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Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer (BEACON CRC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02928224
Recruitment Status : Completed
First Posted : October 10, 2016
Results First Posted : July 14, 2020
Last Update Posted : December 21, 2023
Sponsor:
Collaborators:
Merck KGaA, Darmstadt, Germany
Pierre Fabre Medicament
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Pfizer

Study Description
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Brief Summary:
This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.

Condition or disease Intervention/treatment Phase
BRAF V600E-mutant Metastatic Colorectal Cancer Drug: Encorafenib Drug: Binimetinib Drug: Cetuximab Drug: Irinotecan Drug: Folinic Acid Drug: 5-Fluorouracil Phase 3

Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 702 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer
Actual Study Start Date : October 13, 2016
Actual Primary Completion Date : February 11, 2019
Actual Study Completion Date : November 10, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Safety

Arms and Interventions
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Arm Intervention/treatment
Experimental: Safety Lead-in, Triplet Arm
Encorafenib + binimetinib + cetuximab.
 Drug: Encorafenib
Orally, once daily.

Drug: Binimetinib
Orally, twice daily.

Drug: Cetuximab
Standard of care.
Experimental: Doublet Arm
Encorafenib + cetuximab.
 Drug: Encorafenib
Orally, once daily.

Drug: Cetuximab
Standard of care.
Active Comparator: Control Arm
Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
 Drug: Cetuximab
Standard of care.

Drug: Irinotecan
Standard of care.

Drug: Folinic Acid
Standard of care.
Other Name: FA

Drug: 5-Fluorouracil
Standard of care.
Other Name: 5-FU


Outcome Measures
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Primary Outcome Measures :
  1. (Safety Lead-in) Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (up to 28 days) ]
  2. (Safety Lead-in) Number of Participants With Adverse Events (AEs) [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
    An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants reporting AEs were reported in this outcome measure.

  3. (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Interim Analysis [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
    An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants with dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.

  4. (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Final Analysis [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks) ]
    An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants according to incidence of dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.

  5. (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis [ Time Frame: From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.1 weeks for triplet arm and 52.4 weeks for control arm) ]
    OS was defined as the time from randomization to death due to any cause.

  6. (Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of complete response (CR) or partial response (PR), where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 millimeter [mm] short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.


Secondary Outcome Measures :
  1. (Safety Lead-in) Objective Response Rate (ORR) by Investigator [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  2. (Safety Lead-in) Objective Response Rate (ORR) by BICR [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  3. (Safety Lead-in) Duration of Response (DOR) by Investigator [ Time Frame: From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  4. (Safety Lead-in) Duration of Response (DOR) by BICR [ Time Frame: From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  5. (Safety Lead-in) Time to Response by Investigator [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  6. (Safety Lead-in) Time to Response by BICR [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  7. (Safety Lead-in) Progression-Free Survival (PFS) by Investigator [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  8. (Safety Lead-in) Progression-Free Survival (PFS) by BICR [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  9. (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm [ Time Frame: From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 52.4 weeks for control arm) ]
    OS was defined as the time from randomization to death due to any cause.

  10. (Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm [ Time Frame: From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 89.1 weeks for triplet arm) ]
    OS was defined as the time from randomization to death due to any cause.

  11. (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm Per BICR [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  12. (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per Investigator [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  13. (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm Per BICR [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  14. (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm Per Investigator [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  15. (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  16. (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator [ Time Frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm) ]
    PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  17. (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm Per Investigator [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  18. (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  19. (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  20. (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  21. (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
    ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

  22. (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per BICR [ Time Frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  23. (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per Investigator [ Time Frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  24. (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per BICR [ Time Frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  25. (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per Investigator [ Time Frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  26. (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR [ Time Frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  27. (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator [ Time Frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm) ]
    DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

  28. (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per BICR [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  29. (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per Investigator [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  30. (Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per BICR [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  31. (Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per Investigator [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  32. (Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  33. (Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator [ Time Frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm) ]
    Time to response was defined as the time from first dose to first radiographic evidence of response.

  34. (Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [ Time Frame: Baseline, Cycle(C)1 Day(D)1 , C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days) ]
    The EORTC QLQ-C30 questionnaire consisted of 30 questions generating 5 functional scores (physical, role, cognitive, emotional, & social); a global health (GH) status/global quality of life scale score; 3 symptom scale scores (fatigue, pain, & nausea & vomiting); & 6 standalone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, & diarrhea) & perceived financial burden. All items were graded by severity experienced during previous week & used 4-point-scale (1: not at all, 2: a little, 3: quite a bit, 4: very much). The scores were converted to health-related quality of life (HRQoL) scale ranging from 0-100. Higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).

  35. (Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [ Time Frame: Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days) ]
    FACT-C= Functional Assessment of Chronic Illness Therapy (FACIT), which assessed HRQoL of cancer participants & participants with other chronic illnesses. It consists of total 36 items (27 items of general version of FACT-C and disease-specific subscale containing 9 CRC-specific items), summarized to 5 subscales: physical well-being (7 items), functional well-being (7 items), social/family well-being (7 items); all 3 subscales range:0-28, emotional well-being (6 items) range: 0-24, colorectal cancer subscale (9 items) range: 0-36; higher subscale score= better QoL. All single-item measures range: 0= 'Not at all' to 4= 'Very much'. Table summarizes functional well-being subscale, individual questions are linearly scaled & combined to form functional well-being subscale score (range 0-28). High score represents better QoL.

  36. (Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [ Time Frame: Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days) ]
    The EQ-5D-5L contains 1 item for each of 5 dimensions of health-related QoL (i.e., mobility, self-care, usual activities, pain or discomfort and anxiety or depression). Response options for each item varied from having no problems to moderate problems or extreme problems. The EQ-5D-5L (v4.0) is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L is frequently used for economic evaluations of health care and has been recognized as a valid and reliable instrument for this purpose. The EQ visual analog scale (VAS) is a score that is directly reported by the participant and ranges from 0 to 100 (higher is better quality health).

  37. (Phase 3) Change From Baseline in the Participant Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [ Time Frame: Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days) ]
    The PGIC is a measure of participant's perceptions of change in their symptoms over time that can be used as an anchoring method to determine the minimal clinically important difference for other participant reported outcome (PROs). For this assessment, participants 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."

  38. (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Cetuximab [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  39. (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Encorafenib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  40. (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  41. (Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve From Zero to the Last Measurable Time Point (AUClast) for Metabolite of Binimetinib (AR00426032) [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  42. (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  43. (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  44. (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  45. (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032) [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  46. (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  47. (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  48. (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  49. (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032) [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  50. (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  51. (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  52. (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  53. (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days) ]
  54. (Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib [ Time Frame: 2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days) ]
    The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

  55. (Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib [ Time Frame: 2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days) ]
    The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

  56. (Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab [ Time Frame: 2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days) ]
    The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

  57. Phase 3: Number of Participants With Clinically Notable Shifts in Hematology and Coagulation Laboratory Parameters [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Clinically notable shifts was defined as worsening by at least 2 grades or to more than or equal to (>=) Grade 3 based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.

  58. Phase 3: Number of Participants With Clinically Notable Shifts in Serum Chemistry Laboratory Parameters [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.

  59. Phase 3: Number of Participants With Clinically Notable Shifts in Urinalysis Laboratory Parameters [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.

  60. Phase 3: Number of Participants With Newly Occurring Clinically Notable Vital Sign Abnormalities [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Newly occurring clinically notable changes was defined as participants not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: low/high systolic blood pressure (SBP): <= 90 millimeters of mercury (mmHg) with decrease from baseline of >= 20mmHg or >= 160mmHg with increase from baseline of >= 20mmHg, low or high diastolic blood pressure (DBP): <= 50mmHg with decrease from baseline of >= 15mmHg or >= 100mmHg with increase from baseline of >= 15mmHg, low or high pulse: <= 50 beats/min with decrease from baseline of >= 15 beats/min or >= 120 beats/min with increase from baseline of >= 15 beats/min, low or high temperature: <= 36 degree Celsius (deg C) or >= 37.5 deg C.

  61. Phase 3: Number of Participants With Newly Occurring Clinically Notable Electrocardiogram (ECG) Values [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Newly occurring clinically notable changes was defined as participants not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: heart rate- decrease from baseline > 25% and to a value < 50 and increase from baseline > 25% and to a value > 100. QT interval- new > 450 (millisecond) msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec. QTcF- new > 450 msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec.

  62. Phase 3: Number of Participants With Shift in Visual Acuity Logarithm of the Minimum Angle of Resolution (LogMAR) Score [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Visual acuity was measured using the Snellen visual acuity conversion chart. This was determined by establishing the smallest optotypes that could be identified correctly by the participant at a given observation distance. Snellen visual acuity was reported as a Snellen fraction (m/M) in which the numerator (m) indicated the test distance and the denominator (M) indicated the distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. The LogMAR score was calculated as - log(m/M). The maximum increase in score of <= 0, 0 to < 0.1, 0.1 to < 0.2, 0.2 to < 0.3 and >=0.3 relative to baseline in LogMAR were reported in this endpoint.

  63. Phase 3: Number of Participants With Shifts in Left Ventricular Ejection Fraction (LVEF) From Baseline to Maximum Grade On-treatment [ Time Frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks) ]
    Left ventricular ejection fraction (LVEF) abnormalities were defined according to CTCAE version 4.03 where Grade 0: Non-missing value below Grade 2, Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and < -20%, Grade 3: LVEF between 20% and 39% or absolute change from baseline <= -20%, Grade 4: LVEF lower than 20%. Categories with at least 1 non-zero data values showing any shift in Grade from baseline to 1 day after dose 1 (post-baseline) were reported. Participants whose grade category was unchanged (e.g. Grade 0 to Grade 0) were not reported.


Other Outcome Measures:
  1. (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis [ Time Frame: From randomization to death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm) ]
    OS was defined as the time from randomization to death due to any cause.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Age ≥ 18 years at time of informed consent
  • Histologically- or cytologically-confirmed CRC that is metastatic
  • Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory
  • Progression of disease after 1 or 2 prior regimens in the metastatic setting
  • Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1
  • Adequate bone marrow, cardiac, kidney and liver function
  • Able to take oral medications
  • Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential
  • Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up

Key Exclusion Criteria:

  • Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other epidermal growth factor receptor (EGFR) inhibitors
  • Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks
  • Symptomatic brain metastasis or leptomeningeal disease
  • History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
  • Known history of acute or chronic pancreatitis
  • History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization
  • Uncontrolled blood pressure despite medical treatment
  • Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
  • Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy
  • History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli
  • Concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Residual common terminology criteria for adverse events (CTCAE) ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy
  • Known history of HIV infection
  • Active hepatitis B or hepatitis C infection
  • Known history of Gilbert's syndrome
  • Known contraindication to receive cetuximab or irinotecan at the planned doses
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02928224


Locations
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Sponsors and Collaborators
Pfizer
Merck KGaA, Darmstadt, Germany
Pierre Fabre Medicament
Ono Pharmaceutical Co. Ltd
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] January 11, 2019
Statistical Analysis Plan  [PDF] April 23, 2019

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02928224    
Other Study ID Numbers: ARRAY-818-302
BEACON CRC ( Other Identifier: Alias Study Number )
2015-005805-35 ( EudraCT Number )
C4221009 ( Other Identifier: Pfizer )
First Posted: October 10, 2016    Key Record Dates
Results First Posted: July 14, 2020
Last Update Posted: December 21, 2023
Last Verified: December 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Pfizer:
Colorectal cancer
BRAF
BRAFV600E
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Fluorouracil
Irinotecan
 Cetuximab
Levoleucovorin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Immunological
Antidotes
Protective Agents