Our study focuses on adult patients with BRAFV600-mutant metastatic melanoma treated with
encorafenib and binimetinib, or encorafenib alone (regardless of treatment line).
Encorafenib and binimetinib are BRAF and MEK inhibitors, respectively. They constitute a
combination of oral targeted therapies, with marketing authorization since 2018 in
metastatic melanoma in patients with BRAFV600-mutated melanoma, in first-line treatment
or after progression on immunotherapy.
It is taken orally, at an initial dose of :
- - 450 mg (six 75 mg capsules) once daily for encorafenib ;
- 45 mg (3 x 15 mg tablets) twice daily, 12 hours apart, for a total daily dose of 90
mg.
5 recruiting centers (APHP): Hôpital Ambroise Paré (Boulogne-Billancourt), Hôpital
Avicenne (Bobigny), Hôpital Cochin (Paris 14), Hôpital Henri Mondor (Créteil) and
Hôpital Bichat (Paris 18).
For the purposes of this research, subjects will be identified as follows:
center no. (3 numeric positions)
- - person selection order no.
in center (4 numeric
positions)
- - initial surname - initial first name This reference is unique and will be
kept for the duration of the research.
Patients will be recruited from the dermatology departments of 5 recruiting centers.The
investigator, a dermatologist, will inform the patient at the time of his or her usual
follow-up in the context of melanoma care. Notice of participation in the research will
be collected and transcribed into the patient's medical record. The present protocol does
not interfere with patients' medical management of their melanoma-related pathology.
Eligible patients will be invited to take part in the study by the investigating
physician during a follow-up visit in HDJ or a specific follow-up consultation for their
melanoma. During the visit, the investigating physician will inform eligible patients
about the study and answer any questions they may have about its purpose, constraints,
foreseeable risks and expected benefits. After reading the information letter and taking
some time to think about it, the doctor will obtain the patient's opinion from and an
additional 20 ml blood sample will be taken. Temporality :
- - Determination of plasma concentrations of immune checkpoint inhibitor antibodies: D0
and M1 if treated with checkpoint inhibitors within the last 6 months
(pembrolizumab, nivolumab, ipilimumab).
- - Measurement of encorafenib-binimetinib plasma concentrations: M1, M2, M4 or M1, M3
of combotherapy initiation, depending on the center, then after 6 months of
treatment every 2 to 3 months and at the time of progression (if not on the day of a
re-evaluation HDJ when sampling is already planned) or of a severe toxic episode for
which the patient consults, for 1 year.
NB: The patient can be sampled at any time
between two doses. Encorafenib must be taken in the evening (to avoid skipping doses
on the morning of sampling).
- - Essential information on the sampling sheet: dose, date and time of last dose for
each drug, date and time of sampling.
- - Detection of circulating tumor DNA: D0, M1, M2 then every 2 or 3 months for 1 year,
only if performed as part of routine care.
Sampling and transport methods:
- - Determination of checkpoint inhibitor antibody concentrations: 1 x 5ml tube sent to
UF Biologie du Médicament-Toxicologie at Cochin for all centers except Bichat (sent
to Saint Louis)
- Determination of encorafenib-binimetinib concentrations :
- for patients at Ambroise-Paré hospital: 1 x 5 ml tube sent to the pharmacology
laboratory at Raymond Poincaré hospital (Pr JC Alvarez)
- for patients at Hôpital Bichat: 1 x 5 ml tube sent to the pharmacology laboratory at
Hôpital Saint Louis.
- - for patients from the 3 other centers: 1 x 5 ml tube sent to the UF Biologie du
Médicament-Toxicologie at Hôpital Cochin.
- - Detection of circulating tumor DNA (only if performed as part of routine care) :
- for patients at Ambroise-Paré Hospital: 1 x 10-ml EDTA tube sent to Pr Jean-François
Emile in molecular biology at Ambroise-Paré Hospital.
- - for patients at Avicenne Hospital: 1 x 10 ml EDTA tube sent to Pr Schischmanoff and
Dr Fabre in molecular biology at Avicenne Hospital.
- - for patients at Hôpital Bichat: 1 x 10 ml EDTA tube sent to Pr ANNE COUVELARD in
molecular biology at Hôpital Bichat.
- - for patients from the 2 other centers (Hôpital Cochin and Hôpital Mondor): 1 x 5 ml
cell-free DNA tube sent to the anatomopathology and molecular biology laboratory at
Hôpital Européen Georges Pompidou.
Essential information on the sampling sheet: dose, date and time of last dose for each
drug, date and time of sampling.
Dosage methods :
- - Determination of plasma drug concentrations by liquid chromatography-mass
spectrometry (LC-MS/MS)
- Detection of circulating tumor DNA (BRAFV600 allele) in peripheral blood by digital
droplet PCR (15)
Dosing centers :
- Pharmacology laboratories (drug dosage) :
- Hôpital Cochin and Hôpital Saint Louis: encorafenib, binimetinib,
pembrolizumab, nivolumab, ipilimumab.
- - Raymond Poincaré Hospital: encorafenib, binimetinib.
- - Pathology and molecular biology laboratories (detection of circulating tumor DNA):
- Ambroise Paré Hospital.
- - Georges Pompidou European Hospital.
- - Bichat Hospital Tubes transferred by sorting centers according to standard
procedure.
Bayesian estimation of residual concentrations (Cmin ) and total
exposure (AUC) between two intakes using a KP/POP model.
To this end, the investigators will build two population pharmacokinetic models to
explore the factors of variability in the pharmacokinetics of encorafenib and
binimetinib. Based on these models, residual concentrations of each molecule will be
estimated to explore the PK/PD relationship of encorafenib and binimetinib. The
methodology used to build the models will be based on recommendations in the literature
(16) At the end of the research, the samples will be destroyed. Follow-up of the
population will follow the rhythm of visits scheduled as part of the usual care of
patients with melanoma undergoing targeted therapy. the investigators plan a sampling
period of 1 year, and a clinical follow-up period of 2 years for each patient from
inclusion. Finally, the investigators plan a 1-year period for data analysis and article
writing Clinical and biological data are collected at each visit for 2 years. An
additional 20-ml blood sample (3 tubes with EDTA) is taken in the first year. Sampling
and transport procedures are identical to those for the inclusion visit.
Non-interventional research involving the human body poses no risk to patients. Adverse
reactions observed in patients taking part in research are reported by investigators in
accordance with local vigilance plans set up as part of their care activities.
The data corresponding to the various clinical and biological examinations will be
completed by Dr Sarah Bouchereau in the RedCap database from the medical record and the
analysis results retrieved from the laboratories.
Questionnaire data will be entered directly into the RedCap database by Dr Bouchereau.
Patient anonymity will be ensured, in accordance with the AP-HP promoter's procedure, by
a reference in the form of a center code (3 digits), a center inclusion number (4 digits)
and the initials (one letter for the surname and one letter for the first name) of the
person taking part in the research on all documents required for the research.
Access to e-CRF via the Internet will be secured by a username and password, and data
flow will be encrypted using the https protocol.
Clinical data from each center will be collected in order to gather the following data
from medical records (CRH, CR de consultation) sent to Pr Elisa Funck-Brentano, Dr Sarah
Bouchereau and Benoit Blanchet.
The data will be recorded by each investigator in the patient's file during the usual
follow-up consultations. Sarah Bouchereau, Elisa Funck-Brentano and Benoit Blanchet, who
will have been notified of each letter (via ORBIS, mssanté secure messaging system), will
then transfer these data, which will be considered as source data, directly into the RED
Cap anonymized e-CRFs.
Self-questionnaires completed by patients will be kept in the study binder.
In accordance with GCP :
- - the sponsor is responsible for obtaining the agreement of all parties involved in
the research to guarantee direct access to all research sites, source data, source
documents and reports for quality control and audit purposes by the sponsor,
- investigators will make available to those responsible for monitoring and quality
control, in the event of an audit of research involving the human person, the
documents and individual data strictly necessary for this control, in accordance
with the legislative and regulatory provisions in force Source documents, defined as
any original document or object that can be used to prove the existence or accuracy
of data or facts recorded during the course of research, will be kept for 15 years
by the investigator, or by the hospital in the case of hospital medical records.
Those responsible for quality control in research involving the human body (article
L.1121-3 of the French Public Health Code), will take all necessary precautions to ensure
the confidentiality of information relating to the research, to the persons involved, and
in particular to their identity, and to the results obtained.
These people, like the investigators themselves, are bound by professional secrecy.
During and at the end of research involving the human person, data collected on subjects
and transmitted to the sponsor by the investigators (or any other specialist) will be
rendered non-identifying.
Under no circumstances may the names or addresses of the persons concerned appear in
plain text.
Only the initials of the surname and first name will be recorded, together with a coded
number specific to the research indicating the order of inclusion of subjects.
The sponsor will ensure that each person taking part in the research has given his or her
consent for access to individual data concerning him or her and strictly necessary for
the quality control of the research.
Identification of the person in charge and the location of data entry and processing
management Sarah Bouchereau will enter the non-identifying data of all patients on a
CRF-type paper medium, then transfer it to an Excel-type digital data collection table.
Statistical analysis will be carried out by the investigating team. Based on data from
the Columbus Phase 3 trial (14)the rate of discontinuation due to toxicity was 6% in the
(encorafenib/binimetinib) arm, and 48% of patients had their dose reduced.
Given that DLT (treatment discontinuation or dose reduction) is our primary endpoint, the
investigators considered a frequency of DLT occurrence of 50% in our study.
Furthermore, the investigators hypothesize that the 25% of patients with the highest
encorafenib exposure (quartile 4, Q4) will more frequently present with DLT than patients
with plasma exposures within Q1-Q3 (80% vs.#46; 40%, respectively). Thus, with a two-sided
α-risk of 5% and power of 80%, 59 patients will need to be included in the study to
confirm our hypothesis. the investigators therefore plan to include 66 patients in order
to take into account 10% of potential los de vus.
Population analyzed: all patients meeting inclusion and exclusion criteria will be
analyzed.Rules for handling missing data: missing data will not be taken into account.
Definitions :
- - Dose-limiting toxicity: occurrence of toxicity requiring discontinuation of
encorafenib and/or binimetinib AND/OR reduction in dose by one dose level within the
first 6 months of treatment .
- - Progression-free survival (PFS) will be calculated from the date of D1 of
encorafenib/binimetinib to the date of diagnosis of progression (according to RECIST
criteria) 16 or the date of last news if the date of progression is unknown .
- - Overall survival (OS) will be calculated from the date of D1 of
encorafenib/binimetinib until the date of death or the date of last news if the date
of death is not known.
General statistical approach for exposure-response analysis :
- - Descriptive study of primary endpoints.
- - Group comparison (Q1-3 vs.#46;Q4) with Chi2 or Fisher test for qualitative variables and
Wilcoxon test for quantitative values.
- - Logistic regression for factors predictive (including AUC and Cmin for each
molecule) of the occurrence of dose-limiting toxicity.
Factors associated with the
occurrence of dose-limiting toxicity with a p-value < 0.1 in univariate analysis
will be included in a multivariate model.
- - Cox model for prognostic factors (including mean AUC and Cmin over the first 3
months for each molecule) for PFS and OS.
Factors associated with progression or
death with a p-value < 0.1 in univariate analysis will be included in a multivariate
model.
The aim is to have no missing data for the main evaluation criterion. For other
variables, missing data may be determined by imputation if their proportion does not
exceed 10%.
Data quality control for statistical analyses consists in checking that the data in the
observation books are complete, consistent and plausible. In the event of an anomaly, the
investigator will be asked to correct it. If a verification is necessary in a source
document, it can only be carried out by a member of the medical team supervising the
subject.
The information notes, including the record of non-opposition, will be kept by the head
of the medical team supervising the subjects for a period of 15 years.
Only the initials of the surname and first name will be recorded, along with a coded
number specific to the search.
The sponsor will ensure that each person taking part in the research has not objected to
access to individual data concerning him or her and strictly necessary for the quality
control of the research.
In accordance with article L1121-1-1 of the French Public Health Code, no
non-interventional research may be carried out on a person who has objected to it after
having been provided with the information required under article L11222-1 of the same
code.
The patient is allowed a 15-day cooling-off period, no later than the day before the
inclusion visit, between the time he or she is informed and the time the investigator
signs the no-objection form. The information note is given at the screening visit.
In urgent cases, when the introduction of encorafenib and binimetinib treatment cannot be
delayed, this delay can be reduced to 2 hours in order to be able to include the patient.
This study should in no way delay treatment.
Patient information will be provided orally by the dermatologist investigator during
follow-up visits for metastatic melanoma, who will give the patient an information
document. The patient's information and non-opposition will be documented in the
patient's medical record.
A copy of the information document is given to the person prior to participation in the
research.
The information given to the subject will be recorded in his or her medical file.
The non-opposition of the subject will be recorded in his medical file by the
investigator or the qualified person who collects it.
