Prospective Study on Resistance-associated Mutations in Metastatic Lung Cancer

Lung Cancer Clinical Trial

— MUT-ONC  

Official title:

Prospective Study on Resistance-associated Mutations in Metastatic Lung Neoplasm Patients With Alterations in Driver Oncogenes, Except EGFR, Undergoing Treatment With Specific Inhibitors

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06081270
• Other study ID #: MUT-ONC
• Status: Recruiting
• Start date: December 12, 2021
• Est. completion date: December 31, 2024

Study information

• Verified date: October 2023
• Source: University of Milano Bicocca
• Contact: Clinical Trial Administration
• Phone: +390392333203
• Email: onco.noprofit[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This single-centre prospective study is aimed at analysing, by means of liquid biopsy with next generation sequencing analysis on circulating tumor DNA, resistance mutations arising during therapy with selective inhibitors in patients with RTK-positive NSCLC or with mutations in the Ras/MAPK (mitogen-activated protein kinase) pathway, treated at the San Gerardo Hospital, Monza.

Description:

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease that may have several genetic alterations in oncogenes responsible for progression. 30-40% of NSCLC patients carry mutations affecting the Ras/MAPK pathway, while alterations in receptor tyrosine kinases (RTKs) are found in approximately 25-35% of cases. More than half of the latter are in the Epithelial Growth Factor Receptor (EGFR) gene and have been extensively studied. In the remaining cases, several genes are involved, each with lower frequencies, ranging from around 1% to 5%, depending on the studies. Despite the wide availability of inhibitors, progression remains inevitable due to the emergence of drug resistance mechanisms. The mechanisms by which resistance can be established are essentially of three types: amplification of the target gene, activation of other signal translation pathways (by-pass track) and the occurrence of mutations in the tyrosine kinase domain of the target protein. Liquid biopsy with circulating tumour DNA (ctDNA) analysis provides a non-invasive surrogate method to identify somatic mutations by means of a simple blood sample, without risk to the patient. Moreover, liquid biopsy, by collecting ctDNA from different metastatic sites, could better reflect tumour heterogeneity, both spatial and temporal, and could, therefore, constitute a simple method of longitudinal monitoring during treatment, possibly making it possible to identify relapse early before clinical manifestation. This single-centre prospective study is aimed at analysing, by means of liquid biopsy with next generation sequencing analysis on ctDNA, resistance mutations arising during therapy with selective inhibitors in patients with RTK-positive NSCLC or with mutations in the Ras/MAPK pathway, treated at the San Gerardo Hospital, Monza.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: December 31, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Over 18 years of age.

2. Histological diagnosis of inoperable metastatic or locally advanced lung cancer.

3. Positivity for ALK, ROS1, MET, RET (Rearranged during transfection), NTRK (NEUROTROPHIC TYROSINE RECEPTOR KINASE) rearrangements, or KRAS (Kirsten rat sarcoma)-G12C (glycine 12 cysteine) or BRAF-V600E (valine 600 glutamate) mutations, detected by validated method (IHC Immunohistochemistry 3+, FISH (fluorescence in situ hybridization) or Next Generation Sequencing).

4. Patients undergoing radiological progression according to RECIST 1.1 criteria to treatment with generation I, II or III inhibitors in any line of treatment. Patients may also have been pre-treated with chemotherapy in earlier lines.

5. Presence of measurable disease on radiological investigations. Patients with brain metastases, even as a single site of disease, are eligible for the study.

6. Informed consent freely given and obtained before the start of the study.

Exclusion Criteria:

1. Under 18 years of age

2. Unconfirmed histological diagnosis

3. Absence of rearrangement or mutation of ALK, ROS1, MET, RET, NTRK, KRAS-G12C or BRAF-V600E

4. Progression to chemotherapy in the absence of treatment with TKI or RAS or BRAF inhibitor

5. Unmeasurable disease

Related Conditions & MeSH terms

• Lung Cancer
• Lung Neoplasms

Intervention

Other:
• Liquid biopsy
Blood withdrawal for each patient is performed (i) at the time of treatment initiation with tyrosine kinase inhibitors (TKI); (ii) at the time of the first planned instrumental re-evaluation according to clinical practice regardless of the type of response to the TKI employed (9-12 weeks); (iii) at the time of radiological progression according to RECIST 1 criteria. 1 at computerized tomography scan with contrast or metabolic progression at 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose during TKI therapy; (iv) at the time of the change of therapeutic strategy decided by the investigator when used beyond progression and not coinciding with point iii. The ctDNA is extracted from plasma and analyzed with Illumina sequencing method.

Locations

Country	Name	City	State
Italy	Fondazione IRCCS San Gerardo dei Tintori	Monza	MB

Sponsors (1)

Lead Sponsor	Collaborator
University of Milano Bicocca

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identification of mutation during therapy with selective inhibitors	Evaluation of mutations in ALK (anaplastic lymphoma kinase), ROS1 (ROS proto-oncogene 1), RET, NTRK, MET, KRAS (Kirsten rat sarcoma) and BRAF and in a panel of other known oncogenes during therapy with selective inhibitors by the means of liquid biopsy	At treatment initiation (baseline), up to 12 weeks from treatment initiation, at the date of first documented progression, assessed up to 24 months from treatment initiation