Multicenter Validation of the Sensitivity of Theranostic ALK Rearrangement Detection by FISH Analysis and Prevalence of Escaping Mutations in Circulating Tumor Cells for the Non-invasive Management of Lung Cancer Patients

NCT02372448 | Completed

• 1 other identifier: 13-APN-01
• Study Type: interventional
• Target: 206
• Locations: 1 country
• Sites: 11

Brief Summary

Patients eligibility to targeted therapies relies on a molecular test performed on a tumor sample collected by biopsy. This invasive procedure is associated with a relative high risk of morbidity and requires the intervention of a costly and important technical platform. Thus, inoperable patients can be deprived from potentially more efficient therapies. A "liquid biopsy" of Circulating Tumor Cells (CTCs) present in the blood and their molecular characterization is an appealing alternative to meet an urgent need for these patients. Moreover no CTC-based molecular test is currently routinely available. The 5-year survival rate of patients with non-small cell lung carcinoma (NSCLC) is low. Recent reports demonstrated that the detection of an ALK rearrangement in the tumor tissue allows patients with late-stages NSCLC to benefit from crizotinib treatment. However, 1) the detection of an ALK rearrangement is currently performed on small biopsies or fine-needle aspirates and can be hindered by the limited tissue quantities available. Tumor tissue is difficult to obtain in patients with advanced/metastatic lung cancer for whom surgery is rarely a component of treatment. Finding alternative and more effective means of diagnosing an ALK rearrangement are critical issues for identifying patients who may benefit from treatment with crizotinib; 2) some patients develop resistance to crizotinib due to de novo ALK mutations. In this setting, circulating tumor cells (CTCs), which have been shown to be detectable by ISET (Isolation by Size of Epithelial Tumor Cells) method in 80% to 100 % of late stages lung cancer patients represent a non-invasive and easily accessible source of tumor material for assessing ALK rearrangement and escaping mutations in a kinetic manner. The ISET method was first published in 2000 and several independent teams have now established its high sensitivity and specificity of ISET for NSCLC. With ISET, specificity can be achieved using the same methods and criteria used by cytopathologists to diagnose solid tumors. The high sensitivity and specificity of ISET are two essential starting points for the feasibility of this present project. Low-throughput molecular characterization of CTCs isolated by ISET has also been achieved. The remaining challenge consists in developing high-throughput ISET-based molecular tests for personalized medicine that are transferable to the clinics. The Team 1 at the CHU de Nice and the Team 2 at the Gustave Roussy Institute have demonstrated that the detection of an ALK rearrangement in CTC isolated by ISET is feasible and consistent with results obtained in corresponding tumor tissues. In this context, the aim of this project is to obtain 1) a definitive prospective clinical validation of the use of CTC as an alternative to tumor tissue for ALK analysis-based patients stratification; 2) a proof that escaping mutations can be detected early by kinetic analysis of CTC in patients treated by crizotinib. ALK rearrangement will be prospectively investigated in CTCs isolated by ISET at diagnosis and during follow up from patients with stage IIIb/IV lung cancer and de novo mutations will be searched in patients with resistance to crizotinib. This study will provide both clinical and economic benefit to targeted treatment of patients with advanced lung cancer. This project is strongly original as no CTC-based ALK rearrangement test has been independently validated up to now with clinical samples. The development of non-invasive theranostic test through the genetic analysis of CTCs is a clinically relevant goal for non-invasive stratification of cancer patients, avoiding morbidity related to lung biopsy and surgery. It would allow determining patient's eligibility to targeted therapies on a blood sample analysis. CTC-based ALK test could be useful to guide the choice of ALK targeted therapy in patients with lung cancer. Furthermore, developing biomarkers based on CTCs analysis would open the way to the non-invasive follow up of aggressive cancers, early detection of mutations associated with resistance to targeted therapies and tailoring treatment to a real time analysis of the evolving tumor cell populations. This test is expected to markedly improve patients' quality of life avoiding invasive diagnostic procedures.

Conditions

Lung Neoplasms

Outcome Measures

Primary Outcomes (1)

• sensitivity and specificity of the FISH technique for the detection of the ALK rearrangement in CTCs Change from Baseline to 6 and 12 months

  ALK rearrangement positivity by FISH analysis in CTC will be defined as the presence of an ALK rearrangement in four or more CTCs isolated per 1 ml blood. The proportion of ALK-rearranged CTCs (determined by FISH analysis) among the total numbers of CTCs determined by cytomorphological examination or by combining immunofluorescent staining and cytomorphological examination will be also determined and compared to that obtained in the tumor tissue.

  at the inclusion, 6 months and 12 months

Secondary Outcomes (2)

• sensitivity and specificity of the ICC analysis on CTCs

  at the inclusion, 6 months and 12 months

• association between the ALK-rearranged CTC levels evolution and tumor progression at 6 and 12 months

  at the inclusion, 6 and 12 months

Study Arms (2)

ALK-positive

OTHER

ALK positive analysis on CTCs detected by ISET

Other: ALK analysis on CTCs detected by ISET

ALK-negative

OTHER

ALK negative analysis on CTCs detected by ISET

Other: ALK analysis on CTCs detected by ISET

Interventions

ALK analysis on CTCs detected by ISET OTHER

ALK-negative; ALK-positive

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years old or older
• Histologically confirmed stage IIIb/IV non-squamous NSCLC undergoing biopsy or surgery
• Presence of ALK rearrangement result by FISH analysis (gold standard method) on tumor tissue
• Signed specific informed consent approved by the Institutional Review Board prior to patient entry
• Affiliation to the social security system

You may not qualify if:

• Vulnerable persons: adults under guardianship or persons deprived of their liberty, patients under 18 years old
• Medical and/or psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Nice: lead

Study Sites (11)

Centre François Baclesse

Caen, 14000, France

Location

Grenoble university hospital

Grenoble, 38043, France

Location

Marseille University Hospital

Marseille, 13915, France

Location

Nancy university hospital

Nancy, 54511, France

Location

Centre Antoine Lacassagne

Nice, 06100, France

Location

CHU de Nice

Nice, France

Location

Hôpital Tenon

Paris, 75020, France

Location

Institut arnault tzanck

Saint-Laurent-du-Var, 06700, France

Location

Toulouse University Hospital

Toulouse, 31059, France

Location

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, 54500, France

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

Related Publications (1)

• Heeke S, Benzaquen J, Vallee A, Allegra M, Mazieres J, Fayada J, Rajamani J, Lee M, Ordinario E, Tiotiu A, Cadranel J, Poudenx M, Moro-Sibilot D, Barlesi F, Gervais R, Thariat J, Tanga V, Boutros J, Ilie M, Hofman V, Marquette CH, Denis MG, Hofman P. Detection of ALK fusion transcripts in plasma of non-small cell lung cancer patients using a novel RT-PCR based assay. Ann Transl Med. 2021 Jun;9(11):922. doi: 10.21037/atm-20-7900.

  PMID: 34350237 RESULT

MeSH Terms

Conditions

Lung Neoplasms

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Paul HOFMAN, Pr

  Centre Hospitalier Universitaire de Nice

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2014
• First Posted: February 26, 2015
• Study Start: January 23, 2015
• Primary Completion: November 21, 2019
• Study Completion: November 21, 2019
• Last Updated: March 27, 2026

Record last verified: 2026-03

Locations

FR (11)