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VASCular Impact of Angiogenic Treatment in Patients With Advanced Colorectal Cancer

Study Purpose

Antiangiogenic treatments are used in many tumor locations such as metastatic colorectal cancer (mCRC) with a significant improvement in carcinological results on overall survival and / or progression-free survival. However, their use is characterized by an increase in side effects and in particular cardiovascular effects such as high blood pressure (hypertension). One of the main classes of antiangiogens used in this indication is that of monoclonal antibodies, the leader of which is bevacizumab (Avastin®, Roche, Bale, Switzerland). Bevacizumab works by inhibiting endothelial vascular growth factor-dependent neoangiogenesis (vascular endothelial growth factor VEGF). In the reference studies, the inhibition of VEGF, whether extracellular (monoclonal antibody directed against VEGFA) or intracellular (receptor inhibitors with tyrosine kinase activity), induces hypertension of all grades, observed in 25% to 40 % of patients including 8 to 17% of severe grades (≥ grade 3 NCI-CTCAE). In terms of pathophysiology, inhibition of VEGFA results in a decrease in the availability of nitric oxide (NO) at the endothelial level and the appearance of arteriolar rarefaction. This induces an increase in peripheral resistance responsible ultimately for an increase in blood pressure. The occurrence of hypertension induced by anti-VEGF treatment seems to be predictive of the carcinological response in certain oncological situations such as metastatic breast cancer9, glioblastoma and mRCC. Furthermore, it has also been shown that there is an early attack on the elastic conductance arteries (branches of the aorta and its main ones) characterized by an increase in their rigidity in patients exposed to a VEGF receptor inhibitor with tyrosine activity. kinase or bevacizumab. This increase, whose poor prognostic impact is known at the cardiovascular level is largely independent of the rise in blood pressure and reflects a direct toxicity of treatments at the level of the artery wall. This increase in rigidity, refused when the pressure rises, would be predictive of a low carcinological response rate at 6 months. However, these data are based on populations that are heterogeneous in terms of carcinology and the position prior to or concomitant with other antineoplastic treatments. In this context, the evaluation of arterial stiffness in the same patient population would make it possible to better define the involvement of the conductive arteries in a clearly defined clinical situation. Joint measurements of the plasma concentration of the treatment as well as those of factors derived from the endothelium and circulating tumor markers which, to our knowledge, have never been carried out in these patients, would make it possible to better specify the mechanisms of involvement and the links between exposure, arterial toxicity and carcinologic efficacy of bevacizumab. Of course, in order to assess more precisely the inherent impact of chemotherapy on the conductance arteries, the evolution of arterial stiffness must take into account the possible effects in patients receiving, for essentially clinical and biological reasons, systemic treatment without antiangiogenic.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- Patient at least 18 years old, - Patient with colorectal cancer of the adenocarcinoma type, stage IV, histologically confirmed, mutated or wild tumor RAS status (exons 2, 3 and 4 of the KRAS and NRAS genes), mutated or wild BRAF status, naive in antineoplastic treatment.

- Patient eligible to start systemic carcinological treatment including bevacizumab in combination with chemotherapy based on IV fluoropyrimidine, - General condition WHO grade less than or equal to 3, - Life expectancy greater than 4 months, - Patient who has read and understood the information letter and signed the consent form, - Patient affiliated to a social security scheme, - Effective contraception (see WHO definition) in women of childbearing age (negative pregnancy test).

For postmenopausal women, a confirmatory diagnosis should be obtained (amenorrhea not medically induced for at least 12 months before the inclusion visit).

Exclusion Criteria:

- Previous exposure to anti-VEGF, - Exposure to treatment for metastatic disease in the 12 months prior to inclusion, - Other histologically proven neoplasia not considered in complete remission or considered in complete remission for less than two years, - Bilateral carotid breath, - Absence of peripheral pulse of the two upper limbs, - Contraindication to AVASTIN 25 mg / ml concentrate for solution for infusion: - Hypersensitivity to the active substance or to any of the excipients, - Hypersensitivity to Chinese hamster ovarian cell products or other human or humanized recombinant antibodies, - Patients: - having undergone a major surgical intervention in the 28 days preceding the inclusion or as long as the surgical wound is not completely healed, - Unhealed ulcer or wound, - having uncontrolled pre-existing hypertension (PAS> or = 170 mm Hg after three repeated measurements at rest), - having a history of arterial thromboembolism (transient ischemic attack (TIA), cardiovascular accident (stroke) or recent (<6 months) and / or symptomatic myocardial infarction (MI) - having had an invasive dental procedure in the 28 days preceding inclusion, - with known proteinuria> 2g / 24h or in whom proteinuria> 2g / 24h is discovered in the case of a positive urine strip 3+ for proteins (excluding urinary tract infection), - on aspirin> 325 mg / d, - with a colonic prosthesis in place, - Systemic treatment with anti-EGFR monoclonal antibodies, - Presence or history of lymphedema of the bilateral upper limbs, - Patient with poor understanding of spoken or written French, - Patient deprived of liberty by an administrative or judicial decision or patient placed under the protection of justice, under guardianship or curatorship, - Pregnant or lactating woman or wishing to breastfeed within 6 months after the last administration of the treatment, - Patient participating in another drug trial / having participated in another drug trial within 30 days of inclusion, - History of illness or psychological or sensory abnormality likely to prevent the subject from fully understanding the conditions required for his participation

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04813913
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 4
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University Hospital, Rouen
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Unknown status
Countries	France
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Oncology

Arms & Interventions

Arms

Experimental: bevacizumab

bevacizumab in combination with IV fluoropyrimidine chemotherapy.

Interventions

Drug: - Bevacizumab in combination with chemotherapy based on fluoropyrimidine IV

Enrollement of major patient with colorectal cancer of the adenocarcinoma type, stage IV, histologically confirmed, naive in antineoplastic treatment and eligible to start a systemic carcinological treatment comprising bevacizumab in combination with chemotherapy based on fluoropyrimidine IV. The main objective is to show that there is an increase in the stiffness of the carotid artery at 4 months in patients with stage IV colorectal cancer exposed to bevacizumab.

Contact a Trial Team

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International Sites

CHU de ROUEN, Rouen, France

Status

Recruiting

Address

CHU de ROUEN

Rouen, ,

Site Contact

Maxime FONTANILLES

[email protected]

02 32 88 56 34

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