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Tyrosine

Armelle DUFRESNE

Larotrectinib, a selective TRK inhibitor has showed marked and durable antitumor activity in patients with NTRK gene-fusion-positive tumors regardless of the tumor type, gene partner and patient's age. Because of this and the lack of alternative therapy in this rare but severe disease, the French National Agency for Medicines and Health Products Safety (ANSM) granted in April 2019, a "cohort" Temporary Authorization for Use (ATU) in the indication:"Larotrectinib is indicated as monotherapy for the treatment of adult and paediatric patients from one month, with locally advanced or metastatic solid tumours with a Neurotrophic Tyrosine Receptor Kinase (NTRK) fusion, refractory to standard treatments or in the absence of appropriate therapeutic alternative." Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive tumors which are treated with Larotrectinib, are not well characterized. This study will provide information about the diagnosis and management of patients with locally advanced or metastatic NTRK fusion cancer treated with Larotrectinib under real-world treatment conditions in France, and describes the dosing patterns, safety and effectiveness of this agent.

Tropomyosin receptor kinases (TRK) are a family of tyrosine kinases that bind neurotrophins, a family of growth factors important to the formation and function of the nervous system. In cancer, the neurotrophic tyrosine kinase receptor (NTRK)1, NTRK2 and NTRK3 genes, which encode for the TRKA, TRKB and TRKC proteins, respectively, are subject to gene-arrangements that lead to kinase domain expression and constitutive downstream pathway activation. In preclinical models, NTRK gene fusions have transformative oncogenic potential, and they appear to be widely distributed across histologically diverse adult and pediatric cancers. Hence, these genetic abnormalities, observed in both children and adults, have recently emerged as targets for cancer therapy.

Larotrectinib, a selective TRK inhibitor has showed marked and durable antitumor activity in patients with NTRK gene-fusion-positive tumors regardless of the tumor type, gene partner and patient's age.

Because of this and the lack of alternative therapy in this rare but severe disease, the French National Agency for Medicines and Health Products Safety (ANSM) granted in April 2019, a "cohort" Temporary Authorization for Use (ATU) in the indication:

"Larotrectinib is indicated as monotherapy for the treatment of adult and paediatric patients from one month, with locally advanced or metastatic solid tumours with a Neurotrophic Tyrosine Receptor Kinase (NTRK) fusion, refractory to standard treatments or in the absence of appropriate therapeutic alternative." Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive tumors which are treated with Larotrectinib, are not well characterized.

This study will provide information about the diagnosis and management of patients with locally advanced or metastatic NTRK fusion cancer treated with Larotrectinib under real-world treatment conditions in France, and describes the dosing patterns, safety and effectiveness of this agent.

A Retro-/Prospective, Non-interventional, Cohort Study in Adult Patients With Locally Advanced or Metastatic Tumors With a Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion, Treated With Larotrectinib

LAROTRACKING - A Retro-/Prospective, Non-interventional, Cohort Study in Adult Patients With Locally Advanced or Metastatic Tumors With a Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion, Treated With Larotrectinib

Best objective response rate (BORR) (Complete Response or Partial Response as per RECIST V1.1 assessed by investigators)

Duration of response (DOR) (Best overall response of Complete Response or Partial Response as per RECIST V1.1)

Demographics data, significant or relevant medical history, cancer disease overview

Description of the diagnosis tests used for NTRK fusions

Doses, duration, best tumor response and reasons for discontinuation

Adverse events : Nature, frequency and severity of Adverse Events (AEs), Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARs) graded using Common Terminology Criteria for Adverse Events (CTCAE) V5.0.

Bayer

Centre Leon Berard

Nervous System Diseases

Rare Diseases

Glioma

Diffuse Intrinsic Pontine Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Stem Neoplasms

Infratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.

Larotrectinib administered PO, BID @100 mg/m2 3-5 days prior to definitive surgery, followed by Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.

1. Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone

Larotrectinib

1. Surgical cohort: Larotrectinib x 3-5 days prior to definitive surgery followed by Larotrectinib monotherapy x2 cycles followed by disease evaluation
2. Larotrectinib with or without chemotherapy backbone

Larotrectinib surgical

Leonie Mikael, PhD

Kathleen Doris, MD

Eugene Hwang, MD

Ashley Plant, MD

Susan Chi, MD

David Ashley, MBBS, PhD

Peter de Blank, MD

Maryam Fouladi, MD

Michael J Fisher, MD

Patricia Baxter, MD

Sarah Leary, MD

David Ziegler, MBBS

Tim Hassall, MBBS

Nick Gottardo, MBChB

Eric Bouffet, MD

Genevieve Legault, MD

Olaf Witt, MD

This is a pilot study that will evaluate disease status in children that have been newly diagnosed high-grade glioma with TRK fusion. The evaluation will occur after 2 cycles of the medication (Larotrectinib) have been given.

The study will also evaluate the safety of larotrectinib when given with chemotherapy in your children; as well as the safety larotrectinib when given post-focal radiation therapy.

In this pilot study, we will assess the disease control rate (Continued Complete Response-CCR, Complete Response-CR, Partial Response-PR and Stable Disease-SD) as well as survival rate (overall survival- OS and progression free survival- PFS) in children with newly diagnosed HGG with TRK fusion who receive 2 cycles of larotrectinib monotherapy administered orally, twice daily, at 100 mg/m2 continuously on a 28-day cycle schedule. After 2 monotherapy cycles of larotrectinib, patients with CCR or CR will continue to receive larotrectinib maintenance therapy as monotherapy for a total of 12 cycles. Continuation of treatment beyond 12 cycles, and up to 24 cycles, may be considered for patients on Larotrectinib monotherapy if they are receiving clinical benefit from the study, at the discretion of the treating physician.

Patients ≤ 48 months with PR or SD after 2 cycles of larotrectinib will go on to receive combination therapy with standard backbone chemotherapy (BABYPOG or HIT-SKK). Patients \> 48 months of age (or patients ≥ 36 months of age, or patients with DIPG \>18 months of age, at the discretion of the local investigator) will receive focal radiation therapy. A surgical cohort study will be explored whereby patients who have had a tumor biopsy/partial resection at their local institution and are planned to subsequently undergo definitive resection will receive 3-5 days (6-10 doses) of larotrectinib pre-surgery.

The study design of this trial requires 15 patients evaluable for disease control and for safety/ toxicity of larotrectinib as monotherapy. The surgical cohort will enroll up to 4 patients and will count towards the total 15 evaluable patients. A minimum of 6 patients will be evaluable for safety toxicity of larotrectinib in combination with standard-of-care chemotherapy or radiotherapy.

A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion

A Pilot and Surgical Study of Larotrectinib for Treatment of Children With Newly-Diagnosed High-Grade Glioma With NTRK Fusion

To assess the disease control rate (Complete Response \[CR\], Continued Complete Response \[CCR\], Partial Response \[PR\] and Stable Disease \[SD\]) of larotrectinib in young children newly diagnosed with HGG carrying NTRK fusion after 2 cycles of larotrectinib monotherapy.

To assess the safety and tolerability of larotrectinib given in combination with chemotherapy or post-focal radiation therapy in young children newly diagnosed with HGG carrying NTRK fusion. This will be achieved by calculating the number of participants with, as well as frequency and severity of, larotrectinib-related Adverse Events as assessed by CTCAE v5.0.

To characterize the plasma pharmacokinetics (PK) of larotrectinib in children newly diagnosed with HGG carrying NTRK fusions who undergo a second definitive resection. This will be achieved by measuring the Maximum Plasma Concentration (Cmax) of larotrectinib in blood (plasma) samples collected at pre-dose (day -5), pre-surgery (day -1) and during surgery.

To characterize the tumor pharmacokinetics (PK) of larotrectinib in children newly diagnosed with HGG carrying NTRK fusions who undergo a second definitive resection by measuring the concentration of larotrectinib in tumor tissue collected on day 5 of surgical cycle

To assess the objective response rate (ORR) (Complete Response \[CR\] and Partial Response \[PR\]) of larotrectinib in children newly-diagnosed with HGG carrying NTRK fusion after 2 cycles of larotrectinib monotherapy.

To assess overall (OS) and progression-free survivals (PFS) of children newly diagnosed with HGG carrying NTRK fusion treated with a larotrectinib-containing regimen at 1, 3 and 5 years and compared to historical data from BABYPOG and HIT-SKK.

Nationwide Children's Hospital

Informed consent (IC) before start of any treatment after diagnosis of NTRK fusion-positive cancer. All data after diagnosis of NTRK fusion-positive cancer are collected prospectively.

IC after start of any treatment after diagnosis of NTRK fusion-positive cancer. Data after study inclusion are collected prospectively and retrospectively.

Patients deceased prior to study inclusion (no IC required). All data are collected retrospectively.

Benjamin Kasenda, PD Dr. Dr.

The objective of this registry is to analyze treatment reality and outcome of patients with locally advanced or metastatic solid tumors harboring a fusion of NTRK1, NTRK2 or NTRK3

The REALTRK registry will provide data on treatment reality of patients with locally advanced or metastatic solid tumors harboring NTRK1, NTRK2 or NTRK3 gene fusions, thereby generating real world evidence. It will identify factors that influence treatment decisions after receiving the diagnosis of a NTRK (Neurotrophic Tyrosine Receptor Kinase) fusion-positive cancer. All treatment lines administered before and after the molecular diagnosis of a NTRK fusion-positive cancer, irrespective of the type of antineoplastic treatment, will be documented. Data will be assessed at least 36 months per patient (i.e. until 36 months after inclusion of the last patient in the study). This approach will allow a description of TRK fusion protein-targeted therapies and other therapy strategies regarding effectiveness and disease-related symptomology within the limitations of non-randomized studies in terms of comparative analyses. Intra-individual and inter-individual comparisons (for the latter, provided that a sufficient number of patients with a NTRK fusion-positive cancer are not treated with a TRK inhibitor) could be performed.

The associated biomarker profiling module of the REALTRK registry will aim to set up a decentralized biobank for future research on molecular alterations.

Registry for Molecular Testing, Treatment and Outcome of Patients With Solid Tumors Harboring a NTRK Gene Fusion

Registry for Molecular Testing, Treatment and Outcome of Patients With Locally Advanced or Metastatic Solid Tumors Harboring a Fusion of NTRK1, NTRK2 or NTRK3

Proportion of patients with CR or PR as best response

Descriptive summary of demographics, patient and disease characteristics

Description of test methods used for diagnosis of a NTRK fusion-positive cancer and results thereof

Description of physician-reported factors affecting decision to test for NTRK fusion and treatment decision making after diagnosis of NTRK gene fusion

Description of all treatment lines given to the patient after diagnosis of NTRK gene fusion including: Type of treatment (Systemic TRK inhibitor treatments or Non-TRK inhibitor treatments), treatment duration, dosing, treatment modifications and reasons thereof, reasons for end of treatment.

Treatment-emergent AEs (i.e., AEs which occurred during a specific TRK inhibitor treatment and in the respective survival FU) will be calculated per patient (absolute and relative frequencies) and case-based (absolute frequencies). The occurrence of any (S)AE will be displayed overall and per CTCAE grade. Adverse drug reactions (ADRs) and AESIs will be displayed accordingly.

Incidence of AEs (MedDRA Preferred Term (PT) by System Organ Class (SOC)) will be calculated accordingly for each type of AE/ADR.

Description of physician-reported evaluation of TRK inhibitor therapy

Description of courses of disease-related symptoms (weight loss, ECOG) after diagnosis of NTRK gene fusion (Only for patients of inclusion group I)

Proportion of patients with CR, PR or SD as best response

Time from start of treatment to the first objective tumor response (e.g., tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR

Time from documentation of tumor response to disease progression or death from any cause

Time from start of treatment until disease progression or death

Time from start of treatment until death of any cause

ratio of PFS of the first treatment line with a TRK inhibitor to time to progression (TTP) in the preceding treatment line without a TRK inhibitor

Time from start of treatment until PD or death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Retro-/Prospective, Non-interventional, Cohort Study in Adult Patients With Locally Advanced or Metastatic Tumors With a Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion, Treated With Larotrectinib	NCT04814667	Solid Tumor, Ad... Locally Advance... Metastatic Canc...		25 Years -	Centre Leon Berard
A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion	NCT04655404	High Grade Glio... Diffuse Intrins...	Larotrectinib Larotrectinib s...	- 21 Years	Nationwide Children's Hospital
A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion	NCT04655404	High Grade Glio... Diffuse Intrins...	Larotrectinib Larotrectinib s...	- 21 Years	Nationwide Children's Hospital
Registry for Molecular Testing, Treatment and Outcome of Patients With Solid Tumors Harboring a NTRK Gene Fusion	NCT04557813	NTRK Family Gen...		18 Years -	iOMEDICO AG
A Retro-/Prospective, Non-interventional, Cohort Study in Adult Patients With Locally Advanced or Metastatic Tumors With a Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion, Treated With Larotrectinib	NCT04814667	Solid Tumor, Ad... Locally Advance... Metastatic Canc...		25 Years -	Centre Leon Berard
A Pilot Study of Larotrectinib for Newly-Diagnosed High-Grade Glioma With NTRK Fusion	NCT04655404	High Grade Glio... Diffuse Intrins...	Larotrectinib Larotrectinib s...	- 21 Years	Nationwide Children's Hospital
Registry for Molecular Testing, Treatment and Outcome of Patients With Solid Tumors Harboring a NTRK Gene Fusion	NCT04557813	NTRK Family Gen...		18 Years -	iOMEDICO AG
A Retro-/Prospective, Non-interventional, Cohort Study in Adult Patients With Locally Advanced or Metastatic Tumors With a Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusion, Treated With Larotrectinib	NCT04814667	Solid Tumor, Ad... Locally Advance... Metastatic Canc...		25 Years -	Centre Leon Berard

Spots Global Cancer Trial Database for ntrk gene fusion