Hepatic Impairment Study of Encorafenib in Combination With Binimetinib in BRAF Melanoma

Phase 1

Withdrawn

• Conditions: Unresectable Melanoma; Hepatic Impairment; BRAF V600 Mutation; Metastatic Melanoma
• Interventions: Drug: Encorafenib + Binimetinib

• Registration Number: NCT04759846
• Lead Sponsor: Pierre Fabre Medicament

Brief Summary

Encorafenib in combination with binimetinib have been approved in USA, Europe, Australia, Japan and Switzerland for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600 mutation.

The main objective of this study is to find a safe and effective dose of encorafenib in combination with binimetinib for patients who have BRAF-mutant metastatic or unresectable melanoma with hepatic dysfunction (i.e. moderate or severe impairment).

Detailed Description

This is an open label, multicentre, phase I study to evaluate the impact of moderate and severe hepatic impairment (HI) on the pharmacokinetics and safety of encorafenib in combination with binimetinib, in adult patients with unresectable or metastatic BRAF V600-mutant melanoma.

For each participant, the treatment period will be split in 2 phases:

* a HI assessment phase assessing the impact of hepatic impairment after a single dose (Day 1) and after repeated doses (Day 15).

* a post-HI assessment phase: after completing the HI assessment phase, participants may continue treatment in the post-HI assessment phase until disease progression or unacceptable toxicity.

Participants with hepatic impairment will be enrolled sequentially according to their severity. The study will start first in participants with normal hepatic function and moderate hepatic impairment respectively.

Participants will be assigned to one of the following 3 study groups:

* Group with normal hepatic function: 4 participants

* Group with moderate hepatic impairment (Child-Pugh Class B): 4 participants

* Group with severe impairment (Child-Pugh Class C): 4 participants

An Internal Review Committee (IRC) will review the safety and PK data of encorafenib in combination with binimetinib for group with normal hepatic function and group with moderate hepatic impairment and make a recommendation prior to start group with severe impairment enrolment. The Sponsor will determine whether it is safe and feasible to proceed with group with severe impairment.

Participants will receive treatment doses according to their assigned group.

Study Timeline

• Study First Submitted: 2020-12-21
• Study Start: 2021-01-21
• Study First Submitted QC: 2021-02-15
• Study First Posted: 2021-02-18
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-17
• Last Update Posted: 2023-02-21
• Primary Completion: 2023-05
• Study Completion: 2023-05

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group with moderate hepatic impairment	Encorafenib + Binimetinib	Moderate hepatic impairment (Child-Pugh Class B)
Group with normal hepatic function	Encorafenib + Binimetinib	Normal hepatic function
Group with severe impairment	Encorafenib + Binimetinib	Severe impairment (Child-Pugh Class C)

Primary Outcome Measures

Name	Time	Method
Encorafenib Cmax	Day 1 and Day 15: 0-8 hours post-dose	Maximum Observed Plasma Concentration of encorafenib expressed as total and unbound concentrations
Encorafenib AUC(0-inf)	Day 1 and Day 15: 0-8 hours post-dose	Area Under the Plasma Concentration versus Time Curve from Time 0 to Infinity of encorafenib expressed as total and unbound concentrations
Encorafenib AUClast	Day 1 and Day 15: 0-8 hours post-dose	Area Under the Plasma Concentration versus Time Curve from Time 0 to Time of Last Quantifiable Concentration of encorafenib expressed as total and unbound concentrations

Secondary Outcome Measures

Name	Time	Method
Tmax	Day 1 and Day 15: 0-8 hours post-dose	Time to Reach Maximum Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032)
MRCmax	Derived on Day1 and Day15	Metabolic Ratio of Cmax of LHY746 to Cmax of encorafenib, Metabolic Ratio of Cmax of AR00426032 to Cmax of binimetinib Corrected for Molecular Weights
Cmin	Derived on Day1 and Day15	Minimum Observed Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032) expressed as total and unbound concentrations
CL/F	Day 1 and Day 15: 0-8 hours post-dose	Apparent Total Body Clearance of encorafenib and binimetinib and their metabolites as total and unbound concentrations
T1/2	Day 1 and Day 15: 0-8 hours post-dose	Terminal Phase Plasma Half-life of encorafenib and binimetinib and their metabolite
Vz/F	Day 1 and Day 15: 0-8 hours post-dose	Apparent Volume of Distribution at Terminal Phase of encorafenib and binimetinib and their metabolites as total and unbound concentrations
MRAUC	Derived on Day1 and Day15	Metabolic Ratio of AUC of LHY746 to AUC of encorafenib, Metabolic Ratio of AUC of AR00426032 to AUC of binimetinib Corrected for Molecular Weights

Trial Locations

Locations (7)

Fakultni nemocnice Olomouc; 🇨🇿 Olomouc, Czechia

Fakultni Nemocnice Kralovske Vinohrady; 🇨🇿 Praha, Czechia

all D'Hebron Insitute of Oncology; 🇪🇸 Barcelona, Spain

Hospital Universitario Virgen Macarena; 🇪🇸 Sevilla, Spain

Hospital General de Valencia; 🇪🇸 Valencia, Spain

Irccs Irst; 🇮🇹 Meldola, Italy

Azienda Ospedaliero; 🇮🇹 Siena, Italy