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BRAF V600 MutationPhase 1NCT04759846

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

A Phase 1 study testing Encorafenib + Binimetinib in people with BRAF V600 Mutation and Unresectable Melanoma, run by Pierre Fabre Medicament at 7 sites in 3 countries.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Encorafenib + Binimetinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
7 sitesin 3 countries
Study dates
21 Jan 2021to May 2023
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Participants must meet all of the following inclusion criteria to be eligible for enrolment into the study:
  • Signed written informed consent;
  • Male or female participant, aged ≥ 18 years;
  • Histologically/cytologically confirmed diagnosis of locally advanced, unresectable or metastatic solid tumors;
  • Presence of BRAF V600E or V600K mutation in tumour tissue prior to enrolment, as previously determined using a local test at any time prior to Screening - Only PCR and NGS-based local assays results will be acceptable;
  • Evidence of measurable or non-measurable lesions as detected by radiological or photographic methods according to guidelines based on Response Evaluation Criteria in solid tumors (RECIST) v. 1.1;
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  • Unresectable locally advanced or metastatic solid tumor with no prior treatment or progression on or after prior systemic therapy; Note: Prior therapy with a BRAF inhibitor is permitted except in the regimen immediately prior to study entry. Progression during prior BRAF/MEK inhibitor treatment is not required;
  • Blood pressure (BP; after 5 minutes resting in the supine position) at screening within the following ranges: systolics, 90 to 150 mm Hg, diastolic, 50 to 100 mm Hg;
  • ECOG PS of 0 or 1;
  • Adequate bone marrow, organ function and laboratory parameters:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,
  • Haemoglobin (Hgb) ≥ 9 g/dL without transfusions,
  • Platelets (PLT) ≥ 100 x 109/L without transfusions,
  • International normalized ratio (INR) < 3 at screening or baseline (Day -1),
  • Creatinine ≤ 1.5 mg/dL and calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 50 mL/min,
  • Hepatic function criteria:
  • Inclusion criteria for participant with normal hepatic function (group I) only :
  • Total bilirubin ≤1.5 upper limit of normal (ULN) at screening and baseline (Day -1)
  • Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma- glutamyl transferase, and alkaline phosphatase ≤ 1.5ULN at screening and baseline (Day -1)
  • Serum amylase <140 and lipase < 160ULN at screening and baseline (Day -1)
  • Inclusion Criteria for participants with Hepatic impairment according to Child-Pugh
  • Classification System only:
  • Group II: Child-Pugh Class B or moderate hepatic impairment (7 to 9 points),
  • Group III: Child-Pugh Class C or severe hepatic impairment (10 to 15 points),
  • Able to take oral medications
  • Deemed by the Investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up);
  • Female participant of childbearing potential must be tested negative for pregnancy at enrolment and during the study: Note: Negative serum beta-human chorionic gonadotropin (β-HCG) test (childbearing performed within 72 hours prior to first dose and consent to ongoing urine pregnancy testing during the course of the study and agreement to go on using it during the whole duration of the study and up to 1 month after last administration. Use of an effective method of contraception (hormonal contraception or intra-uterine device) assessed by the Investigator, for at least 2 months before the first study treatment administration, and agreement to go on using it in addition to condom during the whole duration of the study through 30 days after last study treatment administration.
  • Male participants with partners of childbearing potential must be either vasectomized or agree to use a condom in addition to having their partners use of an effective method of contraception. Note: For partner of male participant, contraception should be employed from the time of consent through 90 days after last study treatment administration.
  • Affiliated to a social security system, or is a beneficiary (if applicable in the national regulation)

Who cannot join

  • Participants meeting any of the following criteria are not eligible for enrolment in the study:
  • A calculated Child-Pugh score that showed impairment for a reason other than liver dysfunction (e.g., cancer, cachexia);
  • History or symptoms of encephalopathy (Grade II or worse) within 4 weeks of Day -1 or subjetcs who were treated to control encephalopathy within 4 weeks of Day -1;
  • Clinical evidence of severe ascites (NCI-CTCAE grade 3 or 4);
  • History of surgical portosystemic shunt with complications (i.e., hepatic encephalopathy, heart failure). Trans jugular intrahepatic portosystemic shunt could have been allowed if not in use for ≥1 year;
  • Active bleeding during the last 28 days prior to dosing including variceal bleeding;
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  • Anticoagulant therapy within 7 days prior to the first dose of study treatment (Day 1);
  • Any of the following:
  • Nitrosourea or mitomycin-C within 6 weeks prior to start of study treatment,
  • Other chemotherapy, radiation therapy that included > 30% of the bone, marrow reserve, or biological therapy (e.g., antibodies) within 4 weeks prior to start of study treatment,
  • Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent or within 2 weeks prior to start of study treatment, whichever is the longest,
  • Residual Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 side effects of any such therapy (residual Grade 2 alopecia is permitted),
  • Discontinuation of prior BRAF and/or MEK inhibitor treatment due to severe, intolerable toxicity including left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion, CK elevation and rhabdomyolysis, uveitis;
  • Symptomatic brain metastasis; Note: Participants previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT] demonstrating no current evidence of progressive brain metastases at screening);
  • Leptomeningeal disease;
  • Use, within 2 weeks prior to the first dose of the study treatment (Day 1)any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5;
  • Human immunodeficiency virus (HIV) infection;
  • Active viral hepatitis (HBV-HCV) within 1 month before the first dose of study treatment (Day 1);
  • Known history of acute or chronic pancreatitis;
  • Concurrent neuromuscular disorder that is associated with the potential of elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy;
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
  • Clinically significant cardiac disease including any of the following:
  • Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2),
  • Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or ECHO,
  • Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy,
  • History or presence of clinically significant ventricular arrhythmias or atrial fibrillation,
  • Clinically significant resting bradycardia,
  • Unstable angina pectoris ≤ 3 months prior to the start of study treatment,
  • Acute myocardial infarction ≤ 3 months prior to the start of study treatment,
  • Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value >480 msec,
  • Impaired gastrointestinal function or disease which may significantly alter the absorption of study treatments (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, small bowel resection);
  • History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to to starting study treatment the first dose of study treatment (Day 1);
  • Thromboembolic event (e.g. including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli) except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment (Day 1); Note: Participants with catheter-related thromboembolic events are allowed;
  • Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the participant inappropriate for the study;
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until termination of gestation, confirmed by a positive β- hCG laboratory test (> 5 mIU/mL);
  • Known hypersensitivity or contraindication to any component of study treatment or their excipients;
  • Ongoing/active participation in another interventional clinical trial;
  • Has participated in another clinical trial with the administration of an investigational product within 4 weeks, or five times the half-life of the investigational product, whichever is longer, before the first dose of study treatment (Day 1);
  • Is a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician…).

Trial locations and contacts

7 sites in 3 countries.

7 sites in 3 countries

Spain3 sites

  • all D'Hebron Insitute of Oncology

    Barcelona

  • Hospital Universitario Virgen Macarena

    Seville, 41009

  • Hospital General de Valencia

    Valencia, 46014

Other trials in Spain

Czechia2 sites

  • Fakultni nemocnice Olomouc

    Olomouc, 77900

  • Fakultni Nemocnice Kralovske Vinohrady

    Prague, 10034

Other trials in Czechia

Italy2 sites

  • Irccs Irst

    Meldola, 47014

  • Azienda Ospedaliero

    Siena, 53100

Other trials in Italy

About this study

Official title: 'An Open Label, Multicentre, Phase I Study to Evaluate the Impact of Moderate and Severe Hepatic Impairments on the Pharmacokinetics and Safety of Encorafenib in Combination With Binimetinib in Adult Patients With Unresectable or Metastatic BRAF V600-mutant Solid Tumors'.

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).

Read the 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.

Being tested
Encorafenib + Binimetinib
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Encorafenib + BinimetinibDrug

    Also called Braftovi + Mektovi

    The doses administered to patients with normal hepatic function will be the same as the recommended commercialised doses

  • Encorafenib + BinimetinibDrug

    Also called Braftovi + Mektovi

    A smaller dose than the dose approved for patients with normal hepatic function has been defined

  • Encorafenib + BinimetinibDrug

    Also called Braftovi + Mektovi

    A smaller dose than the dose approved for patients with normal hepatic function has been defined

Study groups in NCT04759846
Study groupRoleWhat they receive
Group with normal hepatic functionExperimentalNormal hepatic function
Receives: Drug: Encorafenib + Binimetinib
Group with moderate hepatic impairmentExperimentalModerate hepatic impairment (Child-Pugh Class B)
Receives: Drug: Encorafenib + Binimetinib
Group with severe impairmentExperimentalSevere impairment (Child-Pugh Class C)
Receives: Drug: Encorafenib + Binimetinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Encorafenib Cmax

    Maximum Observed Plasma Concentration of encorafenib expressed as total and unbound concentrations

    Measured: Day 1 and Day 15: 0-8 hours post-dose

  2. Encorafenib AUClast

    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

    Measured: Day 1 and Day 15: 0-8 hours post-dose

  3. Encorafenib AUC(0-inf)

    Area Under the Plasma Concentration versus Time Curve from Time 0 to Infinity of encorafenib expressed as total and unbound concentrations

    Measured: Day 1 and Day 15: 0-8 hours post-dose

Secondary outcomes (7)

  1. Tmax

    Time to Reach Maximum Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032)

    Measured: Day 1 and Day 15: 0-8 hours post-dose

  2. Cmin

    Minimum Observed Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032) expressed as total and unbound concentrations

    Measured: Derived on Day1 and Day15

  3. T1/2

    Terminal Phase Plasma Half-life of encorafenib and binimetinib and their metabolite

    Measured: Day 1 and Day 15: 0-8 hours post-dose

  4. CL/F

    Apparent Total Body Clearance of encorafenib and binimetinib and their metabolites as total and unbound concentrations

    Measured: Day 1 and Day 15: 0-8 hours post-dose

  5. Vz/F

    Apparent Volume of Distribution at Terminal Phase of encorafenib and binimetinib and their metabolites as total and unbound concentrations

    Measured: Day 1 and Day 15: 0-8 hours post-dose

  6. MRCmax

    Metabolic Ratio of Cmax of LHY746 to Cmax of encorafenib, Metabolic Ratio of Cmax of AR00426032 to Cmax of binimetinib Corrected for Molecular Weights

    Measured: Derived on Day1 and Day15

  7. MRAUC

    Metabolic Ratio of AUC of LHY746 to AUC of encorafenib, Metabolic Ratio of AUC of AR00426032 to AUC of binimetinib Corrected for Molecular Weights

    Measured: Derived on Day1 and Day15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Feb 2021
  2. Study start21 Jan 2021
  3. Primary completionMay 2023 (estimated)
  4. Study completionMay 2023 (estimated)

Why it stopped: no recruitment

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
Participants with hepatic impairment will be enrolled sequentially according to their severity.
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04759846
Sponsor's protocol ID
W00090GE101
Status last verified
Feb 2023
First submitted
21 Dec 2020
Last updated
21 Feb 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Encorafenib + Binimetinib in people with BRAF V600 Mutation and Unresectable Melanoma, run by Pierre Fabre Medicament at 7 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 21 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Spain, Czechia, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Encorafenib Cmax (time frame: Day 1 and Day 15: 0-8 hours post-dose). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04759846.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2023.

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