the scope of the 
study 
Not in the scope of the 
study 
Not in the scope of the 
study 
57% (21) abnormal PFT 
Mild, moderate, and severe 
pulmonary complications in 
29%, 21% and 7% 
Adams (2004) 
 
n=48 (Hodgkin’s 
Disease) 
Not in the scope of the 
study 
Not in the scope of the 
study 
100% (47) abnormal 
screening 
42%: pathologic 
valvular defect 
Not in the scope of the study 
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 61 of 68 
(4 patients had 
anthracyclines) 
Follow-up: 14.3 
[5.9-27.5]* 
75%: conduction defects 
53%: abnormalities in 
stress test, decrease 
mean LV mass 
(restrictive 
cardiomyopathy) 
Schellong (2010) 
 
n=1132 (Hodgkin’s 
Disease) 
(834 had RT / 298 no 
RT) 
Follow-up: 
15.1 [3.1-29.4]* 
Not in the scope of the 
study 
Not in the scope of the 
study 
        CD Cum Inc 
at 20 y 
36 Gy: 10.9%      21% 
30 Gy: 3.7%        10% 
25 Gy: 3.2%        6.4% 
20 Gy: 0.6%        4.9% 
0 Gy: 0.3%          3.2% 
Not in the scope of the study 
* Moderate to severe toxicity, c P value < 0,01, RR: rate ratio, SOB: shortness of breath, GI: gastro-intestinal, SN: secondary neoplasms, RIN: radiation 
induced neoplasm, SMN: secondary malignant neoplasms, RT: radiotherapy, PFT: pulmonary function test, ECG: electrocardiography, LV: left ventricle, 
CD: cardiac disease, Cum Inc: cumulative incidence. 
 
 
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 62 of 68 
Annex 3: Signature pages 
Signature Page – 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that he agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, ________________
_____________ 
 
 
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 63 of 68 
Signature Page – 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that he agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, _________________
____________ 
 
 
DocuSign Envelope ID: 
8/5/2021 | 6:07:19 PM CEST
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 64 of 68 
Signature Page – 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that he agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, __________________
________________ 
 
 
DocuSign Envelope ID: 
8/5/2021 | 10:10:53 PM CEST
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 65 of 68 
Signature Page – 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that he agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, _________________
_______________ 
 
 
DocuSign Envelope ID: 
8/3/2021 | 6:15:42 PM CEST
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 66 of 68 
Signature Page – 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that she agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, _________________
____________ 
 
 
DocuSign Envelope ID: 
8/4/2021 | 3:42:46 PM CEST
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 67 of 68 
Signature Page – 
 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that she agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, _________________
____________ 
 
 
DocuSign Envelope ID: 
8/3/2021 | 11:29:38 AM CEST
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Reference Number: RD-SOP-1214 
Supplement Version: 7 
 
21767; EPI VITRAKVI; v 1.0, 27 JULY 2021 
 
Page 68 of 68 
Signature Page – 
 
Title 
EPI VITRAKVI: A comparison of clinical outcomes in Infantile 
Fibrosarcoma (IFS) patients treated with larotrectinib in the phase I/II 
SCOUT study versus (an) external historical cohort(s) 
Protocol version and date 
v 1.0, 27 JUL 2021 
IMPACT study number 
21767 
Study type / Study phase 
Retrospective, observational, externally-controlled study / Phase IV 
Medicinal product / Active 
substance 
Larotrectinib (BAY 2757556) 
Comparator / Reference therapy 
Standard of care (external historical control) 
Study Initiator and Funder 
Bayer Healthcare SAS 
 
 
The undersigned confirms that he agrees that the study will be conducted under the conditions 
described in the protocol. 
 
 
Print Name: 
 
 
 
Date, Signature: __________________, ________________
________________ 
DocuSign Envelope ID: 
8/4/2021 | 1:21:15 PM CEST
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Last updated: April 08, 2020.