Encorafenib, Binimetinib and Cetuximab in Subjects With Previously Untreated BRAF-mutant ColoRectal Cancer

BRAF V600E-mutant Metastatic Colorectal Cancer Clinical Trial

— ANCHOR-CRC  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03693170
• Other study ID #: W00090 GE 2 01
• Status: Completed
• Phase: Phase 2
• Start date: January 17, 2019
• Est. completion date: April 27, 2023

Study information

• Verified date: January 2024
• Source: Pierre Fabre Medicament
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: April 27, 2023
• Est. primary completion date: June 29, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• BRAF V600E-mutant Metastatic Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• encorafenib
300 mg administered orally once daily (QD)
• Binimetinib
Binimetinib 45 mg administered orally twice daily (BID)
• Cetuximab
Standard of care for the 28 first weeks(*) and then every 2 weeks (**) : (*) 400 mg/m2 administered as a 120-min infusion on Cycle 1 Day 1, followed by 250 mg/m2 administered as a 60-min infusion once weekly (QW) for the first 28 weeks. (**) 500 mg/m2 administered as a 120-min infusion twice weekly (Q2W) from Week 29 (Cycle 8 Day 1) onward. Following implementation of an Urgent Safety Measure on 26 Mar 2020 due to the outbreak of COVID-19 pandemic, cetuximab infusions could be administered Q2W regardless of the cycle number, after investigator's evaluation of the benefit/risk ratio for the subject, with regards to COVID-19 pandemic.

Locations

Country	Name	City	State
Austria	Krankenhaus der Barmherzigen Brüder	Wien
Belgium	Cliniques universitaires Saint-Luc	Brussels
Belgium	UZ Gent, Gastro-Enterology	Gent	East Flanders
Belgium	Trial DIO, UZ Gasthuisberg	Leuven	Flemish Brabant
France	Hôpital Morvan CHRU de Brest Institut de cancérologie et d'hematologie	Brest
France	AP-HM CHU Timone	Marseille
France	ICM- VAL d 'Aurelle	Montpellier	Cedex 5
France	Hôpital Cochin Gastroenterology	Paris
France	Hôpital Europeen Georges Pompidou	Paris
France	Hôpital Saint Antoine	Paris
France	HOPITAL HAUT-LEVEQUE, Av de MAGELLAN	Pessac
France	ICO- Site René Gauducheau	Saint-Herblain
France	CHU TOULOUSE Rangueil	Toulouse
Italy	Fondazione del Piemonte per l'Oncologia IRCC Candiolo	Candiolo
Italy	Ospedale Policlinic San Martin	Genova
Italy	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori	Meldola	Forlì-Cesena
Italy	Ospedale S.M. Misericordia	Perugia
Italy	IRCCS Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo	Foggia
Japan	Pierre Fabre Investigative Site	Fukuoka-shi	Fukuoka
Japan	Pierre Fabre Investigative Site	Kashiwa	Chiba
Japan	Pierre Fabre Investigative Site	Koto-ku,	Tokyo
Japan	Pierre Fabre Investigative Site	Nagaizumi-cho	Shizuoka
Japan	Pierre Fabre Investigative Site	Nagoya	Aichi
Japan	Pierre Fabre Investigative Site	Osaka-shi	Osaka
Netherlands	St Antonius Ziekenhuis	Utrecht
Spain	Hospital Clínic I Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Santa Pau	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Institut Català d'Oncologia (ICO L'Hospitalet)	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Puerta de Hierro	Madrid	Community Of Madrid
Spain	Hospital Universitario HM Sanchinarro	Madrid
Spain	Complejo Hospitalario De Navarra S Oncologia Medica	Pamplona	Navarre
Spain	Hospital Clínico Universitario de	Valencia
Spain	Hospital Universitario y Politécnico La FE	Valencia
Spain	Hospital Alvaro Cunqueiro	Vigo
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	St James Hospital	Leeds
United Kingdom	GI research team, OHCT, Guy's Hospital	London
United Kingdom	GI Research Team, The Christie NHS Foundation Trust	Manchester
United Kingdom	The Royal Marsden NHS Foundation Trust	Sutton	Surrey
United Kingdom	Torbay Hospital, Lowes Bridge	Torquay	Devon
United States	PC dba West Cancer Center	Germantown	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
Pierre Fabre Medicament	Merck KGaA, Darmstadt, Germany, Ono Pharmaceutical Co. Ltd, Pfizer

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  France,  Italy,  Japan,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Confirmed Overall Response Rate (cORR) Based on Local Tumor Assessments	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.	From initiation of treatment to disease progression up to a maximum of 17.6 months.
Secondary	Confirmed Overall Response Rate (cORR) Based on Central Tumor Assessment	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.	From initiation of treatment to disease progression up to a maximum of 17.6 months
Secondary	Overall Response Rate (ORR) Based on Local Tumor Assessments	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.	From initiation of treatment to disease progression up to a maximum of 17.6 months
Secondary	Overall Response Rate (ORR) Based on Central Tumor Assessments	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.	From initiation of treatment to disease progression up to a maximum of 17.6 months
Secondary	Duration of Response (DOR) Per Local Assessment	Time from first radiographic evidence of response based on local radiologist/investigator review to the earliest documented PD or death due to underlying disease	From first radiographic evidence of response to disease progression up to a maximum of 17.6 months
Secondary	Duration of Response (DOR) Per Central Assessment	Time from first radiographic evidence of response based on central review to the earliest documented PD or death due to underlying disease	From first radiographic evidence of response to disease progression up to a maximum of 17.6 months
Secondary	Time to Response (TTR) Per Local Review	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	From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months
Secondary	Time to Response (TTR) Per Central Review	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	From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months
Secondary	Progression-Free Survival (PFS) Per Local Review	Time from first dose to the earliest documented date of disease progression based on local radiologist/investigator review or death due to any cause	From initiation of treatment to disease progression or death up to a maximum of 17.6 months
Secondary	Progression of Free Survival (PFS) Per Central Review	Time from first dose to the earliest documented date of disease progression based on central review or death due to any cause	From initiation of treatment to disease progression or death up to a maximum of 17.6 months
Secondary	Overall Survival (OS)	Time from first dose to death due to any cause	From initiation of treatment to death up to a maximum of 17.6 months
Secondary	Plasma Concentration of Encorafenib	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)
Secondary	Plasma Concentration of Binimetinib	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)
Secondary	Plasma Concentration of Cetuximab	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)
Secondary	Change From Baseline in EORTC QLQ-C30 Over Time	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.	From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months
Secondary	Change From Baseline in EQ-5D-5L Over Time	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.	From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months
Secondary	PGIC Scores Over Time	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."	From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months