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

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ClinicalTrials.gov Identifier: NCT04759846
Recruitment Status : Not yet recruiting
First Posted : February 18, 2021
Last Update Posted : September 16, 2021
Sponsor:
Information provided by (Responsible Party):
Pierre Fabre Medicament

Study Description
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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).


Condition or disease Intervention/treatment Phase
BRAF V600 Mutation Unresectable Melanoma Metastatic Melanoma Hepatic Impairment Drug: Encorafenib + Binimetinib Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Participants with hepatic impairment will be enrolled sequentially according to their severity.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open Label, Phase I Study to Evaluate Impact of Moderate and Severe Hepatic Impairment on the Pharmacokinetics and Safety of Encorafenib in Combination With Binimetinib in Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma
Estimated Study Start Date : October 30, 2021
Estimated Primary Completion Date : March 2024
Estimated Study Completion Date : April 2024

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Group with normal hepatic function
Normal hepatic function
 Drug: Encorafenib + Binimetinib
The doses administered to patients with normal hepatic function will be the same as the recommended commercialised doses
Other Name: Braftovi + Mektovi
Experimental: Group with moderate hepatic impairment
Moderate hepatic impairment (Child-Pugh Class B)
 Drug: Encorafenib + Binimetinib
A smaller dose than the dose approved for patients with normal hepatic function has been defined
Other Name: Braftovi + Mektovi
Experimental: Group with severe impairment
Severe impairment (Child-Pugh Class C)
 Drug: Encorafenib + Binimetinib
A smaller dose than the dose approved for patients with normal hepatic function has been defined
Other Name: Braftovi + Mektovi


Outcome Measures
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Primary Outcome Measures :
  1. Encorafenib Cmax [ Time Frame: Day 1 and Day 15: 0-8 hours post-dose ]
    Maximum Observed Plasma Concentration of encorafenib expressed as total and unbound concentrations

  2. Encorafenib AUClast [ Time Frame: 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

  3. Encorafenib AUC(0-inf) [ Time Frame: 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


Secondary Outcome Measures :
  1. Tmax [ Time Frame: 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)

  2. Cmin [ Time Frame: Day 15: 0-8 hours post-dose ]
    Minimum Observed Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032) expressed as total and unbound concentrations

  3. T1/2 [ Time Frame: Day 1 and Day 15: 0-8 hours post-dose ]
    Terminal Phase Plasma Half-life of encorafenib and binimetinib and their metabolite

  4. CL/F [ Time Frame: 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

  5. Vz/F [ Time Frame: 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

  6. MRCmax [ Time Frame: Day 1: 0-8 hours post-dose ]
    Metabolic Ratio of Cmax of LHY746 to Cmax of encorafenib, Metabolic Ratio of Cmax of AR00426032 to Cmax of binimetinib Corrected for Molecular Weights

  7. MRAUC [ Time Frame: Day 1: 0-8 hours post-dose. AUC will be AUC(0-inf) and/or AUClast depending on evaluability of AUC(0-inf). ]
    Metabolic Ratio of AUC of LHY746 to AUC of encorafenib, Metabolic Ratio of AUC of AR00426032 to AUC of binimetinib Corrected for Molecular Weights


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically/cytologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma
  2. Presence of BRAF V600E or V600K mutation
  3. ECOG PS of 0 or 1
  4. Adequate bone marrow, organ function and laboratory parameters

  5. Hepatic function criteria:

    • Group with normal hepatic function
    • Group with moderate hepatic impairment (Child-Pugh Class B)
    • Group with severe impairment (Child-Pugh Class C)

Exclusion Criteria:

  1. A calculated Child-Pugh score that showed impairment for a reason other than liver dysfunction (e.g., cancer cachexia)
  2. History or symptoms of encephalopathy (Grade II or worse)
  3. Clinical evidence of severe ascites
  4. History of surgical portosystemic shunt with complications
  5. Active bleeding during the last 28 days prior to the first dose of study treatment
  6. Anticoagulant therapy
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04759846


Contacts
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Contact: Asmaa Boudribila +33 5 34 50 60 98 asmaa.boudribila@pierre-fabre.com
Contact: Amandine Laurans +33 5 34 50 62 04 amandine.laurans@pierre-fabre.com

Locations
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Czechia
Fakultni nemocnice Olomouc
Olomouc, Czechia, 77900
Contact: Pavla Pickova    +420 588 443 895    pavla.pickova@fnol.cz   
Principal Investigator: Bohuslav Melichar         
Fakultni Nemocnice Kralovske Vinohrady
Praha, Czechia, 10034
Contact: Barbora Roudnicka    +420 267 162 633    roudnickakh@gmail.com   
Principal Investigator: Petr Arenberger         
Italy
Irccs Irst
Meldola, Italy, 47014
Contact: Flavia Pagan    +39 0543 739423    flavia.pagan@irst.emr.it   
Contact: Giorgia Gentili    +39 0543 739423    giorgia.gentili@irst.emr.it   
Principal Investigator: Massimo Guidoboni         
Azienda Ospedaliero
Siena, Italy, 53100
Contact: Elisa Ibba    +39 0577 586056    elisa.ibba@ao-sienatoscana.it   
Principal Investigator: Michele Maio         
Spain
Hospital Universitario Virgen Macarena
Sevilla, Spain, 41009
Contact: Maria Candon    +34 600162731    mariacandon.oncomacarena@gmail.com   
Principal Investigator: Luis De La Cruz         
Hospital General de Valencia
Valencia, Spain, 46014
Contact: Iris Ramos    0034963131800 ext 437635    ramos_iri@gva.es   
Contact: Vicente Castellano    0034963187527    castellano_vic@gva.es   
Principal Investigator: Alfonso Berrocal         
Sponsors and Collaborators
Pierre Fabre Medicament
Investigators
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Principal Investigator: Petr Arenberger Fakultni Nemocnice Kralovske Vinohrady, Czech Republic
More Information
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Responsible Party: Pierre Fabre Medicament
ClinicalTrials.gov Identifier: NCT04759846    
Other Study ID Numbers: W00090GE101
First Posted: February 18, 2021    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Melanoma
Liver Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
 Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Digestive System Diseases