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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II, Open-label, Single Arm, Multicenter Study of Encorafenib, Binimetinib Plus Cetuximab in Subjects With Previously Untreated BRAF V600E -Mutant Metastatic Colorectal Cancer

Conditions
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BRAF V600E-mutant Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: encorafenib
* Drug: Binimetinib
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 Arm<br>encorafenib plus binimetinib plus cetuximab | Drug: encorafenib<br>* 300 mg administered orally once daily (QD)<br>* Other names: Braftovi;Drug: Binimetinib<br>* Binimetinib 45 mg administered orally twice daily (BID)<br>* Other names: Mektovi;Drug: Cetuximab<br>* 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.<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Colorectal Cancer