A Study to Determine the Incidence of NTRK Fusions in Subjects With Locally Advanced/Unresectable or Metastatic Solid Tumors With NTRK Fusions and Related Treatment Outcomes.
Conditions: Metastatic Solid Tumors
Sponsor: Institut Bergonié

 
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ID: IB2015-
NTRK 
    A Retrospective Study to Determine the Incidence of NTRK 
Fusions. NTRK Study 
 
 
 
The format of this form can be modified, but the criteria mentioned herein are considered minimum. Information 
to be obtained about an IIR prior to Second-tier Review. 
Document history 
November 2, 2021 
 
 
General information 
Please provide information for all items marked “M” (mandatory).  
Items marked “O” are optional. 
M 
Investigator/institution and contact person: Antoine ITALIANO 
Institut Bergonié, Bordeaux, France 
 
 
 
M 
IIR Subtype 
Non-interventional/Observational 
M 
Study Title (Full) 
 
 
A retrospective Study to Determine the Treatment Outcomes 
of Subjects with Locally advanced/unresectable or Metastatic 
Solid Tumors with NTRK Fusions 
 
M 
Indication: Solid Tumors 
 
 
 
M 
Phase of Study 
Observational 
M 
Country 
France 
M 
Retrospective or 
prospective study 
Retrospective  
M 
Planned number of 
sites/ subjects 
3750 subjects (up to 10 sites) 
M 
Blinding & Control 
n/a 
 
Additional request details 
M 
Primary Endpoint/ 
objective is safety 
No 
M  
Study exploring new combinations, alternative dosing/dosing 
schdules or new formulations 
No 

 
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M 
Study with clinical pharmacology objectives, including biomarker, 
pharmacokinetic (PK) or pharmacodynamics (PD) evaluations 
No 
O 
Author 
Antoine Italiano, MD, PhD 
Institut Bergonie 
Early Phase Trials and Sarcoma Units 
229 cours de l'Argonne 
33000 Bordeaux 
Phone: + 33 5 47 30 60 88 
Fax: + 33 5 47 30 60 83 
E-mail: a.italiano@bordeaux.unicancer.fr 
O 
Investigator 
Operations Manager 
email 
Antoine Italiano, MD, PhD 
 
Head of Clinical Research Unit: 
Simone MATHOULIN-PÉLISSIER 
Institut Bergonié – Bordeaux  
Phone :+ 33 5 56 33 33 98  
E-mail : s.mathoulin@bordeaux.unicancer.fr 
M 
Study support 
Financial 
M 
Study is financially supported by other organizations 
No 
 
 
 
Rationale and objectives 
O 
Please explain why this study is non-blinded (if applicable): This is a retrospective 
study. 
M 
Study Type and Design 
This multicenter, retrospective study has a primary objective to assess the impact of 
NTRK gene fusions on the PFS of first-line systemic therapy for the treatment of 
locally advanced/unresectable or metastatic solid tumors.  
Control subjects will be matched based on the characteristics of the NTRK fusion 
study population to the greatest extent possible. 
 
 
 
M 
Rationale  
The tropomyosin receptor kinase (Trk) receptor family comprises 3 transmembrane proteins 
referred to as Trk A, B and C (TrkA, TrkB and TrkC) receptors that are encoded by the 
NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases are 
expressed in human neuronal tissue and play an essential role in the physiology of 
development and function of the nervous system through activation by neurotrophins. Gene 
fusions involving NTRK genes lead to transcription of chimeric Trk proteins with constitutively 
activated or overexpressed kinase function conferring oncogenic potential. These genetic 
abnormalities have recently emerged as targets for cancer therapy, because novel 
compounds have been developed that are selective inhibitors of the constitutively active 
rearranged proteins. Developments in this field are being aided by next generation 
sequencing methods as tools for unbiased gene fusions discovery. However, the incidence 

 
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of NTRK aberrations in solid tumors is unknown as well as the natural history of NTRK-
rearranged tumors.  
 
 
 
M 
Primary Study Objective 
To assess retrospectively the effect of NTRK gene fusions on the progression free survival 
(PFS) of first-line systemic therapy for the treatment of locally advanced/unresectable or 
metastatic solid tumors 
 
 
 
O 
Secondary Study Objectives 
 
To evaluate the frequency of NTRK gene fusions in subjects with locally 
advanced/unresectable or metastatic solid tumors. 
 
 
To assess the treatment outcome to first-line anti-cancer therapy in terms of 
objective response rate (ORR), duration of response (DOR), and overall 
survival (OS) in subjects with locally advanced/unresectable or metastatic solid 
tumors with NTRK gene fusions. 
 
To explore possible demographic characteristics prevalent in subjects with 
locally advanced/unresectable or metastatic solid tumors and NTRK gene 
fusions. 
 
To explore the frequency and treatment outcome interaction of concomitant 
genetic alterations. 
 
To look for trends in the data that may suggest relationships between 
covariates of interest and treatment outcome in subjects with locally 
advanced/unresectable or metastatic solid tumors harboring NTRK gene 
fusions. 
 
 
 
M 
Study operational/organizational aspects 
 
 
This will be a multicenter, retrospective study. Institut Bergonié as the Sponsor of this 
study, will be responsible for getting regulatory approvals, selecting the investigational 
sites, capturing study data in an appropriate data base 
 
Population and methods 
M 
Study Population 
 
 
Adult and pediatric patients with locally advanced/unresectable or metastatic solid 
tumors  
M 
Inclusion Criteria (detailed) 
 
 
For inclusion of a subject in the study population, all of the following criteria 
must be fulfilled: 
 
1. Age ≥ 1 month. 

 
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2. Subject has/had a histologically or cytologically confirmed 
diagnosis of solid tumor including but not exclusively: soft tissue 
sarcoma, BRAF wild type melanoma, KRAS wild-type colorectal 
cancer, central nervous system, EGFR-wild type non-small cell 
lung cancer. 
3. Subject has locally advanced/unresectable or metastatic disease. 
 
4. Subject has received at least one systemic anti-cancer therapy for locally 
advanced/unresectable or metastatic disease for which there is available 
outcome information in terms of PFS, or the latter can be estimated based 
on the subject’s records. 
 
5. Subject has tumor material available for immunoscreening (IHC for NTRK 
gene fusions). 
6. Written and voluntary informed consent understood, signed and dated, or a 
waiver of consent is granted according to French regulations 
 
Subjects who are tested positive by IHC (Pan-Trk IHC testing with mAb EPR17341) 
will be the subject of molecular assays such as next-generation sequencing (Archer 
Dx fusion assay) of tumor material [parrafin embedded material]), so that tumor 
harboring NTRK1, NTRK2 or NTRK3 gene fusions, is identified properly. 
After identification of the NTRK fusion study population, control subjects with locally 
advanced/unresectable or metastatic solid tumors, who do not have NTRK fusions 
will be selected in an attempt to closely match NTRK fusion subjects. 
 
 
M 
Exclusion Criteria 
The following exclusion criterion should be considered: 
Subjects who have not yet received or completed at least one systemic anti-cancer therapy 
for locally advanced/unresectable or metastatic cancer. 
 
 
 
M 
Test Treatment(s) (Description) 
n/a 
 
 
. 
O 
Test Treatment(s) or Investigated Treatment(s): Rationale for unusual or novel 
approaches 
 
 
n/a 
M 
Request for Study Drug Supply 
 
 
No 
M 
Reference Treatment or Modality/Treatment or Modality of Comparison (Description) 

 
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n/a 
 
Safety reporting 
M 
 
Safety reporting (valid for clinical studies only)  
n/a 
 
 
 
Statistical analysis 
O/M Standard of Reference/Standard of Truth 
 
 
n/a 
M 
Rationale for selection of a reference treatment 
 
 
n/a 
M 
Assignment of subjects to study arms or groups (Randomization/Stratification) 
 
 
n/a (this will be a retrospective study) 
M 
Blinding 
 
 
n/a 
M 
Concomitant Treatment(s) 
 
 
n/a 
M 
Primary Outcome 
 
 
Progression-free survival observed with first-line anti-cancer therapy 
O 
Secondary Outcomes 
 
 
Frequency of NTRK fusions in subjects with locally advanced/unresectable or 
metastatic  solid tumors. 
 
 
Treatment outcome to first-line anti-cancer therapy in terms of objective 
response rate (ORR), duration of response (DOR), and overall survival (OS) in 
subjects with locally advanced/unresectable or metastatic HNSCC with NTRK 
gene fusions. 
 
Demographic characteristics in subjects with locally advanced/unresectable 
or metastatic  solid tumors harboring NTRK gene fusions 
 
 
 
M 
Safety Outcomes  
 
 
n/a 
O 
Measurement of results (How assessed) 

 
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Data collection (see below) 
M 
Visit schedule 
 
 
Activity 
Screening 
Data 
Collection 
for Enrolled 
Subjects 
ICF, Inclusion/exclusion criteria evaluation 
X 
Collection of Demographic Information: 
• 
Date of birth 
• 
Vital status: dead/alive/unknown 
• 
Gender 
• 
Smoking status: Smoker/never 
smoker/prior smoker at the time of first 
line treatment 
• 
Other relevant carcinogen exposure 
(e.g. consumption of betel nut) 
X 
Collection of Medical Information: 
• 
Date of initial diagnosis of cancer 
• 
Stage of disease at diagnosis 
• 
Anatomical disease site(s) at diagnosis 
• 
Anatomical (organ) disease site(s) (e.g. 
lung metastases) at the time of first line 
treatment 
• 
Locally advanced/unresectable or metastatic 
disease at the time of first line treatment 
• 
Current stage of disease 
• 
Other relevant medical history. Date of 
prior medical events 
X 
Collection of Treatment Information: 
• 
Prior/current surgical treatments for cancer. 
 
Dates of surgeries 
• 
Prior/current radiological treatments 
for cancer. 
 
Anatomical sites. 
 
Dates of radiation treatments 
• 
First line systemic treatment for locally 
advanced/unresectable or metastatic 
cancer: 
 
Dates of treatment (start, end). 
 
Performance status at the time of first 
line therapy for treatment of recurrent 
or metastatic disease. 
 
Treatment outcome (response 
and response criteria). 
 
Date of progression(s) 
(progression criteria). 
• 
Other prior/current systemic treatments 
for cancer. 
 
Dates of treatment (start, end). 
 
Treatment outcome (response 
and response criteria). 
• 
Date of progression(s) (progression 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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criteria) 
• 
Date of death (if any) and cause of death 
 
Collection of NTRK fusion Information: 
• Anatomical biopsy sample site (including 
blood/urine sample). Date of sampling and 
setting (initial diagnosis, locally 
advanced/unresectable or metastatic 
disease) 
• Matrix (tumor biopsy, blood, urine) 
• Tumor histology (from biopsy sample or 
primary diagnosis) 
• NTRK fusion in sample. Allele frequency (if 
available); this information is not applicable 
for control subjects. 
• Other relevant mutations or genetic 
alterations, if available. Allele frequencies (if 
available) 
• Test platform (e.g. NGS). Mutations tested 
(PCR methods) or exons sequenced 
(sequencing methods). 
_____________
 
 
_________________
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M 
Follow-up period 
 
 
n/a 
M 
Statistical & Analytical Plan and Methodology 
The primary objective of this descriptive study is to determine if there are statistically 
significant differences in PFS to first line systemic therapy between subjects with 
recurrent/metastatic disease and NTRK fusion versus those without a known NTRK 
fusion. 
The two groups will be matched with respect to histological subtype, sex, age (+/-5 
years), and pathological tumor-node-metastasis (TNM) stage.  
The Kaplan-Meier method will be employed for the analysis of PFS. A nonparametric 
test, such as the log-rank test, based on the Kaplan-Meier estimator for survival curves, 
will be employed to assess the association between PFS and the presence of NTRK 
fusion. In addition, predictive modeling, including Cox proportional hazards models with 
NTRK fusion as a predictor may also be used to estimate the relative risk of the exit-
event of subjects with tumors with NTRK fusion versus subjects with tumors without 
known NTRK fusion. If the data allow it, other types of predictive modeling may also be 
explored. If the proportionality of hazard assumption fails, then parametric approaches 
will be used. 

 
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Given the rarity of NTRK fusions among subjects with solid tumors, the sample size 
for this study will not be driven by powering the study. A post hoc power calculation 
will be provided. Clinically relevant changes will be defined as increases in median 
survival times that are greater than 30%, regardless of confidence interval width. 
 
An assessment of the impact of certain covariates will be conducted by comparing their 
associated hazard ratios from the Cox proportional hazard (or parametric model) 
analysis. 
 
Descriptive statistics will be employed to define demographic and treatment outcome, as 
well as overall frequency of NTRK fusions in the screened population. This will include 
exploration of potential effects on subject’s treatment outcomes of different forms of 
NTRK fusions and of other genetic alterations. 
 
 
 
 
  
 
Timelines 
M 
Planned Study Timelines: 
 
 
1. Enrolment rate (patients per month): 300 patients/months 
2. Planned estimate of treatment duration: not applicable 
3. Submission date to health authority/ethics: not applicable 
4. Start of subject enrolment: December  2018 
5. End of Subject enrolment: December 2019 
6. All patients completed: December 2019 
7. End of Study: March 2020 
8. Report (as described in the contract): Report every 3 months 
9. Planned publication/presentation: June 2020 
 
Limitations 
O 
Criteria for selection of evaluable cases:  
 
 
All patients: 
who have received at least one systemic anti-cancer therapy for locally 
advanced/unresectable or metastatic disease for which there is available outcome 
information in terms of PFS,  
who have tumor material tested by IHC for NTRK gene fusions, 
will be included in the analysis. 
M 
Interim Analyses (if applicable) 

 
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Interim analyses will be the subject of periodic reports based upon collection of data on 
first 1,000, 2,000 patients and a final analysis will be conducted after completion of the 
whole data set analysis.  
At each interim analyses, the proportion of NTRK-rearranged cases will be estimated 
in order to assess the feasibility of a comparative analysis with matched controls. 
M 
Number of Evaluable Patients (estimate): it is anticipated to collect data on 3,700 
patients 
M 
Sample Size Assumptions/Target Number of Valid Cases 
(incl. Power and Confidence) 
 
 
No sample size estimate has been calculated. It is assumed that a sample size of 3,700 
patients should be sufficient to address the primary objective of this study. 
0 
 
Statistical analyses 
 
Quantitative variables will be described using mean and standard deviations if the normality 
assumption is satisfied, else other descriptive statistics (median, range, quartiles) will be 
reported.  
 
Qualitative variables will be described using frequency, percentage and 95% confidence 
interval (binomial law).  
 
Survival endpoints will be analysed using the Kaplan-Meier method. The median survival 
rates will be reported with a 95% confidence interval. Median follow-up will be calculated 
using the reverse Kaplan-Meier method.  
 
 
M 
Health Economic Variables (if applicable) 
 
 
n/a