A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer

Not Applicable

Recruiting

• Conditions: Metastatic Colorectal Cancer; BRAF V600E Mutation Positive
• Interventions: Other: Collection of blood samples

• Registration Number: NCT05639413
• Lead Sponsor: UNICANCER

Brief Summary

The study will be conducted in patients with metastatic colorectal cancer (mCRC) harboring a BRAFV600E mutation, to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with this pathology.

Detailed Description

Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC.

This collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned:

i. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to:

* Evaluate its positive and negative predictive value.

* Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy.

ii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring).

iii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.

Study Timeline

• Study First Submitted: 2022-11-15
• Study First Submitted QC: 2022-11-25
• Study First Posted: 2022-12-06
• Study Start: 2023-07-24
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-12
• Last Update Posted: 2024-12-13
• Primary Completion: 2027-07
• Study Completion: 2028-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

1. Men and women aged 18 years or older
2. Histologically confirmed BRAFV600E metastatic colorectal cancer (mCRC), chemotherapy-naive in the metastatic setting or having initiated a first line of chemotherapy in the metastatic setting (except encorafenib-cetuximab treatment)
3. Available tumor tissue sample obtained before inclusion with sufficient tissue left for biological studies. Patients with only fine-needle aspirations are not eligible.
4. Known MMR/microsatellite status (immunohistochemistry [IHC] and polymerase chain reaction [PCR]) (or under analysis)
5. Patients must have signed a written informed consent form prior to any trial specific procedures. If the patients are physically unable to give their written consent, a trusted person of their choice, not related to the investigator or the sponsor, can confirm in writing the patient's consent.
6. Patients must be willing and able to comply with the study procedures
7. The patient must be affiliated to a social security system or benefit of such a system.

Exclusion Criteria

1. Patient with another cancer concomitantly with the mCRC requiring treatment or influencing the prognosis according to the medical staff.
2. Patients for whom the follow-up will not be assured by the investigator or its team.
3. Any condition that may jeopardize patient participation in the study as well as non-contraception for men and women with child-bearing potential, and pregnancy or breast feeding for women.
4. Persons deprived of their liberty or under protective custody or guardianship.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
COBRAF	Collection of blood samples	A 30 mL blood samples (6 mL in each of 5 EDTA tubes) will be collected from each patient at the following timepoints: * At the starts of cycle 1, 2 and 3, * At 3 and 6 months after starting of each treatment line, if applicable. * At disease progression after second-line treatment with encorafenib combined with cetuximab, if applicable. * At disease progression after immunotherapy-based treatment in dMMR/MSI patients. At most 390 mL of blood will be collected from each patient during the study.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From date of first diagnosis of mCRC and the date of death, whatever the cause, up to 5 years	OS of patients with BRAFV600E mCRC in the real-life setting. The OS is defined as the time between the date of first diagnosis of mCRC and the date of death, whatever the cause. The patients alive at the time of analysis will be censored at the date of their last follow up.

Secondary Outcome Measures

Name	Time	Method
ctDNA kinetics modeling outcome parameters	From date of first diagnosis of mCRC until the date of first disease progression, up to 5 years	The detection of ctDNA level assessed by next generation sequencing in the blood of patients with deficient DNA mismatch repair (dMMR) / microsatellite instability (MSI) will be measured at the start of cycle 1, cycle 2, and cycle 3, and at 3 months and 6 months after starting each treatment line, as well as at disease progression.; The level of ctDNA measured at each time point will provide information on how the body interacts with administered treatments overtime.
Disease control rate	From baseline to first disease progression, up to 5 years	The disease control rate (DCR) is defined as the percentage of patients with a CR, a PR or stable disease for a given treatment line.
Progression-free survival	From baseline to first disease progression, up to 5 years	The progression-free survival (PFS) for each treatment line is defined as the time interval between the start of treatment of the given line and the date of the first disease progression (radiological or clinical) or the start of another anticancer therapy, or death from any cause, whichever occurs first.
Correlation between predictive biomarkers and response to treatment	Throughout study completion, up to 5 years	These biomarkers of response/resistance to combination treatment with anti-EGFR/anti-BRAF will be assessed by immunohistochemistry analysis of peripheral blood and tumor tissues.
Collection of prospective data about BRAFV600E mCRC	Throughout study completion, up to 5 years	Prospective collection of data collected during the normal clinical care. A descriptive analysis of the disease (Patients and tumors characteristics), current medical practices (molecular genotyping in France), and therapeutic sequences and composition of each treatment line (patients treated with immunotherapy, patients enrolled in clinical studies, metastatic surgeries). The resulting qualitative data analysis of the population will be expressed in number with percentage.
Correlation between prognostic markers and overall survival	Throughout study completion, up to 5 years	To identify clinical and biological prognostic markers of OS on blood and tumor samples. the OS is defined as the length of time from first diagnosis of mCRC that patients enrolled in the study are still alive. OS will then be correlated to clinical and biological prognostic markers analyzed at date of first diagnosis of mCRC and date of first progression or death by clinical testing used in routine cancer treatment practice (blood test analysis and tumor sample analysis). The Cox proportional-hazards model will then be used to study potential prognostic parameters OS.
Correlation between prognostic markers and progression-free survival	From date of first diagnosis of mCRC and date of first progression or death, up to 5 years	PFS is defined as the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. PFS will then be correlated to clinical and biological prognostic markers analyzed at date of first diagnosis of mCRC and date of first progression or death by clinical testing used in routine cancer treatment practice (blood test analysis and tumor sample analysis). The Cox proportional-hazards model will then be used to study potential prognostic parameters PFS.
Objective response rate	From baseline to first disease progression, up to 5 years	The objective response rate (ORR) for each treatment line is defined as the percentage of patients with a complete response (CR) or a partial response (PR) for a given treatment line.

Trial Locations

Locations (38)

CH Fleyriat; 🇫🇷 Bourg-en-Bresse, France

Centre d'Oncologie Saint Yves; 🇫🇷 Vannes, France

Centre Hospitalier D'Avignon; 🇫🇷 Avignon, France

Centre Hospitalier de Bayeux; 🇫🇷 Bayeux, France

Chu Estaing de Clermont-Ferrand; 🇫🇷 Clermont-Ferrand, France

Aphp - Hopital Henri Mondor; 🇫🇷 Créteil, France

CH Dr TECHER; 🇫🇷 Calais, France

CH Louis Pasteur; 🇫🇷 Le Coudray, France

Hôpital privé Jean Mermoz; 🇫🇷 Lyon, France

CHR d'Orléans; 🇫🇷 Orléans, France

Hôpital Privé de la Loire; 🇫🇷 Saint Etienne, France

Institut Bergonie; 🇫🇷 Bordeaux, France

Ch de Cahors; 🇫🇷 Cahors, France

Infirmerie Protestante de Lyon; 🇫🇷 Caluire-et-Cuire, France

Groupe Hospitalier Mutualiste de Grenoble; 🇫🇷 Grenoble, France

Chu de Grenoble Alpes - Hopital Michallon; 🇫🇷 La Tronche, France

Groupe Hospitalier Emile Roux; 🇫🇷 Le Puy-en-Velay, France

Hopital Franco-Britannique; 🇫🇷 Levallois-Perret, France

Chu Dupuytren; 🇫🇷 Limoges, France

Centre Leon Berard; 🇫🇷 Lyon, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Aphp - Hopital Bichat; 🇫🇷 Paris, France

Aphp - La Pitie Salpetriere; 🇫🇷 Paris, France

Intitut Paoli Calmettes; 🇫🇷 Marseille, France

Grand Hopital de L'Est Francilien - Site de Meaux; 🇫🇷 Meaux, France

Aphp - Hopital Saint Louis; 🇫🇷 Paris, France

Hopital Saint Antoine; 🇫🇷 Paris, France

Institut Mutualiste Montsouris; 🇫🇷 Paris, France

Ch Perpignan; 🇫🇷 Perpignan, France

Chru de Nancy; 🇫🇷 Vandœuvre-lès-Nancy, France

Gh Diaconesses Croix Saint Simon; 🇫🇷 Paris, France

Chu Poitiers; 🇫🇷 Poitiers, France

Chu Rennes Pontchaillou; 🇫🇷 Rennes, France

ICANS; 🇫🇷 Strasbourg, France

Chu de Reims; 🇫🇷 Reims, France

Chu de Rouen; 🇫🇷 Rouen, France

Ch de Saint Malo; 🇫🇷 Saint-Malo, France

Chu de Tours; 🇫🇷 Tours, France