Neoplasms

Digestive System Diseases

All Conditions

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Herbal and Botanical

Cetuximab

Antineoplastic Agents, Immunological

Cola

Encorafenib: 4 capsules 75 mg/day (300 mg) , 7 days/7 during 6 weeks Cetuximab: 500mg/m2 intravenous route every 2 weeks (D1, D14, D28), for 3 cycles over 4 weeks.

Encorafenib Oral Capsule + Cetuximab

Project Manager

Claire GALLOIS, Dr

Claire Gallois, MD

This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.

If the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.

Furthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.

Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer

Combination of Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With Braf v600e-mutates Localised Colon or Upper Rectum Cancer (Neoraf Study)

with centralised review after neoadjuvant treatment with encorafenib and cetuximab, in patients with RAS wild type localised colon or upper rectum cancer (CC) and carriers of the BRAF V600E mutation.

Pierre Fabre Laboratories

Merck Sharp & Dohme LLC

Federation Francophone de Cancerologie Digestive

Colonic Diseases

Immunomodulating Agents

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.

A 30 mL blood samples (6 mL in each of 5 EDTA tubes) will be collected from each patient at each timepoint.

Collection of blood samples

Emilie BRUMENT

Anne-Sophie BACH, PHD

Annie PEYTIER, MD

Slim LASSOUED, MD

Marine JARY, MD

Charlotte FENIOUX, MD

Victoire GRANGER, MD

Vanessa PANTE, MD

Benoist CHIBAUDEL, MD

Frédéric THUILLIER, MD

Clélia COUTZAC, MD

Christelle DE LA FOUCHARDIERE, MD

Christophe LOCHER, MD

Ludovic EVESQUE, MD

Thomas APARICIO, MD

Emilie SOULARUE, MD

David TOUGERON, MD

Olivier BOUCHE, MD

Géraldine PERKINS, MD

David SEFRIOUI, MD

Anaïs BODERE, MD

Meher BEN ABDELGHANI, MD

Romain CHAUTARD, MD

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.

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.

The COBRAF study was designed as a prospective, multicenter, study. The study is without a therapeutic intervention and is of minimal risk and constraints (category 2 according to the "Loi Jardé"). The study will be conducted in patients with mCRC harboring a BRAFV600E mutation.

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

A Study to Collect Patients, Medical, and Biological Data From Patients Being Treated for Metastatic Colorectal Cancer With a Specific Genetic Mutation: BRAFV600E

Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Pierre Fabre Medicament

UNICANCER

Pembrolizumab

Immune Checkpoint Inhibitors

Participants receive encorafenib orally + cetuximab IV + pembrolizumab IV.

Encorafenib

Pfizer CT.gov Call Center

The purpose of this study is to learn about the effects of three study medicines (encorafenib, cetuximab, and pembrolizumab) given together for the treatment of colorectal cancer that:

* is metastatic (spread to other parts of the body);
* has the condition of genetic hypermutability (tendency to mutation) or impaired DNA mismatch repair (MMR)
* has a certain type of abnormal gene called "BRAF" and;
* has not received prior treatment.

All participants in this study will receive pembrolizumab at the study clinic as an intravenous (IV) infusion (given directly into a vein) at the study clinic.

In addition, half of the participants will take encorafenib by mouth at home every day and cetuximab by IV infusion at the study clinic.

The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.

This is an open-label, multicenter study of encorafenib and cetuximab plus pembrolizumab (Triplet Arm \[Arm A\]) versus pembrolizumab alone (Control Arm \[Arm B\]) as first-line treatment in participants with BRAF inhibitor (BRAF) V600E-mutant and microsatellite instability-high/ deficient mismatch repair (MSI-H/dMMR) mCRC. Randomization will be stratified by ECOG (0 vs 1)

A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic Colorectal Cancer

A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF ENCORAFENIB AND CETUXIMAB PLUS PEMBROLIZUMAB VERSUS PEMBROLIZUMAB ALONE IN PARTICIPANTS WITH PREVIOUSLY UNTREATED BRAF V600E-MUTANT, MSI H/DMMR METASTATIC COLORECTAL CANCER

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

PFS per investigator, defined as the time from randomization until PD based on investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first:

Incidence and severity of AEs graded according to the NCI CTCAE v4.03: encorafenib and cetuximab + pembrolizumab (Arm A) vs pembrolizumab (Arm B)

OS is defined as the time from the date of randomization to the date of death due to any cause: encorafenib and cetuximab + pembrolizumab (Arm A) vs pembrolizumab (Arm B)

OR is defined as a CR or PR per RECIST version 1.1 recorded from the date of randomization until date of first documentation of PD, death, or start of new anti-cancer therapy: encorafenib and cetuximab + pembrolizumab (Arm A) vs pembrolizumab (Arm B)

Merck KGaA, Darmstadt, Germany

Eli Lilly and Company

Pfizer

All BRAFV600E mutant patients having initiated a first-line treatment for mCRC between 01 January, 2016 and 31 December, 2018 (both days inclusive) with drugs registered for mCRC in respective country

Non Interventional study

Bernard Asselain, MD, PhD

Dirk Arnold, MD, PhD

Erika Martinelli, MD, PhD

The presence of a BRAFV600E mutation is considered a marker of poor prognosis in patients with mCRC, and findings from clinical trials have largely remained inconclusive regarding the efficacy of first line treatments for BRAF-mutant mCRC patients. In the absence of targeted/specific treatment for BRAF-mutant mCRC, treatment practices can vary based on local practices and guidelines. There is, therefore, an unmet need to document the current practices for first-line treatment of BRAF-mutant mCRC, and their effectiveness and safety in a real-world setting.

This real-world, multicenter non-interventional study (NIS) will describe the treatment patterns, effectiveness and safety of current treatment regimens in BRAFV600E mutant mCRC patients in Europe, with the aim to put the clinical study findings of the ongoing Phase 2, single-arm, open label trial (ANCHOR) into context of the current treatment landscape excluding investigational therapies. Additionally, the NIS output may be used to support future health technology assessment submissions and publications.

This retrospective, multi-center longitudinal study on BRAFV600E mutant mCRC patients will be conducted in Europe to characterize the first-line treatment patterns. All BRAFV600E mutant patients having initiated a first-line treatment for mCRC between January 1st, 2016 and December 31st, 2018 (both days inclusive) with drugs registered for mCRC in respective country will be eligible to participate. The study will not provide or recommend any treatment or procedure; all decisions regarding treatment are made at the sole discretion of the treating physician in accordance with their usual practices and all eligible patients will be considered for enrollment.

The target countries for patient enrollment will include Germany, France, Italy, United Kingdom, Spain, Belgium, Austria and the Netherlands. Approximately 300 adult patients (≥18 years) from a mix of academic and non-academic sites (up to 65 sites) will be enrolled.

A Retrospective Non Interventional Study on First Line Treatment for Patients With BRAFV600E Mutant Metastatic Colorectal Cancer (mCRC)

Agent or combination of agents received, Duration of treatment, Maintenance therapy (if any)

Description of the demographic and clinical profile of patients at the time of treatment initiation (for mCRC)

the length of time between initiation of first-line treatment for mCRC and the first documented disease progression

length of time between first-line treatment initiation (for mCRC) and death (due to any cause)

number of complete response (CR) or partial response (PR)

the length of time between initiation of first-line treatment for mCRC and documented disease progression (or start of subsequent Line Of Treatment (LOT), if disease progression is not well documented in patient medical record), treatment discontinuation or switch to another treatment (defined as change from one treatment regimen to another treatment regimen, e.g., change from FOLFOX-based regimen to FOLFIRI or irinotecan-based regimen)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer	NCT05706779	Colorectal Canc... BRAF V600E Muta...	Encorafenib Ora...	18 Years -	Federation Francophone de Cancerologie Digestive
A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer	NCT05639413	Metastatic Colo... BRAF V600E Muta...	Collection of b...	18 Years -	UNICANCER
A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic Colorectal Cancer	NCT05217446	Metastatic Colo...	Encorafenib Cetuximab Pembrolizumab	16 Years -	Pfizer
A Retrospective Non Interventional Study on First Line Treatment for Patients With BRAFV600E Mutant Metastatic Colorectal Cancer (mCRC)	NCT04317599	BRAF V600E Muta... Metastatic Colo...	Non Interventio...	18 Years -	Pierre Fabre Medicament
Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer	NCT05706779	Colorectal Canc... BRAF V600E Muta...	Encorafenib Ora...	18 Years -	Federation Francophone de Cancerologie Digestive
A Retrospective Non Interventional Study on First Line Treatment for Patients With BRAFV600E Mutant Metastatic Colorectal Cancer (mCRC)	NCT04317599	BRAF V600E Muta... Metastatic Colo...	Non Interventio...	18 Years -	Pierre Fabre Medicament
A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer	NCT05639413	Metastatic Colo... BRAF V600E Muta...	Collection of b...	18 Years -	UNICANCER
A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic Colorectal Cancer	NCT05217446	Metastatic Colo...	Encorafenib Cetuximab Pembrolizumab	16 Years -	Pfizer
A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic Colorectal Cancer	NCT05217446	Metastatic Colo...	Encorafenib Cetuximab Pembrolizumab	16 Years -	Pfizer

Spots Global Cancer Trial Database for braf v600e mutation positive