Neoplasms

All Conditions

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

ctDNA analysis of patients with suspected primary glioma tumors and in patients with suspected recurrence.

ctDNA analysis

GARNIER Louis, Dr

Delphine PONCET, Dr

PONCET Delphine, DR

Gliomas represent the most frequent primary brain tumor, with 2,500 to 3,000 new cases per year in France. Their diagnosis, although highly complex, is essential for determining patient management. While grade I gliomas (infrequent) are curable by surgery or present a slow progression, grades II to IV require heavy treatment (surgery and radio-chemotherapy), and are associated with a prognosis ranging from 10-15 years for grade II to only 15 months for glioblastoma.

One of the key processes in glioma oncogenesis is the activation of a telomeric maintenance mechanism (TMM). Two TMMs ensure the maintenance of a telomere size compatible with intense cell proliferation (TERT mutation and ATRX loss).

Liquid biopsy is used for the routine diagnosis and monitoring of treatment efficacy of different cancers. To date, no routine clinical testing of liquid biopsies is available for gliomas.

The detection of glioma-specific oncogenic processes, by liquid biopsy, in peripheral blood (ctDNA) could improve diagnosis and follow-up and then avoid surgery for patients with suspected lesions.

Three oncogenic markers can be used to detect gliomas: IDH mutation, TERT mutation, and a marker correlated with ATRX loss on total blood cells.

We hypothesized that the circTeloDIAG will improve and accelerate the diagnostic/prognostic value of the actual classification and provide a new tool to manage patient response to treatment via liquid biopsy. It will combine detection of three markers in liquid biopsy, to produce a versatile tool for all types of gliomas.

Patients with suspected newly diagnosed or recurrent glioma will be included.

Gliomas, heterogeneous and aggressive tumors awaiting new therapeutic approaches.

Gliomas are the most frequent primary brain tumors, with 2,500 to 3,000 new cases per year in France. They concern the elderly but can also affect children and young adults. Their diagnosis is often complex (differential diagnoses, delicate classification). However, this diagnosis is essential to determine the therapeutic management. Thus, while grade I gliomas (infrequent) are curable by surgery or have a slow progression, grades II to IV have a cost in terms of therapeutic costs (surgery and radio-chemotherapy), in connection with a prognosis ranging from heavy 10-15 years for grades II to only 15 months for glioblastoma (grade IV). New biotherapies (such as anti-VEGF) have not improved the prognosis and to date there are no targeted therapies or immune systems that have shown a benefit.

It is more than ever necessary to propose targeted treatments against alterations of each type of glioma and to develop in parallel the therapeutic tests allowing their prescription.

DIAGNOSIS OF GLIOMAS: IMPORTANCE OF BIOMARKERS

The diagnosis of gliomas was subject to a high rate of inter-observer discrepancies. Molecular criteria have recently made it possible to refine and secure the diagnosis1. Thus, in hospital routine, mutations in Isocitrate Dehydrogenases (IDH1 and 2), 1p19q deletion, EGFR amplification, loss of CDKN2A, mutations in histones H3.3 and H3.1 (G35R / V, K28M), methylation of MGMT, as well as two telomeric markers: mutations of the TERT promoter (TERTmt) and the deletion of ATRX (lost ATRX) (see below). Thus, the new "histo-molecular" classification of WHO1 (2016) and its following updates define different classes of gliomas:

* Oligodendrogliomas (OD) (IDHmt, 1p19q lost) (grades II-III)
* IDHmt (A) Astrocytomas (IDHmt and ATRXperdu / TP53 positive) (grades II-III)
* IDHmt Glioblastomas (GBM IDHmt) (IDHmt and ATRXperdu) (grade IV)
* IDHwt (GBM) Glioblastomas (IDHwt and TERTmt) (grade IV)
* IDHwt Astrocytomas (A IDHwt) (IDHwt) (grades II-III)
* midline mutated histone gliomas (G35R / V, K28M)

However, this classification does not fully reflect the actual aggressiveness of the tumors and has prognostic insufficiencies. Adaptations are therefore regularly made to these initial categories. Despite these diagnostic adaptations, some tumors present discrepancies between the immunohistological and molecular diagnosis, they are annotated NEC (Not Elsewhere Classified).

LIQUID BIOPSY: AN EXPECTED DIAGNOSIS TOOL FOR GLIOMAS

Liquid biopsy-type approaches have rapidly developed in the clinic; they already make it possible to monitor and / or participate in the diagnosis of various cancers on a routine basis (eg: EGFR mutations in lung cancers). In the case of gliomas, their benefit is obvious: in addition to imaging, or as a replacement for stereotaxic biopsy (1% mortality), they could improve the quality of follow-up and speed up the initial diagnosis. In particular, 47% of patients with GBM have an MRI imaging suggesting progression after radiotherapy, the detection of a circulating marker would make it possible to differentiate a progression (27%) from a "pseudo-progression" (20%). When monitoring gliomas, the reappearance of the circulating marker would make it possible to objectify the recurrence and to set up a second line or inclusion in a clinical trial more quickly. Finally, during the initial diagnosis, the delay of one month after biopsy or surgery necessary for the conventional diagnostic circuit could be reduced to one week thanks to this type of test; therapeutic management could then be accelerated.

At this time, there is no such test for gliomas. However, preliminary studies carried out on cerebrospinal fluid (CSF) collected during surgery show a sensitivity of around 100% for the detection of TERTmt9. However, the removal of LCS for follow-up is an invasive act to which we should favor approaches by blood sampling.

The first studies of this type on circulating DNA (cfDNA) in plasma, via whole exome sequencing (a very expensive technique) detected gene abnormalities in nearly 50% of the cfDNAs analyzed. However, detection of diagnostic hotspots characteristic of gliomas such as TERTmt is insufficient on cfDNA (0-8% detection for glioblastomas). Other studies have looked at the analysis of tumor DNA carried by exosome-like vesicles, but have not been satisfactory. Finally, an alternative is based on the purification of circulating tumor cells (CTC). The latter have been detected in nearly 77% of gliomas; the best results having been obtained using density gradient centrifugation techniques, such as that offered by the OncoQuick kits combining a density gradient with filtration. Using this technique, from 1 to 10 CTC per 7.5 ml of blood were detected in 31 patients with gliomas of different grades. The advantage of this approach is that it preserves the entire genome of the tumor cell and will therefore allow the identification of characteristic diagnostic hotspots such as TERTmt and IDH1 / 2mt. The search for these mutations will then be objectivable by inexpensive techniques (such as the digital PCR droplet), already used routinely and not by high-throughput techniques (eg: whole genome sequencing) unsuitable for routine.

There is therefore a real expectation regarding liquid biopsies for the diagnosis and follow-up of gliomas. The targeted research approach for hotspot alterations with diagnostic value in glioma (such as TERTmt and IDH1 / 2mt), via CTC enrichment appears to be a promising avenue.

ctDNA of blood's patient with glioma tumour

The circTeloDIAG: Liquid Biopsy for Glioma Tumor

The circTeloDIAG: a New Approach of Liquid Biopsy for the Diagnosis and Follow-up of Patients With Glioma Tumor

The main objective is to evaluate the performances of the diagnostic test "circTeloDIAG" dedicated to liquid biopsy. Primary endpoint is the sensitivity and specificity of the circTeloDIAG assay, at time of initial surgery. It will be established in CTCs in comparison with tumoral with positivity of one of the three markers tested

Hospices Civils de Lyon

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Disease Progression

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Antibodies

Osimertinib

Immunoglobulins

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Oral administration of TAGRISSO® 80mg (Osimertinib) as a single daily dose until disease progression or unacceptable toxicity.

Tumor biopsies performed at baseline and clinical progression. ctDNA analysis by Collection of plasma (two 10-ml Streck tubes) at each time point indicated in the trial.

Oral administration of TAGRISSO® 80mg (Osimertinib) as a single daily dose until disease progression or unacceptable toxicity.

TAGRISSO® 80mg (Osimertinib)

Tumor biopsies performed at baseline and clinical progression will be processed (fixed) on site, and sent to Nantes University Hospital for analysis.

The following analysis will be performed:

1. Analyses performed on a regular basis, in order to allow subsequent inclusion in other clinical trials :

   * C797S testing (digital PCR)
   * MET amplification (dPCR/FISH)
   * Histological examination of the tissue sample (to identify small cell transformation)
   * Expression of proteins by immunohistochemistry: PD-L1 (Ventana SP263 antibody); CD73 ; CD4; CD8.
2. At the end of inclusions, deep sequencing analysis to identify acquired mutations and copy number variations (amplifications).

Tumor biopsies

ctDNA analysis by Collection of plasma (two 10-ml Streck tubes) at each time point indicated in the trial.

These samples will be sent at room temperature by courier to the central laboratory (Nantes University Hospital). There they will be centrifuged, and plasma will be frozen (-80°C).

Analyses :

* Detection of the EGFR activating mutation in plasma at baseline By dPCR (characterization of patients enrolled)
* Detection of the EGFR activating mutation at d7 and m1 by dPCR (early detection of response to osimertinib)
* Analysis of the plasma samples collected at clinical progression in order to identify acquired mechanisms of resistance by NGS (and comparison with analysis of the biopsies).
* Kinetics studies of the alterations

Jaafar BENNOUNA, MD,PhD

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer.

The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p\<0.001).

In addition, clinical data show that patients with mutated EGFR NSCLC receiving osimertinib in first line, presented an objective response rate of 77 % with a disease control rate of 98 % and a median PFS was 19.3 months.

Finally, The FLAURA study randomized phase 3 study clearly demonstrated the superiority of osimertinib compared with erlotinib or gefitinib in EGFR mutated nonpretreated NSCLC (median PFS of 18.9 months versus 10.2 months).

However, several issues remain unknown or debated :

* What are the mechanisms of resistance to osimertinib prescribed in first-line?
* What are the consequences of prolonged exposure to osimertinib on the expression of markers of response to immunotherapy?
* Is there an association between kinetic parameters of ctDNA (circulating tumor DNA) and prediction of response to osimertinib and/ or and prediction of therapeutic escape under osimertinib? In order to respond to all these questions, this phase II trial will be the first to systemically analyze the mechanisms of resistance to Osimertinib based on the analysis of biopsy, and collection of plasma from all patients during the course of treatment.

MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib

MELROSE: Phase 2 Study Evaluating MEchanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtinib Until and Beyond Radiological Progression : the MELROSE Trial

Analyze of the proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2 (Human Epidermal Growth factor receptor 2), and cMET expression and/or amplification) at the point of clinical disease progression.

Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease and death, or one year if no event. The rPFS is defined according to RECIST 1.1.

Radiological Progression Free Survival (rPFS): Time from first study dose to first event between rPFS or death. The rPFS is defined according to RECIST 1.1.

Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib.

Duration of Response (DoR): Disease Control Rate (DCR)

Monitoring of Adverse events (grade 3 and 4)

By the study of the expression of molecules involved in the efficacy of check point inhibitors determined by immunohistochemistry (PD-L1; CD73; CD4; CD8) on tumor tissue collected at progression

Analyze of mutation at progression on tumor tissue and ctDNA

Analyze of the presence of tumors ctDNA at baseline, clinical progression disease

Analyze of absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease

Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression

Analyze of the EGFR mutation identified in the tumor biopsy and in the ctDNA

Analyze of the absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease

AstraZeneca

Nantes University Hospital

Adenocarcinoma

Carcinoma

PDAC patients as described in the inclusion criteria

antonio pea, MD PHD

Elisa Venturini

The main objective is the evaluation of the prognostic value of ctDNA (circulating tumor DNA) as a marker of surgical futility in patients with operable PDAC.

In the era of personalized medicine and treatments guided by tumor biology, no specific tumor marker has real prognostic value. This is the reason why the search for a specific marker through a noninvasive blood test that can give indications on the usefulness of the resectability of pancreatic adenocarcinoma would be very valuable. Our project proposes the evaluation of ctDNA during various treatment courses of patients with PDAC in order to evaluate its efficacy as a prognostic and predictive marker of response to treatment.

Circulating Tumor DNA as Surgical Biomarker in Patients With PancrEatic Adenocarcinoma for Statement of Resectability

Azienda Ospedaliera Universitaria Integrata Verona

Carcinoma, Bronchogenic

Bronchial Neoplasms

blood sample at Baseline, 3weeks, 9 weeks after treatment, at progression if applicable

Marc DENIS

In patients with locally advanced or metastatic tumors, first-line therapeutic management is based on the use of targeted therapies (EGFR, BRAF ALK and ROS1 inhibitors), immunotherapies (anti-PD1/ anti-PDL1-antibodies or chemotherapy.

Despite patient selection based on histo-pathological and molecular criteria, not all patients respond to treatment. There are currently no markers to definitively guarantee a patient's response.

An alternative is to identify early patient response to treatment. The investigator hypothesize that change in circulating tumor DNA concentration (ctDNA) allow to early identify patients' therapeutic response (and non-response) of patients, regardless of the type of treatment used in the first line setting.

The primary objective is to determine whether early evolution (between baseline and week 3) of circulating tumor DNA concentration predicts the radiological response to first-line treatment of advanced or metastatic NSCLC patients, regardless of treatment

Early Assessment of Response to Treatment of Metastatic LUng Tumors Based on CIrculating Tumor DNA

Non-controlled Prospective Pilot Study Assessing Prognostic Performance of Circulating Tumour DNA Kinetic Analysis for Monitoring Response to Treatment of Metastatic Non-small Cell Lung Cancers

Changes of the amount of ctDNA between baseline and week 3 will make it possible to determine the biological response: increase, stability or decrease in ctDNA.

Radiological assessment, based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1, will be: complete response, partial response, progression or stabilization. Biological response will be: increase, stability or decrease in ctDNA.

Biological progression will be: increase in ctDNA - Radiological progression will be defined according to RECIST criteria v1.1 will be: progression

Biological response will be: increase, stability or decrease in ctDNA and Radiological response will be defined according to RECIST criteria v1.1 will be: complete or partial response

Radiological assessment, based on RECIST criteria v1.1, will be: complete response or partial response. Biological response will be: increase, stability or decrease in ctDNA.

Centre Hospitalier Departemental Vendee

Skin and Connective Tissue Diseases

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Nivolumab

Ipilimumab

Trametinib

Dabrafenib

Dabrafenib + Trametinib

Switch to N+I at first progression

Dabrafenib + Trametinib

Switch to N+I when ctDNA levels in the blood have dropped by ≥80%.

Regular ctDNA analysis, which upon a decrease in mutant BRAF VAF (variant allele frequency) level of ≥80% the switch to N+I is triggered.

Paul Lorigan

The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.

The optimal scheduling of targeted and immune therapies in metastatic melanoma is unknown. At present, patients are treated with targeted therapy until acquired resistance develops, and then switched to immune therapy. Pre-clinical data has revealed that BRAF inhibition results in an environment that can enhance immune responses. Tumours responding to BRAF inhibitors but not resistant have been shown to have increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines. Furthermore, in response to targeted therapy LDH levels, which are associated with decreased response to immune therapy reduces, which may improve efficacy of immunotherapy.

A precise definition of response is required in order to decide upon a switch to immune therapy. A radiological definition of response is currently the standard assessment. However a scan at a fixed time point of 2 or 3 months does not reflect the wide range of response dynamics or allow decision making on an individual patient basis. The investigators have developed techniques using circulating tumour DNA (ctDNA) in the metastatic setting, which are able to accurately monitor tumour burden over time.

The aim of this pilot study is to provide a signal as to whether:

1. In BRAF mutant melanoma the efficacy of immune therapy is enhanced by response to pre-treatment with MAPK pathway inhibition with dabrafenib + trametinib.
2. Changes in ctDNA levels can be used to accurately inform when to switch from targeted to immune therapy.

Data from this study will provide the basis for follow on studies with sufficient power to assess whether tumours responding to BRAF inhibition as defined by response in ctDNA can improve efficacy of immune therapy.

CAcTUS - Circulating Tumour DNA Guided Switch

A Parallel Arm, Biomarker Driven, Phase II Trial to Determine the Role of Circulating Tumour DNA in Guiding a Switch Between Targeted Therapy and Immune Therapy in Patients With Advanced Cutaneous Melanoma

Time to first progression measured by ctDNA

Time to second progression measured by ctDNA

To explore the relationship between observing a rise in ctDNA level of mutant BRAF VAF and progressive disease observed from scheduled scan results

To compare duration in ctDNA level of mutant BRAF VAF response to targeted therapy between study arms

To compare duration in ctDNA level of mutant BRAF VAF (within ctDNA) response to immune therapy between study arms

To explore whether switching from targeted to immune therapy on treatment response as guided by ctDNA levels of mutant BRAF VAF will increase response to therapy

Feasibility of returning samples to hospitals from the laboratory to inform clinical decisions

To assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% on targeted therapy is an appropriate cut off for switching to immune therapy

To assess whether BRAF VAF (within the ctDNA) of ≥1.5% is an appropriate target for study inclusion (by assessing the number and proportion of screen failures

To explore whether PFS at 12 months would improve in patients switching from targeted to immune therapy on response to treatment as guided by ctDNA levels of mutant BRAF VAF

Explore whether survival outcomes would improve in patients switching from targeted to immune therapy on response to treatment as guided by ctDNA levels of mutant BRAF VAF

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The circTeloDIAG: Liquid Biopsy for Glioma Tumor	NCT04931732	Glioma	ctDNA analysis	18 Years - 90 Years	Hospices Civils de Lyon
MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib	NCT03865511	Non-small Cell ...	TAGRISSO® 80mg ... Tumor biopsies ctDNA analysis	18 Years -	Nantes University Hospital
Circulating Tumor DNA as Surgical Biomarker in Patients With PancrEatic Adenocarcinoma for Statement of Resectability	NCT05853198	PDAC - Pancreat...	ctDNA analysis	18 Years -	Azienda Ospedaliera Universitaria Integrata Verona
Early Assessment of Response to Treatment of Metastatic LUng Tumors Based on CIrculating Tumor DNA	NCT03926260	Metastatic Non-...	ctDNA analysis	18 Years -	Centre Hospitalier Departemental Vendee
MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib	NCT03865511	Non-small Cell ...	TAGRISSO® 80mg ... Tumor biopsies ctDNA analysis	18 Years -	Nantes University Hospital
Circulating Tumor DNA as Surgical Biomarker in Patients With PancrEatic Adenocarcinoma for Statement of Resectability	NCT05853198	PDAC - Pancreat...	ctDNA analysis	18 Years -	Azienda Ospedaliera Universitaria Integrata Verona
CAcTUS - Circulating Tumour DNA Guided Switch	NCT03808441	Melanoma	ctDNA analysis	16 Years -	The Christie NHS Foundation Trust

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