Encorafenib, Binimetinib and Cetuximab in Subjects With Previously Untreated BRAF-mutant ColoRectal Cancer
- Conditions
- BRAF V600E-mutant Metastatic Colorectal Cancer
- Interventions
- Registration Number
- NCT03693170
- Lead Sponsor
- Pierre Fabre Medicament
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 95
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 1 Arm encorafenib encorafenib plus binimetinib plus cetuximab 1 Arm Binimetinib encorafenib plus binimetinib plus cetuximab 1 Arm Cetuximab encorafenib plus binimetinib plus cetuximab
- Primary Outcome Measures
Name Time Method Confirmed Overall Response Rate (cORR) Based on Local Tumor Assessments From initiation of treatment to disease progression up to a maximum of 17.6 months. The confirmed overall response rate (cORR) is the percentage of confirmed responses, defined as complete response (CR) or partial response (PR), as assessed by local radiologist/investigator review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI:
Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.
- Secondary Outcome Measures
Name Time Method Confirmed Overall Response Rate (cORR) Based on Central Tumor Assessment From initiation of treatment to disease progression up to a maximum of 17.6 months The confirmed overall response rate (cORR) is the percentage of confirmed responses, defined as complete response (CR) or partial response (PR), as assessed by central radiologist review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI:
Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.Duration of Response (DOR) Per Central Assessment From first radiographic evidence of response to disease progression up to a maximum of 17.6 months Time from first radiographic evidence of response based on central review to the earliest documented PD or death due to underlying disease
Overall Response Rate (ORR) Based on Local Tumor Assessments From initiation of treatment to disease progression up to a maximum of 17.6 months The overall response rate (ORR) is the percentage of responses, defined as complete response (CR) or partial response (PR), as assessed by local radiologist/investigator review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI:
Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.Overall Response Rate (ORR) Based on Central Tumor Assessments From initiation of treatment to disease progression up to a maximum of 17.6 months The overall response rate (ORR) is the percentage of responses, defined as complete response (CR) or partial response (PR), as assessed by central radiologist review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI:
Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.Duration of Response (DOR) Per Local Assessment From first radiographic evidence of response to disease progression up to a maximum of 17.6 months Time from first radiographic evidence of response based on local radiologist/investigator review to the earliest documented PD or death due to underlying disease
Time to Response (TTR) Per Local Review From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months The TTR is defined as the time from the first dose until the first documented radiographic evidence of response of CR or PR per local review
Time to Response (TTR) Per Central Review From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months The TTR is defined as the time from the first dose until the first documented radiographic evidence of response of CR or PR per central review
Progression-Free Survival (PFS) Per Local Review From initiation of treatment to disease progression or death up to a maximum of 17.6 months Time from first dose to the earliest documented date of disease progression based on local radiologist/investigator review or death due to any cause
Progression of Free Survival (PFS) Per Central Review From initiation of treatment to disease progression or death up to a maximum of 17.6 months Time from first dose to the earliest documented date of disease progression based on central review or death due to any cause
Overall Survival (OS) From initiation of treatment to death up to a maximum of 17.6 months Time from first dose to death due to any cause
Plasma Concentration of Encorafenib 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) Plasma concentration of encorafenib
Plasma Concentration of Binimetinib 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) Plasma concentration of binimetinib
Plasma Concentration of Cetuximab 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) Plasma concentration of cetuximab
Change From Baseline in EORTC QLQ-C30 Over Time From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for cancer subjects (EORTC QLQ-C30) includes a global health status/QoL. The scale ranges in score from 0 to 100, higher score on the global health status/QoL scale indicate higher QoL.
Changes from baseline in EORTC QLQ-C30 global health status/quality of life (QoL) over time are presented in this record.Change From Baseline in EQ-5D-5L Over Time From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L VAS records the patient's self-rated health on a vertical visual analogue scale numbered from 0 ("The worst health you can imagine") to 100 ("The best health you can imagine"). Changes from baseline in EQ-5D-5L VAS over time are presented in this record.
PGIC Scores Over Time From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months The Patient Global Impression of Change (PGIC) is a measure of patients' perceptions of change in their symptoms over time. For this assessment, subjects answered the following question: "Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse."
Trial Locations
- Locations (40)
AP-HM CHU Timone
🇫🇷Marseille, France
ICO- Site René Gauducheau
🇫🇷Saint-Herblain, France
Hôpital Europeen Georges Pompidou
🇫🇷Paris, France
HOPITAL HAUT-LEVEQUE, Av de MAGELLAN
🇫🇷Pessac, France
Hospital Universitario y Politécnico La FE
🇪🇸Valencia, Spain
CHU TOULOUSE Rangueil
🇫🇷Toulouse, France
Fondazione del Piemonte per l'Oncologia IRCC Candiolo
🇮🇹Candiolo, Italy
St Antonius Ziekenhuis
🇳🇱Utrecht, Netherlands
Hospital Clínic I Provincial de Barcelona
🇪🇸Barcelona, Spain
Hôpital Cochin Gastroenterology
🇫🇷Paris, France
Hospital Universitario HM Sanchinarro
🇪🇸Madrid, Spain
GI research team, OHCT, Guy's Hospital
🇬🇧London, United Kingdom
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
🇮🇹Meldola, Forlì-Cesena, Italy
UZ Gent, Gastro-Enterology
🇧🇪Gent, East Flanders, Belgium
Torbay Hospital, Lowes Bridge
🇬🇧Torquay, Devon, United Kingdom
Krankenhaus der Barmherzigen Brüder
🇦🇹Wien, Austria
Trial DIO, UZ Gasthuisberg
🇧🇪Leuven, Flemish Brabant, Belgium
IRCCS Ospedale Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, Foggia, Italy
The Royal Marsden NHS Foundation Trust
🇬🇧Sutton, Surrey, United Kingdom
Ospedale S.M. Misericordia
🇮🇹Perugia, Italy
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Cliniques universitaires Saint-Luc
🇧🇪Brussels, Belgium
PC dba West Cancer Center
🇺🇸Germantown, Tennessee, United States
ICM- VAL d 'Aurelle
🇫🇷Montpellier, Cedex 5, France
Hôpital Morvan CHRU de Brest Institut de cancérologie et d'hematologie
🇫🇷Brest, France
Hospital Alvaro Cunqueiro
🇪🇸Vigo, Spain
Hôpital Saint Antoine
🇫🇷Paris, France
Hospital Puerta de Hierro
🇪🇸Madrid, Community Of Madrid, Spain
Ospedale Policlinic San Martin
🇮🇹Genova, Italy
St James Hospital
🇬🇧Leeds, United Kingdom
Pierre Fabre Investigative Site
🇯🇵Koto-ku,, Tokyo, Japan
Complejo Hospitalario De Navarra S Oncologia Medica
🇪🇸Pamplona, Navarre, Spain
Institut Català d'Oncologia (ICO L'Hospitalet)
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Marañón
🇪🇸Madrid, Spain
Hospital Clínico Universitario de
🇪🇸Valencia, Spain
Hospital de la Santa Creu i Santa Pau
🇪🇸Barcelona, Spain
Hospital Universitario Miguel Servet
🇪🇸Zaragoza, Spain
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
GI Research Team, The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom