Encorafenib, Binimetinib and Cetuximab in Subjects With Previously Untreated BRAF-mutant ColoRectal Cancer (ANCHOR-CRC)

• ClinicalTrials.gov Identifier: NCT03693170
• Recruitment Status: Completed
• First Posted: October 2, 2018
• Results First Posted: August 30, 2022
• Last Update Posted: February 2, 2024
• Sponsor: Pierre Fabre Medicament
• Collaborators: Pfizer; Merck KGaA, Darmstadt, Germany; Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Pierre Fabre Medicament

Tracking Information

• First Submitted Date: September 17, 2018
• First Posted Date: October 2, 2018
• Results First Submitted Date: January 13, 2022
• Results First Posted Date: August 30, 2022
• Last Update Posted Date: February 2, 2024
• Actual Study Start Date: January 17, 2019
• Actual Primary Completion Date: June 29, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 19, 2022)

Confirmed Overall Response Rate (cORR) Based on Local Tumor Assessments [ Time Frame: 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.

Original Primary Outcome Measures (submitted: October 1, 2018)

Confirmed Overall Response Rate (cORR) based on local tumor assessments [ Time Frame: Duration of the study, approximately 25 months ]

Assessment of tumor evaluation change from baseline

Current Secondary Outcome Measures (submitted: April 19, 2022)

• Confirmed Overall Response Rate (cORR) Based on Central Tumor Assessment [ Time Frame: 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.
• Overall Response Rate (ORR) Based on Local Tumor Assessments [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
• Duration of Response (DOR) Per Central Assessment [ Time Frame: 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
• Time to Response (TTR) Per Local Review [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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."

Original Secondary Outcome Measures (submitted: October 1, 2018)

• Confirmed Overall Response Rate (cORR) based on central tumor assessment [ Time Frame: globally assessed by subject based on tumor evaluations every 6 weeks for the first 12 weeks and then every 8 weeks. ]
  Percentage of subjects with complete response (CR) and partial response (PR)
• Overall response (ORR) based on local tumor assessments [ Time Frame: Globally assessed by subject based on tumor evaluations every 6 weeks for the first 12 weeks and then every 8 weeks. ]
  Percentage of subjects with complete response (CR) and partial response (PR)
• Overall response (ORR) based on central tumor assessments [ Time Frame: Globally assessed by subject based on tumor evaluations every 6 weeks for the first 12 weeks and then every 8 weeks. ]
  Percentage of subjects with complete response (CR) and partial response (PR)
• Duration of Response (DOR) per local assessment [ Time Frame: Duration of study approximately 25 months ]
  Time from first radiographic evidence of response assessed based on local radiologist/investigator review to the earliest documented PD or death due to underlying disease
• Duration of Response (DOR) per central assessment [ Time Frame: Duration of study approximately 25 months ]
  Time from first radiographic evidence of response review to the earliest documented PD or death due to underlying disease
• Time to Response (TTR) per local review [ Time Frame: Duration of study approximately 25 months ]
  Time from first dose until first documented radiographic evidence of response of CR or PR
• Time to Response (TTR) per central review [ Time Frame: Duration of study approximately 25 months ]
  Time from first dose until first documented radiographic evidence of response of CR or PR
• Progression of Free Survival (PFS) per local review [ Time Frame: Duration of study approximately 25 months ]
  Time from first dose to the earliest documented date of disease progression or death due to any cause
• Progression of Free Survival (PFS) per central review [ Time Frame: Duration of study approximately 25 months ]
  Time from first dose to the earliest documented date of disease progression or death due to any cause
• Overall Survival (OS) [ Time Frame: Duration of study approximately 25 months ]
  Time from first dose to death due to any cause
• Safety through the incidence of adverse events [ Time Frame: Duration of study approximately 25 months ]
• Plasma concentration of encorafenib [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
• Comparison of Quality of Life from Baseline to end of the study [ Time Frame: At screening, at Cycle 1 Day 1 and at the end of the study (each cycle is 28 days) ]
  Change in the Quality of Life Questionnaire for Cancer subjects.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:

All involved know the identity of the intervention assignment.

Primary Purpose: Treatment

• Condition: BRAF V600E-mutant Metastatic Colorectal Cancer

Intervention

• Drug: encorafenib
  300 mg administered orally once daily (QD)
  Other Name: Braftovi
• Drug: Binimetinib
  Binimetinib 45 mg administered orally twice daily (BID)
  Other Name: Mektovi
• Drug: 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.

  Other Name: Erbitux

Study Arms

Experimental: 1 Arm

encorafenib plus binimetinib plus cetuximab

Interventions:

• Drug: encorafenib
• Drug: Binimetinib
• Drug: Cetuximab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 3, 2020): 95
• Original Estimated Enrollment (submitted: October 1, 2018): 90
• Actual Study Completion Date: April 27, 2023
• Actual Primary Completion Date: June 29, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, France, Italy, Japan, Netherlands, Spain, United Kingdom, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT03693170
• Other Study ID Numbers: W00090 GE 2 01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pierre Fabre Medicament
• Original Responsible Party: Same as current
• Current Study Sponsor: Pierre Fabre Medicament
• Original Study Sponsor: Same as current

Collaborators

• Pfizer
• Merck KGaA, Darmstadt, Germany
• Ono Pharmaceutical Co. Ltd

Investigators

• Study Director: Isabelle KLAUCK, MD; Corporate Medical&Patient/Consumer Division, Pierre Fabre Medicament

• PRS Account: Pierre Fabre Medicament
• Verification Date: January 2024