Etude : CONVERCE /



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Acronyme
Nom
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme : CONVERCE

Nom :

Traitement : Métastasique ou localement avancé

Type d'étude : Ciblage moléculaire / Innovation thérapeutique

Dernière MÀJ : 30/07/2019
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : Étude de phase 2, évaluant l’efficacité et la tolérance d’un traitement associant cobimetinib et vémurafénib, chez des patients ayant des métastases cérébrales d'un mélanome cutané avec mutation BRAF V600.

Spécialité : Peau
Localisation : C43 - Mélanome malin de la peau
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : Les patients sont inclus dans 3 cohortes :
- Cohorte A. Les patients neurologiquement asymptomatiques et non traités localement.
- Cohorte B. Les patients neurologiquement asymptomatiques et prétraités localement.
- Cohorte C. Les patients neurologiquement symptomatiques, prétraités localement ou non.

Les patients reçoivent à chaque cure de 28 jours du vémurafénib PO 2 fois par jour de J1 à J28 en continu et du cobimétinib PO 1 fois par jour de J1 à J21, jusqu’à progression de la maladie ou toxicité inacceptable. Si les patients peuvent tirer un bénéfice à la poursuite du traitement, ils peuvent continuer la prise de vémurafénib et de cobimétinib après accord du coordonnateur de l’étude.

Pendant le traitement, les patients sont suivis au cours d’examens cliniques, dermatologiques, ophtalmologiques, neurologiques, cardiologiques et réalisation d’IRM et bilans biologiques.
Après le traitement, le suivi des patients est fait à 30 jours après l’arrêt du traitement et toutes les 8 semaines en cas d’arrêt pour toxicité ou toute autre raison que la progression de la maladie.

Objectif principal : Évaluer l’efficacité de l’association cobimétinib + vémurafénib chez des patients ayant un mélanome muté BRAF V600 avec des métastases cérébrales asymptomatiques préalablement non traitées (cohorte A).

Objectifs secondaires :
- Évaluer l’efficacité de l’association cobimétinib + vémurafénib chez des patients ayant un mélanome muté BRAF V600 avec des métastases cérébrales asymptomatiques préalablement traitées localement (cohorte B).
- Évaluer l’efficacité de l’association cobimétinib + vémurafénib chez des patients ayant un mélanome muté BRAF V600 avec des métastases cérébrales symptomatiques (cohorte C).
- Évaluer la tolérance de l’association cobimétinib + vémurafénib globalement pour les trois cohortes (métastases cérébrales asymptomatiques préalablement non traitées, asymptomatiques préalablement traités localement et symptomatiques).
- Étudier la pharmacocinétique par mesure de la pénétration du vémurafénib et du cobimétinib à travers la barrière hémato-encéphalique.
- Étudier la cinétique du taux de mutation BRAF comme biomarqueur prédictif de la réponse.
- Étudier la pharmacogénétique : recherche de variants génétiques prédictifs de la réponse clinique.

Phase : II

Stade : IV

1, 2, 3
Critères d'inclusion
Critères de non-inclusion
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1. Men and women ≥ 18 years of age.
2. Histologically confirmed metastatic cutaneous melanoma, mucous melanoma, or melanoma of unknown primary origin (stage IV).
3. Documented BRAFV600 mutation determined in a hospital center specializing in the molecular genetics of cancer that is certified by the French national cancer institute (INCa).
4. Presence of Brain Metastases (BM) for which surgical resection is not a reasonable treatment option but that may be amenable to treatment with targeted therapy, to be decided in the onco-dermatology and/or neuro-oncology multidisciplinary team meeting (MDTM).
5. At least one measurable BM in at least one dimension between 5 and 40 mm on magnetic resonance imaging (MRI) with gadolinium (modified RECIST 1.1).
6. Patients having previously received a maximum of two systemic therapies during the metastatic phase, except BRAF, Map ERK Kinase (MEK) or Extracellular signal Go to Regulated Kinase (ERK) inhibitors or tyrosine kinase pan-inhibitors (TKIs); prior ipilimumab therapy is allowed if patients have documented cerebral progression 12 weeks after the last injection of treatment and if MRI confirms progression at least 4 weeks later. A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
7. For patients who have received prior whole brain radiotherapy or radiosurgery and/or surgery for BM (cohorts B and C) demonstration of a significant progression of at least one lesion according to RECIST 1.1 criteria, . after at least 4 weeks have elapsed since this treatment has ended, and MRI at inclusion must demonstrate a significant progression of at least one lesion according to RECIST 1.1 criteria.
8. Patients with symptomatic or asymptomatic BM.
9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
10. Patients must have recovered from all the side effects (grade ≤ 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCICommonToxicity Criteria for Adverse Event (CTCAE), version 4.03) of their most recent systemic or local treatment (except alopecia).
11. Signed and dated informed consent before carrying out any procedures that are specific to the trial and are not procedures (examinations) conducted as part of normal patient care.
12. Patients willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other trial procedures.
13. Negative serum pregnancy test within 10 days of the first dose of the study
treatment for women of childbearing age. Women of non-childbearing potential may be included if they are surgically sterile or postmenopausal for ≥ 1 year.
14. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after the last administration of the study treatment. Effective methods of contraception are defined as those that have a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as injectable implants combined with oral contraception or intra-uterine devices, or as total abstinence in cases where the lifestyle of the patient ensures compliance.
15. Adequate hematologic, renal and hepatic function within 14 days of the
administration of treatment:
Hematologic Leucocytes > 2.0 x 109/L Neutrophils > 1.0 x 109/L Hemoglobin (transfusion allowed) > 9 g/dL Platelets > 100 x 109/L Liver Total bilirubin < 1.5 x upper limit of normal (ULN) (< 3.0 mg/dL for patients with Gilbert syndrome) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if there is liver metastasis) Alkaline phosphatase (ALP) < 3 x ULN (< 5 x ULN if there is liver or bone metastasis) Kidney Creatinine Or creatinine clearance < 1.5 x ULN ≥ 40 mL/min (Cockcroft-Gault formula)

Critères de non-inclusion : 1. Uveal melanoma. Patients with mucous melanoma or melanoma of unknown
primary origin are eligible if BRAFV600 mutation is confirmed.
2. Symptomatic or diffuse leptomeningeal involvement.
3. Symptoms of uncontrolled intracranial pressure. Increasing corticosteroid dose during the 7 days prior to the first dose of the study treatment is an exclusion criterion. Patients receiving corticosteroids and patients presenting intermittent seizures may be enrolled if the dose of corticosteroids and anti-epileptic treatments has been stable for at least 2 weeks before inclusion.
4. Indication for urgent neurosurgery or radiotherapy.
5. Prior malignancy active within the previous 3 years except for locally curable
cancers that have been treated to complete remission or untreated stage I chronic lymphoid leukemia.
6. Known human immunodeficiency virus (HIV) infection.
7. Prior treatment with BRAF, MEK, or ERK inhibitors or pan-TKIs.
8. Concurrent administration of any anticancer therapies other than those
administered in this study.
9. Treatment with any cytotoxic and/or investigational drug or targeted therapy within 4 weeks of the first dose of the study treatment, or ipilimumab, anti-PD-1 or anti-PDL1 immunotherapy within 8 weeks of the study treatment and/or radiation therapy within 2 weeks of the study treatment.
10. Pregnant or breastfeeding women.
11. Refractory nausea and vomiting, intestinal malabsorption, or significant bowel resection that would preclude adequate absorption or cause an inability to swallow tablets.
12. Ulcerative colitis, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticula or other gastrointestinal condition increasing the risk of perforation.
13. Any of the following within the 6 months prior to the first dose of study treatment:
◦ myocardial infarction,
◦ severe/unstable angina,
◦ symptomatic congestive heart failure (New York Heart Association grade ≥2),
◦ cerebrovascular accident or transient ischemic attack,
◦ pulmonary embolism,
◦ grade > 2 hypertension not controlled by medications.
14. History or presence of clinically significant ventricular or atrial arrhythmia ≥ grade 2 (NCI-CTCAE Version 4.03).
15. Corrected QT (cQT) interval ≥ 450 ms and left ventricular ejection fraction (LVEF) below the lower limit of normal (LLN) or < 50% (scintigraphy or ultrasound).
16. History, risk factor or retinal pathology that increases the risk of retinal vein
occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology that is considered a risk factor for RVO or CSR, or a history of retinal detachment, central serous chorioretinopathy or retinal vein thrombosis. The risk factors for RVO are listed below:
◦ Uncontrolled glaucoma with intraocular pressures > 21 mm Hg,
◦ Serum cholesterol ≥ Grade 2 (≥ 7.75 mmol/L),
◦ Hypertriglyceridemia ≥ Grade 2 (≥ 3.42 mmol/L),
◦ Hyperglycemia (fasting) ≥ Grade 2 (≥ 8.9 mmol/L).
17. Serious or uncontrolled medical disorders that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the patient to follow the protocol, or interfere with the interpretation of study results.
18. Patients Under guardianship or curators, maintenance of justice, non-informed about diagnosis, unable to follow study medical requirement for geographical, social or psychic reasons.
19. Patients with abnormal blood electrolyte test (Ca, Mg, K and Na) that could not be corrected.
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT02537600
Promoteur :
CENTRE EUGÈNE MARQUIS
Type de sponsor : Institutionnel
35000 RENNES

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Laurent MORTIER

TEC / ARC / IDE :
Benoît MINART
benoit.minart@
chru-lille.fr
03 20 44 64 15

Ouverture de l'essai : CLOS

MAJ : 10/04/2019