Clinical trial NCT03693170: Encorafenib, Binimetinib and Cetuximab in Subjects With Previously Untreated BRAF-mutant ColoRectal Cancer
Official title: Phase II, Open-label, Single Arm, Multicenter Study of Encorafenib, Binimetinib Plus Cetuximab in Subjects With Previously Untreated BRAF V600E -Mutant Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: BRAF V600E-mutant Metastatic Colorectal Cancer
Keywords: Metastatic Colorectal Cancer
Lead sponsor: Pierre Fabre Medicament
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
name: Merck KGaA, Darmstadt, Germany
name: Ono Pharmaceutical Co. Ltd
First posted: 2018-10-02
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of the combination of study drugs encorafenib, binimetinib and cetuximab in patients who have BRAF V600 mutant metastatic colorectal cancer and have not received any prior treatment for their metastatic disease.

Detailed description: The presence of a BRAFV600E mutation is considered a marker of poor prognosis in subjects with mCRC. The preclinical results and preliminary clinical data together justify the evaluation of this triple combination in the first-line setting of this population. The primary objective of the study is to evaluate the antitumor activity of the combination of encorafenib, binimetinib and cetuximab by assessing the overall response rate in adult subjects with previously untreated BRAFV600E-mutant metastatic colorectal cancer. It will also assess the effect of the triple combination on the duration of response, time to response, progression-free survival and overall survival and assess the effect on quality of life. It will also characterize the safety and tolerability of the triple combination as well as describe the pharmacokinetics (PK) of encorafenib, binimetinib, and cetuximab.

Eligibility criteria: Inclusion Criteria:

* Male or female ≥ 18 years of age
* Histologically or cytologically confirmed CRC that is metastatic
* Presence of BRAF V600E in tumor tissue determined by local assay at any time prior to screening
* Evidence of measurable disease as per RECIST, v1.1
* Subject able to receive cetuximab as per approved label with regards to RAS status
* Eastern Cooperative Oncology Group Status (ECOG) 0 or 1
* Adequate renal, hepatic, cardiac and bone marrow functions and adequate electrolytes as per protocol
* Subject able to take oral medications

Exclusion Criteria:

* Prior systemic therapy for metastatic disease
* Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti-EGFR inhibitors
* Symptomatic brain metastasis or Leptomeningeal disease
* History or current evidence of Retinal Vein Occlusion (RVO) or current risk factors for RVO
* History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to first dose.
* Impaired cardiovascular function or clinically significant cardiovascular diseases: history of myocardial infarction or coronary disorders within 6 months prior to start of study treatment, symptomatic congestive heart failure (grade 2 or higher), past or current clinically significant arrhythmia and/or conduction disorder within 6 months prior to study treatment start
* History of thromboembolic or cerebrovascular events within 6 months prior to start of study treatment
* Concurrent neuromuscular disorder that is associated with potential elevation of Creatine Kinase
* Known contraindication to cetuximab administration as per SPC/approved label

Primary outcomes:
measure: Confirmed Overall Response Rate (cORR) Based on Local Tumor Assessments
timeFrame: From initiation of treatment to disease progression up to a maximum of 17.6 months.
Secondary outcomes:
measure: Confirmed Overall Response Rate (cORR) Based on Central Tumor Assessment
timeFrame: From initiation of treatment to disease progression up to a maximum of 17.6 months
measure: Overall Response Rate (ORR) Based on Local Tumor Assessments
timeFrame: From initiation of treatment to disease progression up to a maximum of 17.6 months
measure: Overall Response Rate (ORR) Based on Central Tumor Assessments
timeFrame: From initiation of treatment to disease progression up to a maximum of 17.6 months
measure: Duration of Response (DOR) Per Local Assessment
timeFrame: From first radiographic evidence of response to disease progression up to a maximum of 17.6 months
measure: Duration of Response (DOR) Per Central Assessment
timeFrame: From first radiographic evidence of response to disease progression up to a maximum of 17.6 months
measure: Time to Response (TTR) Per Local Review
timeFrame: From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months
measure: Time to Response (TTR) Per Central Review
timeFrame: From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months
measure: Progression-Free Survival (PFS) Per Local Review
timeFrame: From initiation of treatment to disease progression or death up to a maximum of 17.6 months
measure: Progression of Free Survival (PFS) Per Central Review
timeFrame: From initiation of treatment to disease progression or death up to a maximum of 17.6 months
measure: Overall Survival (OS)
timeFrame: From initiation of treatment to death up to a maximum of 17.6 months
measure: Plasma Concentration of Encorafenib
timeFrame: 2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)
measure: Plasma Concentration of Binimetinib
timeFrame: 2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)
measure: Plasma Concentration of Cetuximab
timeFrame: 2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)
measure: Change From Baseline in EORTC QLQ-C30 Over Time
timeFrame: From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months
measure: Change From Baseline in EQ-5D-5L Over Time
timeFrame: From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months
measure: PGIC Scores Over Time
timeFrame: From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Germantown
country: United States
facility: PC dba West Cancer Center
state: Tennessee
city: Wien
country: Austria
facility: Krankenhaus der Barmherzigen Brüder
city: Gent
country: Belgium
facility: UZ Gent, Gastro-Enterology
state: East Flanders
city: Leuven
country: Belgium
facility: Trial DIO, UZ Gasthuisberg
state: Flemish Brabant
city: Brussels
country: Belgium
facility: Cliniques universitaires Saint-Luc
city: Montpellier
country: France
facility: ICM- VAL d 'Aurelle
state: Cedex 5
city: Brest
country: France
facility: Hôpital Morvan CHRU de Brest Institut de cancérologie et d'hematologie
city: Marseille
country: France
facility: AP-HM CHU Timone
city: Paris
country: France
facility: Hôpital Cochin Gastroenterology
city: Paris
country: France
facility: Hôpital Europeen Georges Pompidou
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Pessac
country: France
facility: HOPITAL HAUT-LEVEQUE, Av de MAGELLAN
city: Saint-Herblain
country: France
facility: ICO- Site René Gauducheau
city: Toulouse
country: France
facility: CHU TOULOUSE Rangueil
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Ospedale Casa Sollievo della Sofferenza
state: Foggia
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
state: Forlì-Cesena
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCC Candiolo
city: Genova
country: Italy
facility: Ospedale Policlinic San Martin
city: Perugia
country: Italy
facility: Ospedale S.M. Misericordia
city: Nagoya
country: Japan
facility: Pierre Fabre Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Pierre Fabre Investigative Site
state: Chiba
city: Fukuoka-shi
country: Japan
facility: Pierre Fabre Investigative Site
state: Fukuoka
city: Osaka-shi
country: Japan
facility: Pierre Fabre Investigative Site
state: Osaka
city: Nagaizumi-cho
country: Japan
facility: Pierre Fabre Investigative Site
state: Shizuoka
city: Koto-ku,
country: Japan
facility: Pierre Fabre Investigative Site
state: Tokyo
city: Utrecht
country: Netherlands
facility: St Antonius Ziekenhuis
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro
state: Community Of Madrid
city: Pamplona
country: Spain
facility: Complejo Hospitalario De Navarra S Oncologia Medica
state: Navarre
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic I Provincial de Barcelona
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia (ICO L'Hospitalet)
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Santa Pau
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La FE
city: Vigo
country: Spain
facility: Hospital Alvaro Cunqueiro
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Torquay
country: United Kingdom
facility: Torbay Hospital, Lowes Bridge
state: Devon
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
state: Surrey
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Leeds
country: United Kingdom
facility: St James Hospital
city: London
country: United Kingdom
facility: GI research team, OHCT, Guy's Hospital
city: Manchester
country: United Kingdom
facility: GI Research Team, The Christie NHS Foundation Trust
Study officials:
affiliation: Corporate Medical&Patient/Consumer Division, Pierre Fabre Medicament
name: Isabelle KLAUCK, MD
role: STUDY_DIRECTOR
References: