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

NCT04759846 | Withdrawn Phase 1 DMC

• 1 other identifier: W00090GE101
• Study Type: interventional
• Target: N/A
• Locations: 3 countries
• Sites: 7

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).

Conditions

BRAF V600 Mutation; Unresectable Melanoma; Metastatic Melanoma; Hepatic Impairment

Outcome Measures

Primary Outcomes (3)

• Encorafenib Cmax

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

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

• 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

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

• 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

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

Secondary Outcomes (7)

• Tmax

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

• Cmin

  Derived on Day1 and Day15

• T1/2

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

• CL/F

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

• Vz/F

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

Study Arms (3)

Group with normal hepatic function

EXPERIMENTAL

Normal hepatic function

Drug: Encorafenib + Binimetinib

Group with moderate hepatic impairment

EXPERIMENTAL

Moderate hepatic impairment (Child-Pugh Class B)

Drug: Encorafenib + Binimetinib

Group with severe impairment

EXPERIMENTAL

Severe impairment (Child-Pugh Class C)

Drug: Encorafenib + Binimetinib

Interventions

Encorafenib + Binimetinib DRUG

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

Also known as: Braftovi + Mektovi

Group with normal hepatic function

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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:

You may not qualify if:

• 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;
• 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;

Sponsors & Collaborators

• Pierre Fabre Medicament: lead

Study Sites (7)

Fakultni nemocnice Olomouc

Olomouc, 77900, Czechia

Location

Fakultni Nemocnice Kralovske Vinohrady

Prague, 10034, Czechia

Location

Irccs Irst

Meldola, 47014, Italy

Location

Azienda Ospedaliero

Siena, 53100, Italy

Location

all D'Hebron Insitute of Oncology

Barcelona, Spain

Location

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

Location

Hospital General de Valencia

Valencia, 46014, Spain

Location

MeSH Terms

Conditions

Melanoma

Interventions

encorafenib; binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Petr Arenberger

  Fakultni Nemocnice Kralovske Vinohrady, Czech Republic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants with hepatic impairment will be enrolled sequentially according to their severity.

Study Record Dates

• First Submitted: December 21, 2020
• First Posted: February 18, 2021
• Study Start: January 21, 2021
• Primary Completion: May 1, 2023
• Study Completion: May 1, 2023
• Last Updated: February 21, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (2); ES (3); IT (2)