BEACON CRC: 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

Sponsor

Pfizer (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02928224

Collaborator

Merck KGaA, Darmstadt, Germany (Industry), Pierre Fabre Medicament (Industry), Ono Pharmaceutical Co. Ltd (Industry)

702

Enrollment

429

Locations

Arms

71.6

Anticipated Duration (Months)

1.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Actual Enrollment :

702 participants

Allocation:

Randomized

Intervention Model:

Parallel 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 :

Oct 13, 2016

Actual Primary Completion Date :

Feb 11, 2019

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

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 Names: FA Drug: 5-Fluorouracil Standard of care. Other Names: 5-FU

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 Names:

Drug: 5-Fluorouracil

Standard of care.

Other Names:

5-FU

Outcome Measures

Primary Outcome Measures

(Safety Lead-in) Number of Participants With Dose-limiting Toxicities (DLTs) [Cycle 1 (up to 28 days)]
(Safety Lead-in) Number of Participants With Adverse Events (AEs) [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
Refer to AE/SAE section for additional data that were measured and analyzed.
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) 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 [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]

Secondary Outcome Measures

(Safety Lead-in) Response Rate (ORR) by Investigator [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
(Safety Lead-in) Response Rate (ORR) by BICR [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
ORR per RECIST, v1.1, defined as the number of patients achieving an overall best response of CR or partial response (PR) divided by the total number of patients
(Safety Lead-in) Duration of Response (DOR) by Investigator [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
(Safety Lead-in) Duration of Response (DOR) by BICR [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
DOR defined as the time from first radiographic evidence of response to the earliest documented disease progression or death due to underlying disease
(Safety Lead-in) Time to Response by Investigator [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
Time to response defined as the time from first dose to first radiographic evidence of response
(Safety Lead-in) Time to Response by BICR [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
Time to response defined as the time from first dose to first radiographic evidence of response
(Safety Lead-in) Progression-free Survival (PFS) by Investigator [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
(Safety Lead-in) Progression-free Survival (PFS) by BICR [Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)]
PFS defined as the time from first dose to the earliest documented disease progression or death due to any cause
(Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Progression-free Survival (PFS) in Doublet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Progression-free Survival (PFS) in Doublet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
(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 [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
FACT-C is a well-characterized and commonly used questionnaire that belongs to the Functional Assessment of Chronic Illness Therapy Measurement System (FACIT). The FACT-G (G for general) questionnaire (27 questions) constitutes the core of all subscales and is applicable to all tumor types. The FACT-C questionnaire contains 9 additional questions on symptoms specific to CRC, 2 of which are only answered by patients with ostomy appliances. These 9 CRC-specific questions are categorized as "additional concerns" on the questionnaire and constitute the "colorectal cancer subscale" score. The patient self-reports his/her QoL for the previous 7 days. The overall score is calculated across all items and a higher score reflects better quality of life (QoL). The table summarizes the functional well-being subscale, the individual questions are linearly scaled and combined to form the functional well-being subscale score, which ranges from 0-28 (higher is better QoL).
(Phase 3) Change From Baseline in the EuroQol-5D-5L (EQ-5D-5L) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
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 patient and ranges from 0 to 100 (higher is better quality health).
(Phase 3) Change From Baseline in the Patient Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet [Duration of Phase 3, approximately 6 months (up to 28 days per cycle)]
The PGIC is a measure of patients' 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 patient reported outcome (PROs). For this assessment, patients 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."
(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Cetuximab [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Encorafenib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Binimetinib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Metabolite of Binimetinib (AR00426032) [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032) [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032) [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib [Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2]
(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib [2 and 6 hours post-dose on Day 1 of Cycle 1. Predose and 2 hours post-dose on Day 1 of Cycle 2.]
The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib [2 and 6 hours post-dose on Day 1 of Cycle 1. Predose and 2 hours post-dose on Day 1 of Cycle 2.]
The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
(Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab [2 and 6 hours post-dose on Day 1 of Cycle 1. Predose and 2 hours post-dose on Day 1 of Cycle 2.]
The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Hospital	Phoenix	Arizona	United States	85054
2	Mayo Clinic	Phoenix	Arizona	United States	85054
3	Mayo Clinic	Scottsdale	Arizona	United States	85259
4	City of Hope (City of Hope National Medical Center, City of Hope Medical Center)	Duarte	California	United States	91010
5	Compassionate Care Research Group, Inc. at Compassionate Cancer Care Medical Group, Inc.	Fountain Valley	California	United States	92708
6	Keck Hospital of USC - Norris Healthcare Center (HC3)	Los Angeles	California	United States	90033
7	Keck Hospital of USC	Los Angeles	California	United States	90033
8	LAC+USC Medical Center	Los Angeles	California	United States	90033
9	Norris Healthcare Center 3 (HC3)	Los Angeles	California	United States	90033
10	USC Eye Institute	Los Angeles	California	United States	90033
11	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
12	Hoag Memorial Hospital Presbyterian	Newport Beach	California	United States	92663
13	Harvard Eye Associates	Orange	California	United States	92868
14	Rocky Mountain Lions Eye Institute	Aurora	Colorado	United States	80045
15	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
16	University of Colorado Denver CTO (CTRC)	Aurora	Colorado	United States	80045
17	University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)	Aurora	Colorado	United States	80045
18	University of Colorado Hospital Inpatient Pavillion'	Aurora	Colorado	United States	80045
19	Smilow Cancer Hospital at Yale - New Haven	New Haven	Connecticut	United States	06510
20	Temple Medical Center	New Haven	Connecticut	United States	06510
21	Yale University, Yale Cancer Center	New Haven	Connecticut	United States	06520
22	Smilow Cancer Hospital Care Center at North Haven	North Haven	Connecticut	United States	06473
23	The Lennar Foundation Medical Center	Coral Gables	Florida	United States	33146
24	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
25	Dr. Clayton Berger (opthalmology)	Fort Lauderdale	Florida	United States	33316
26	Mehmet F. Hepgur, MD - Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
27	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
28	Bascon Palmer Eye Institue	Miami	Florida	United States	33136
29	Sylvester Comprehensive Cancer Center/UMHC	Miami	Florida	United States	33136
30	Sylvester at Kendall	Miami	Florida	United States	33176
31	Illinois CancerCare- Bloomington	Bloomington	Illinois	United States	61704
32	University of Chicago Medical Center	Chicago	Illinois	United States	60637
33	Illinois CancerCare- Galesburg	Galesburg	Illinois	United States	61401
34	University of Chicago Comprehensive Cancer Center at Silver Cross Hospital	New Lenox	Illinois	United States	60451
35	The University of Chicago Medicine Center for Advanced Care Orland Park	Orland Park	Illinois	United States	60462
36	Illinois CancerCare- Ottawa	Ottawa	Illinois	United States	61350
37	Illinois Cancer Care, PC	Peoria	Illinois	United States	61615
38	Illinois Eye Center	Peoria	Illinois	United States	61615
39	Carle Cancer Center	Urbana	Illinois	United States	61801
40	Indiana University Health Hospital	Indianapolis	Indiana	United States	46202
41	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
42	Investigational Drug Services IUHSCC	Indianapolis	Indiana	United States	46202
43	Sidney &Lois Eskenazi Hospital	Indianapolis	Indiana	United States	46202
44	IU Health Springmill	Indianapolis	Indiana	United States	46290
45	Baptist Health Floyd Cancer Center	New Albany	Indiana	United States	47150
46	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
47	The University of Kansas Clinical Research Center	Fairway	Kansas	United States	66205
48	The University of Kansas Hospital	Kansas City	Kansas	United States	66160
49	KU Eye	Prairie Village	Kansas	United States	66208
50	The University of Kansas Cancer Center and Medical Pavilion	Westwood	Kansas	United States	66205
51	The University of Kansas Cancer Center, Investigational Drug Services	Westwood	Kansas	United States	66205
52	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
53	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287
54	The Investigational Drug Pharmacy (IDS) in the Sidney Kimmel Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287
55	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287
56	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
57	Ophthalmic Consultants of Boston Inc	Boston	Massachusetts	United States	02114
58	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
59	Dana-Farber Cancer Institute (DFCI)	Boston	Massachusetts	United States	02215
60	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
61	Mayo Clinic	Rochester	Minnesota	United States	55905
62	Siteman Cancer Center - West County	Creve Coeur	Missouri	United States	63141
63	SSM Health Saint Louis University Hospital	Saint Louis	Missouri	United States	63104
64	Barnes Jewish Hospital	Saint Louis	Missouri	United States	63110
65	Saint Louis University	Saint Louis	Missouri	United States	63110
66	SSM Health Saint Louis University Hospital	Saint Louis	Missouri	United States	63110
67	Washington University Infusion Center Pharmacy	Saint Louis	Missouri	United States	63110
68	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
69	Siteman Cancer Center - South County	Saint Louis	Missouri	United States	63129
70	Siteman Cancer Center - St Peters	Saint Peters	Missouri	United States	63376
71	Memorial Sloan Kettering: Commack	Commack	New York	United States	11725
72	Memorial Sloan Kettering: Rockefeller Outpatient Pavilion	New York	New York	United States	10022
73	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
74	Gabrail Cancer Center Research	Canton	Ohio	United States	44718
75	Cleveland Clinic Taussig Cancer Institute	Cleveland	Ohio	United States	44195
76	Casey Eye Institute-South Waterfront	Portland	Oregon	United States	97239
77	OHSU Center for Health and Healing	Portland	Oregon	United States	97239
78	OHSU Research Pharmacy Services	Portland	Oregon	United States	97239
79	Oregon Health and Science University	Portland	Oregon	United States	97239
80	Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
81	Vanderbilt Eye Institute	Nashville	Tennessee	United States	37232
82	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
83	Scott & White Clinic - Temple Pavilion	Temple	Texas	United States	76504
84	Scott & White Medical Center - Temple	Temple	Texas	United States	76508
85	Medical Oncology Associates, PS DBA Summit Cancer Centers	Spokane Valley	Washington	United States	99216
86	Spokane Eye Clinic	Spokane	Washington	United States	99204
87	Inland Imaging, LLC Holy Family Hospital	Spokane	Washington	United States	99208
88	Medical Oncology Associates, PS DBA Summit Cancer Centers	Spokane	Washington	United States	99208
89	Providence Holy Family Nuclear Medicine	Spokane	Washington	United States	99208
90	University of Wisconsin Clinical Science Center	Madison	Wisconsin	United States	53792
91	CLINICA PERGAMINO S.A. (Centro de Investigacion Pergamino S.A.)	Pergamino	Buenos Aires	Argentina	2700
92	Centro Medico INFINITO	Santa Rosa	LA Pampa	Argentina	L6300EAN
93	Centro Medico CAIPO (Centro para la Atención del paciente Oncológico)	San Miguel de Tucumán	Tucumán	Argentina	T4000GTB
94	Clinica Universitaria Reina Fabiola	Cordoba		Argentina	X5004FHP
95	Centro Oncologico Riojano Integral - CORI	La Rioja		Argentina	5300
96	St Vincent's Clinic	Darlinghurst	NEW South Wales (nsw)	Australia	2010
97	St Vincent's Hospital Sydney	Darlinghurst	NEW South Wales (nsw)	Australia	2010
98	Marsden Eye Specialists	Parramatta	NEW South Wales (nsw)	Australia	2150
99	Newcastle Eye Centre	Sydney	NEW South Wales (nsw)	Australia	2300
100	Mater Misericordiae Limited	South Brisbane	Queensland	Australia	4101
101	Central Adelaide Local Health Network Inc. operating as Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
102	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
103	Central Adelaide Local Health Network Inc. operating as The Queen Elizabeth Hospital	Woodville South	South Australia	Australia	5011
104	Monash Health Translation Precinct - Monash Health	Clayton	Victoria	Australia	3168
105	Austin Health	Heidelberg	Victoria	Australia	3084
106	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
107	Klinikum Wels - Grieskirchen GmbH, Abteilung fuer Innere Medizin IV	Wels	Oberoesterreich	Austria	4600
108	Klinikum Wels-Grieskirchen GmbH, Abteilung fuer Augenheilkunde und Optometrie	Wels	Oberoesterreich	Austria	4600
109	Klinikum Wels-Grieskirchen GmbH, Abteilung fuer Innere Medizin II	Wels	Oberoesterreich	Austria	4600
110	Klinikum Wels-Grieskirchen GmbH, Apotheke	Wels	Oberoesterreich	Austria	4600
111	Klinikum Wels-Grieskirchen GmbH, Institut fuer Nuklearmedizin	Wels	Oberoesterreich	Austria	4600
112	Klinikum Wels-Grieskirchen GmbH, Institut fuer Radiologie I	Wels	Oberoesterreich	Austria	4600
113	DZU, Diagnose Zentrum Urania GmbH	Wien		Austria	1010
114	AKH Wien	Wien		Austria	1090
115	Medizinische Universitaet Wien/AKH Wien	Wien		Austria	1090
116	Medizinische Universität Wien/AKH Wien	Wien		Austria	1090
117	Centre Hospitalier de l'Ardenne - Site de Libramont	Libramont-Chevigny	Luxembourg	Belgium	6800
118	AZ Sint-Jan Brugge - Oostende AV - Campus Sint-Jan - Oncology	Brugge	WEST Vlaanderen	Belgium	8000
119	Imelda Ziekenhuis	Bonheiden		Belgium	2820
120	Grand Hopital de Charleroi (GHdC)	Charleroi		Belgium	6000
121	UZ Antwerpen	Edegem		Belgium	2650
122	AZ Maria Middelares	Gent		Belgium	9000
123	University Hospital Gasthuisberg (UZ Leuven)	Leuven		Belgium	3000
124	Centre Hospitalier Universitaire (CHU) de Liege	Liege		Belgium	4000
125	CHC Saint Joseph	Liege		Belgium	4000
126	AZ Delta Roeselaere-Menen	Roeselaere		Belgium	8800
127	Centre Hospitalier Regional (CHR) - Verviers	Verviers		Belgium	4800
128	Hospital do Hlho	Salvador	Bahia	Brazil	41820-020
129	CENOB - Centro de Oncologia da Bahia SS Ltda / Oncovida	Salvador	Bahia	Brazil	41820-021
130	CEMES Centro Medico Especializado em Oftalmologia	Cachoeiro de Itapemirim	ES	Brazil	29300-045
131	Centro de Pesquisas Clínicas em Oncologia	Cachoeiro de Itapemirim	ES	Brazil	29308-014
132	Hospital Evangelico de Cachoeiro de Itapemirim	Cachoeiro de Itapemirim	ES	Brazil	29308-055
133	Instituto Vizibelli	Belo Horizonte	Minas Gerais	Brazil	30110-921
134	CENANTRON - Centro Avancado de Tratamento Oncologic	Belo Horizonte	Minas Gerais	Brazil	30130-090
135	Fundação Universidade de Caxias do Sul	Caxias do Sul	RS	Brazil	95070-560
136	Daniel Lubisco Pandolfi	Lajeado	RS	Brazil	95900-000
137	Sociedade Beneficencia e Cardade de Lajeado/Hospital Bruno Born	Lajeado	RS	Brazil	95900-000
138	Sociedade Beneficencia e Cardade de Lajeado/Hospital Bruno Born	Lajeado	RS	Brazil	95900-010
139	Associacao Hospitalar Beneficente Sao Vicente de Paulo / Hospital Sao Vicente de Paulo	Passo Fundo	RS	Brazil	99010-080
140	Consultorio Medico de Oftalmologia - Dr. Ricardo Tres	Passo Fundo	RS	Brazil	99010-080
141	Hospital Sao Vicente de Paulo	Passo Fundo	RS	Brazil	99010-090
142	Thiago Vernetti Ferreira	Pelotas	RS	Brazil	96010-140
143	Leandro Becker	Pelotas	RS	Brazil	96015-280
144	Fernanda Mendes	Pelotas	RS	Brazil	96020-080
145	UPCO - Unidade de Pesquisas Clinicas em Oncologia	Pelotas	RS	Brazil	96020-080
146	Fernanda Lauermann	Pelotas	RS	Brazil	96020-260
147	Diogo Duarte Torre	Porto Alegre	RS	Brazil	90020-013
148	Farmacia Central da Irmandade da Santa Casa de Misericordia de Porto Alegre	Porto Alegre	RS	Brazil	90020-090
149	Irmandade da Santa Casa de Misericordia de Porto Alegre	Porto Alegre	RS	Brazil	90020-090
150	Nucleo de Novos Tratamentos em Cancer	Porto Alegre	RS	Brazil	90050-170
151	Centro de Pesquisa Clínica de Oncologia e Hematologia - Hospital Mãe de Deus/AESC	Porto Alegre	RS	Brazil	90110-270
152	Clinica de Oftalmologia Lavinsky	Porto Alegre	RS	Brazil	90470-340
153	Hospital Mãe de Deus	Porto Alegre	RS	Brazil	90880-480
154	Clinica Toller	Barretos	SAO Paulo	Brazil	14780-110
155	Olhos Centro Diagnostico e Laser LTDA	Barretos	SAO Paulo	Brazil	14780-300
156	Fundacao Pio XII	Barretos	SAO Paulo	Brazil	14784-400
157	Giuliano Santos Borges - ME / Clinica de Neoplasias Litoral - Centro de Novos Tratamentos Itajai	Itajai	SC	Brazil	88301-220
158	FUNDAÇÃO DO ABC - Faculdade de Medicina do ABC	Santo Andre	SP	Brazil	09060-650
159	FUNDAÇÃO DO ABC - Faculdade de Medicina do ABC	Santo Andre	SP	Brazil	09060-870
160	Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto	Sao Jose do Rio Preto	SP	Brazil	15090-000
161	CEPOS - Centro de Estudos e Pesquisas Oncologicas de Sorocaba	Sorocaba	SP	Brazil	18030-075
162	Instituto de Oncologia de Sorocaba "Dr. Gilson Delgado"	Sorocaba	SP	Brazil	18030-200
163	Karen Miyuki Kubokawa Shorer	Sorocaba	SP	Brazil	18040-425
164	Oftalmologia Diagnostica de Sorocaba (ODS)	Sorocaba	SP	Brazil	18047-620
165	Instituto de Ensino e Pesquisa São Lucas	São Paulo		Brazil	01236-030
166	Instituto de Ensino e Pesquisa São Lucas - Pharmacy	São Paulo		Brazil	01242-020
167	Hospital Leforte	São Paulo		Brazil	01507-000
168	IPEPO - Instituto da Visao	São Paulo		Brazil	04038-020
169	Eye Care Centre, Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 3N9
170	BC Cancer, Vancouver Center	Vancouver	British Columbia	Canada	V5Z 4E6
171	The Ottawa Hospital Cancer Centre	Ottawa	Ontario	Canada	K1H 8L6
172	Sunnybrook Research Institute	Toronto	Ontario	Canada	M4N 3M5
173	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
174	Centre integre universitaire de sante et de services sociaux de l'Ouest-de-l'Ile-de-Montreal	Montreal	Quebec	Canada	H3T 1M5
175	Instituto Clinico Oncologico del Sur (ICOS)	Temuco	Region DE LA Araucania	Chile	4810469
176	Hospital Clinico Vina Del Mar	Vina del Mar	V Region Valparaiso	Chile	2520612
177	Ocni ordinace Oftalpro s.r.o.	Brno		Czechia	603 00
178	Masarykuv onkologicky ustav	Brno		Czechia	656 53
179	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
180	Fingerlanduv ustav patologie	Hradec Kralove		Czechia	500 05
181	I. interni kardioangiologicka klinika	Hradec Kralove		Czechia	500 05
182	Klinika nemoci koznich a pohlavnich	Hradec Kralove		Czechia	500 05
183	Nemocnicni lekarna - Usek klinickych studii	Hradec Kralove		Czechia	500 05
184	Ocni klinika	Hradec Kralove		Czechia	500 05
185	Radiologicka klinika	Hradec Kralove		Czechia	500 05
186	Fakultni nemocnice Olomouc, I. interni klinika - kardiologicka	Olomouc		Czechia	779 00
187	Fakultni nemocnice Olomouc, Lekarna	Olomouc		Czechia	779 00
188	Fakultni nemocnice Olomouc	Olomouc		Czechia	779 00
189	Odense University Hospital (OUH)	Odense C		Denmark	DK-5000
190	Hopital Jean Minjoz	Besancon Cedex		France	25030
191	CHU Morvan	BREST Cedex		France	29609
192	Centre Ophtalmologique - Pole Vision - Clinique Val d'Ouest	Ecully		France	69130
193	Centre Leon Berard	Lyon Cedex 08		France	69373
194	ICM Val d'Aurelle	Montpellier Cedex 5		France	34298
195	CHU HOTEL-Dieu	Nantes Cedex		France	44093
196	Centre hospitalier national d'ophtalmologie des Quinze-Vingts	Paris Cedex 12		France	75571
197	Centre Hospitalier National d'Opthalmologie des Quinze-Vingts (CHNO des XV-XX)	Paris Cedex 12		France	75571
198	Hopital Georges Pompidou	Paris		France	75015
199	CHU Robert Debre	Reims Cedex		France	51092
200	SCM Centre d'ophtalmologie	Saint Jeand De Vedas		France	34430
201	CHU Toulouse-Institut Inuversitaire du Cancer Toulouse	Toulouse Cedex 9		France	31059
202	CHU Toulouse-Rangueil	Toulouse Cedex 9		France	31059
203	CHU Toulouse - Purpan, hopital Pierre-Paul Riquet	Toulouse		France	31057
204	Gustave Roussy	Villejuif Cedex		France	94805
205	Universitaetsklinikum Tuebingen	Tuebingen	Baden-wuerttemberg	Germany	72076
206	Universitaetsklinikum Ulm	Ulm	Baden-wuerttemberg	Germany	89081
207	Augenklinik der Universitaet Muenchen	Muenchen	Bayern	Germany	80336
208	LMU Klinikum der Universitaet Muenchen, Campus Grosshadern	Muenchen	Bayern	Germany	81377
209	Augenarzt-Gemeinschaftspraxis Dr.med.Andreas Kind & Dr.med. Ute Kariger-Schweigert	Falkensee	Brandenburg	Germany	14612
210	Medizinische Hochschule Hannover (MHH)	Hannover	Niedersachsen	Germany	30625
211	Medizinische Hochschule Hannover	Hannover	Niedersachsen	Germany	30625
212	Kliniken Essen Mitte / Knappschaftskrankenhaus	Essen	Nordrhein-westfalen	Germany	35136
213	Praxis fuer Augenheilkunde Dr. Edmund Meyer-Schwickerath	Essen	Nordrhein-westfalen	Germany	45131
214	Kliniken Essen-Mitte	Essen	Nordrhein-westfalen	Germany	45136
215	Universitaetsklinikum Essen (AoeR), Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum	Essen	Nordrhein-westfalen	Germany	45147
216	Universitaetsklinikum Essen; Diagnostischeu. Interventionelle Radiologie u. Neuroradiologie	Essen	Nordrhein-westfalen	Germany	45147
217	Universitaetsklinikum Essen; Nuklearmedizin	Essen	Nordrhein-westfalen	Germany	45147
218	Universitaetsklinikum Essen; Zentralapotheke	Essen	Nordrhein-westfalen	Germany	45147
219	Evang. Krankenhaus Essen - Werden; Klinik fuer Augenheilkunde	Essen	Nordrhein-westfalen	Germany	45239
220	Kliniken Essen Mitte / Knappschaftskrankenhaus	Essen	Nordrhein-westfalen	Germany	45276
221	Augentagesklinik Maria-Hilf Krankenhaus	Moenchengladbach	Nordrhein-westfalen	Germany	41063
222	Kliniken Maria Hilf GmbH - Franziskuskrankenhaus	Moenchengladbach	Nordrhein-westfalen	Germany	41063
223	Kliniken Maria Hilf GmbH; Klinik fuer Radiologie	Moenchengladbach	Nordrhein-westfalen	Germany	41063
224	Lukaskrankenhaus Neuss; Zentrale Apotheke	Neuss	Nordrhein-westfalen	Germany	41464
225	Institut f. Pathologie - Ruhr-Universitaet Bochum, Prof. Dr. med. Andrea Tannapfel	Bochum	North Rhine Westfalia	Germany	44789
226	Augenarzt Praxis Dr. med. Petra Huelsmann	Worms	Rheinland-pfalz	Germany	67547
227	Gemeinschaftspraxis fuer Radiologie und Nuklearmedizin, Standort Worms	Worms	Rheinland-pfalz	Germany	67547
228	Martin Apotheke	Worms	Rheinland-pfalz	Germany	67547
229	Onkologische Schwerpunktpraxis Worms	Worms	Rheinland-pfalz	Germany	67547
230	Praxisgemeinschaft Kruse + Hofstaetter	Worms	Rheinland-pfalz	Germany	67547
231	Evangelisches Waldkrankenhaus Spandau	Berlin		Germany	13589
232	Universitaetsklinikum Carl Gustav Carus der Technischen Universitaet Dresden	Dresden		Germany	01307
233	Universitaetsklinikum Hamburg Eppendorf, Klinik fuer Augenheilkunde	Hamburg		Germany	20246
234	Facharztzentrum Eppendorf	Hamburg		Germany	20249
235	Universitaetsklinikum Hamburg Eppendorf, Zentrum fuer Radiologie und Endoskopie	Hamburg		Germany	20251
236	ZytoService Deutschland GmbH, Standort-Hamburg-Jenfeld	Hamburg		Germany	22045
237	HKS Kardiologische Praxis am Israelitischen Krankenhaus	Hamburg		Germany	22297
238	Radiologie im Israelitischen Krankenhaus	Hamburg		Germany	22297
239	Zala Megyei Szent Rafael Korhaz - Onkologiai Osztaly	Zalaegerszeg	Zala	Hungary	H-8900
240	Szent Margit Kórház	Budapest		Hungary	1032
241	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest		Hungary	1062
242	Egyesitett Szent Istvan es Szent Laszlo Korhaz-Rendelointezet	Budapest		Hungary	1097
243	Uzsoki Utcai Korhaz	Budapest		Hungary	1145
244	Debreceni Egyetem Klinikai Kozpont	Debrecen		Hungary	4032
245	Pecsi Tudomanyegyetem Altalanos Orvostudomanyi Kar	Pecs		Hungary	7624
246	Pecsi Tudomanyegyetem Klinikai Kozpont	Pecs		Hungary	7624
247	Tel Aviv Sourasky Medical Center - Oncology	Tel-Aviv	NAP	Israel	6423906
248	The Barzilai Medical Center - Oncology Institute	Ashkelon		Israel	7830604
249	Soroka University Medical Center	Be'er-Sheva		Israel	8410101
250	MOR Institute	Bnei Brak		Israel	5126413
251	Ein-Karem Department of Medical Imaging of Hadassah Medical Organization, Hadassah Medical Center,	Jerusalem		Israel	9112001
252	Hadassah Medical Organization, Hadassah Medical Center, Ein-Karem	Jerusalem		Israel	9112001
253	Pharmacy of Hadassah Medical Organization, Hadassah Medical Center, Ein-Karem	Jerusalem		Israel	9112001
254	Mt. Scopus Department of Medical Imaging of Hadassah Medical Organization,	Jerusalem		Israel	91240
255	Imaging Department of Meir Medical Center	Kfar Saba		Israel	4428164
256	Meir Medical Center	Kfar Saba		Israel	4428164
257	Pharmacy of Meir Medical Center	Kfar Saba		Israel	4428164
258	Pharmacy of Rabin Medical Center, Beilinson Hospital	Petah Tikva		Israel	4941492
259	Rabin Medical Center, Beilinson Hospital	Petah Tikva		Israel	4941492
260	The Chaim Sheba Medical Center	Tel-Hashomer		Israel	5262100
261	Ospedali Riuniti Umberto I	Torrette Di Ancona	Ancona	Italy	60020
262	ASST Bergamo Ovest, Ospedale Treviglio Caravaggio di Trevigl	Treviglio	Bergamo	Italy	24047
263	Farmacia - ASST Papa Giovanni XXIII	Bergamo	BG	Italy	24127
264	Oculistica, ASST Papa Giovanni XXIII	Bergamo	BG	Italy	24127
265	Oncologia, ASST Papa Giovanni XXIII	Bergamo	BG	Italy	24127
266	Clinica di Oncologia Medica AOU di Cagliari Presidio Duilio Casula Monserrato	Monserrato	Cagliari	Italy	09042
267	Farmacia AOU di Cagliari Presidio Duilio Casula Monserrato	Monserrato	Cagliari	Italy	09042
268	Radiologia AOU di Cagliari Presidio Duilio Casula Monserrato	Monserrato	Cagliari	Italy	09042
269	Oculistica - ASST Cremona, Ospedale di Cremona	Cremona	CR	Italy	26100
270	SC Farmacia Aziendale - ASST Cremona, Ospedale di Cremona	Cremona	CR	Italy	26100
271	SC Oncologia - ASST Cremona, Ospedale di Cremona	Cremona	CR	Italy	26100
272	U.O. Oculistica, Istituto Clinico HUMANITAS	Rozzano	Milano	Italy	20089
273	U.O. di Oncologia ed Ematologia, Istituto Clinico HUMANITAS	Rozzano (MI)	Milan	Italy	20089
274	IRCCS Ospedale San Raffaele - U.O. di Medicina Oncologica	Milano	MI	Italy	20132
275	Servizio di Farmacia - IRCCS Ospedale San Raffaele	Milano	MI	Italy	20132
276	S.C. Radiologia diagnostica e interventistica - Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	MI	Italy	20133
277	SC Farmacia - Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	MI	Italy	20133
278	SC Oncologia Medica 1, SS Oncologia Medica Gastroenterologica	Milano	MI	Italy	20133
279	Cardiologia per i pazienti oncologici - Istituto Oncologico Veneto I.R.C.C.S	Padova	PD	Italy	35128
280	Clinica Oculistica - Azienda Ospedaliera di Padova	Padova	PD	Italy	35128
281	Servizio Farmacia - Istituto Oncologico Veneto I.R.C.C.S	Padova	PD	Italy	35128
282	U.O. Oncologia Medica 1 - Istituto Oncologico Veneto I.R.C.C.S	Padova	PD	Italy	35128
283	Policlinico S.Orsola Malpighi, AOU di Bologna - Oncologia Medica	Bologna		Italy	40138
284	Divisione Anatomia Patologica Presidio San Giovanni di Dio	Cagliari		Italy	09124
285	Oculistica AOU di Cagliari Presidio San Giovanni di Dio	Cagliari		Italy	09124
286	AOU Careggi - Oncologia Medica 1	Firenze		Italy	50134
287	SC oncologia Medica I - Azienda Ospedaliero Universitaria Careggi	Firenze		Italy	50134
288	Radiologia	Milano		Italy	20141
289	Servizio Farmacia Ospedaliera	Milano		Italy	20141
290	Unita di Oncologia Medica Gastrointestinale e Tumori Neuroendocrini	Milano		Italy	20141
291	Grande Ospedale Metropolitano Niguarda	Milano		Italy	20162
292	Dipartimento Interaziendale Farmaceutico - AOU Policlinico di Modena	Modena		Italy	41124
293	SC di Oftalmologia - AOU Policlinico di Modena	Modena		Italy	41124
294	SC di Radiologia, Dipartimento Interaziendale integrato Diagnostica per Immagini	Modena		Italy	41124
295	SSD Day Hospital Oncologico - Dipartimento ad attivita integrata di Oncologia, Ematologia	Modena		Italy	41124
296	AOU Universita degli Studi della Campania L. Vanvitelli - DAI di Medicina Interna e Specialistica	Napoli		Italy	80131
297	AOU Universita degli Studi della Campania L. Vanvitelli - U. Ma.Ca.	Napoli		Italy	80131
298	AOU Universita degli Studi della Campania L. Vanvitelli	Napoli		Italy	80131
299	AOU Universita degli Studi della Campania L. Vanvitelli	Napoli		Italy	80138
300	UO Oculistica - AOU Pisana, Stabilimento Ospedaliero di Cisanello	Pisa		Italy	56124
301	SOD Radiodiagnostica 3 - AOU Pisana, Stabilimento Ospedaliero di Santa Chiara	Pisa		Italy	56126
302	UO Farmaceutica, Gestione del Farmaco - AOU Pisana, Stabilimento Ospedaliero di Santa Chiara	Pisa		Italy	56126
303	UO Oncologia Medica 2 - AOU Pisana, Stabilimento Ospedaliero di Santa Chiara	Pisa		Italy	56126
304	U.O.C. Farmacia Clinica - Fondazione PTV Policlinico Tor Vergata	Roma		Italy	00133
305	U.O.S.D. Oncologia Medica, Dipartimento di Medicina - Fondazione PTV Policlinico Tor Vergata	Roma		Italy	00133
306	U.O.S.D. Patologie Retiniche - Fondazione PTV Policlinico Tor Vergata	Roma		Italy	00133
307	Chayagasaka Eye Clinic	Nagoya	Aichi	Japan	464-0092
308	Aichi Cancer Center Hospital	Nagoya	Aichi	Japan	464-8681
309	National Cancer Center Hospital East	Kashiwa-shi	Chiba	Japan	277-8577
310	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
311	Kanazawa University Hospital	Kanazawa	Ishikawa	Japan	920-8641
312	St. Marianna University School of Medicine Hospital	Kawasaki	Kanagawa	Japan	216-8511
313	Tsukahara Eye Clinic	Yokohama	Kanagawa	Japan	241-0821
314	Kanagawa Cancer Center	Yokohama	Kanagawa	Japan	241-8515
315	Osaka University Hospital Laboratory for Clinical Investigation	Suita	Osaka	Japan	565-0871
316	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
317	National Hospital Organization Kyushu Cancer Center	Fukuoka		Japan	811-1395
318	Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers	Fukuoka		Japan	815-8588
319	National Hospital Organization Osaka National Hospital	Osaka		Japan	540-0006
320	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
321	Ajou University Hospital	Suwon	Gyeonggi-do	Korea, Republic of	16499
322	Hallym University Sacred Heart Hospital	Anyang	Gyeonggido	Korea, Republic of	14068
323	Chonnam National University Hwasun Hospital	Hwasun-gun	Jeollanam-do	Korea, Republic of	58128
324	Korea University Guro Hospital	Seoul	Seoul Teugbyeolsi	Korea, Republic of	08308
325	Dong-A University Hospital	Busan		Korea, Republic of	49201
326	Gachon University Gil Medical Center	Incheon		Korea, Republic of	21565
327	Korea University Anam Hospital IRB	Seoul		Korea, Republic of	02841
328	Seoul National University Hospital	Seoul		Korea, Republic of	03080
329	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
330	Asan Medical Center	Seoul		Korea, Republic of	05505
331	Samsung Medical Center	Seoul		Korea, Republic of	06351
332	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	06591
333	Superare Centro de Infusion S.A. de C.V.	Delegacion Cuauhtemoc	Ciudad DE Mexico	Mexico	06760
334	Consultorio dentro de la Torre Medica Dalinde (Oncologia Medica)	Ciudad de Mexico	Cuauhtemoc	Mexico
335	Rijnstate Hospital Arnhem	Arnhem	Gelderland	Netherlands	6815 AD
336	Rijnstate Hospital Velp	Velp	Gelderland	Netherlands	6883 AZ
337	Maastricht University Medical Center (MUMC)	Maastricht	Limburg	Netherlands	6229HX
338	The Netherlands Cancer Institute	Amsterdam	Noord-holland	Netherlands	1066 CX
339	Onze Lieve Vrouwen Gasthuis	Amsterdam	Noord-holland	Netherlands	1091 AC
340	Haga Ziekenhuis	Den Haag	Zuid-holland	Netherlands	2545 AA
341	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584 CX
342	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584CX
343	Colosseum Øyelegesenter C/O LB Holdings AS	Lommedalen		Norway	1350
344	Colosseum Øyelegesenter C/O LB Holdings AS	Oslo		Norway	0369
345	Oslo universitetssykehus, Radiumhospitalet	Oslo		Norway	0379
346	Sykehusapoteket Oslo, Radiumhospitalet	Oslo		Norway	0379
347	Szpital Specjalistyczny W Brzozowie, Podkarpacki Osrodek Onkologiczny Im.Ks.B.Markiewicza	Brzozow		Poland	36-200
348	Wojewodzki Szpital Zespolony, Oddzial Onkologiczny	Elblag		Poland	82-300
349	Szpital Specjalistyczny im. L. Rydygiera w Krakowie Sp.z.o.o.	Krakow		Poland	31-826
350	Europejskie Centrum Zdrowia Otwock, Szpital im. F. Chopina	Otwock		Poland	05-400
351	NZOZ Centrum Medyczne HCP	Poznan		Poland	61-485
352	NZOZ Przychodnia Specjalistyczna GUTMED	Poznan		Poland	61495
353	Centrum Medyczne MAVIT Sp. z o.o.	Warszawa		Poland	01-673
354	MAGODENT Sp. z o.o. Szpital Elblaska	Warszawa		Poland	01-748
355	Magodent Sp. z o.o., Przychodnia Specjalistyczna i Rehabilitacja, Poradnia Okulistyczna	Warszawa		Poland	02-524
356	MAGODENT Sp. z o.o. Szpital Onkologiczny, Oddzial Onkologii Klinicznej i Chemioterapii	Warszawa		Poland	03-291
357	Magodent Sp. z o.o., Szpital Onkologiczno-Kardiologiczny, Dzial Farmacji Szpitalnej	Warszawa		Poland	04-125
358	Regional Budgetary Healthcare Institution Kursk Regional Clinical	Kursk	Kursk Region	Russian Federation	305524
359	Evimed Llc	Chelyabinsk		Russian Federation	454048
360	Federal State Budget Institution "N.N. Blokhin Russian Cancer Research Center" of the	Moscow		Russian Federation	115478
361	Federal State Budget Institution "N.N. Blokhin Russian Cancer Research Center"	Moscow		Russian Federation	115478
362	A. Tsyb Medical Radiological Research Center - branch of the	Obninsk		Russian Federation	249036
363	State Budgetary Educational Institution of Higher Professional Education First Saint Petersburg	Sankt-Petersburg		Russian Federation	197022
364	Complejo Hospitalario de Jaen	Jaen	Andalucia	Spain	23007
365	Sercosa - Clinica de las Nieves	Jaen	Andalucia	Spain	23007
366	Hospital Universitario Son Espases	Palma de Mallorca	Baleares	Spain	07010
367	Institut Catala d'Oncologia	L'Hospitalet de Llobregat	Barcelona	Spain	08908
368	Hospital Universitari Parc Tauli	Sabadell	Barcelona	Spain	08208
369	Hospital Universitario Reina Sofía	Cordoba	Cordona	Spain	14004
370	Hospital Nuestra Señora del Rosario	Madrid	Madrid, Communidad Delaware	Spain	28006
371	Hospital Universitari Sant Joan de Reus	Reus	Tarragona	Spain	43204
372	Hospital del Mar	Barcelona		Spain	08003
373	Clinica Corachan	Barcelona		Spain	08017
374	Hospital Quiron Salud Barcelona	Barcelona		Spain	08023
375	Cetir Centre Medic S.L.	Barcelona		Spain	08029
376	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
377	Hospital Universitario de Burgos	Burgos		Spain	09006
378	Consulta Dr. Juan Carlos Castillo Dominguez	Cordoba		Spain	14008
379	Gabinete Radiologico Dr. Pita	Madrid		Spain	28006
380	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28007
381	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
382	Hospital Clinico San Carlos	Madrid		Spain	28040
383	Hospital Universitario Fundacion Jimenez Diaz	Madrid		Spain	28040
384	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
385	Hospital Universitario La Paz	Madrid		Spain	28046
386	Hospital HM Universitario Sanchinarro	Madrid		Spain	28050
387	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
388	Clinica Oftalvist	Valencia		Spain	46004
389	Fundacion Instituto Valenciano de Oncologia	Valencia		Spain	46009
390	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
391	Hospital General Universitario de Valencia	Valencia		Spain	46014
392	Hospital Quiron Salud Zaragoza	Zaragoza		Spain	50006
393	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
394	Changhua Christian Hospital	Changhua city	Changhua County	Taiwan	500
395	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan	807
396	China Medical University Hospital	Taichung		Taiwan	40447
397	National Cheng Kung University Hospital	Tainan		Taiwan	704
398	National Taiwan University Hospital	Taipei		Taiwan	10002
399	Chang Gung Memorial Hospital, Linkou	Taoyuan		Taiwan	333
400	Ege University Medical Faculty	Izmir	Bornova	Turkey	35100
401	Izmir Medical Park Hospital - Medical Oncology	Izmir	Izmir, Karsiyaka	Turkey	35575
402	Istanbul Medeniyet University Göztepe Training and Research Hospital	Istanbul	Kadikoy	Turkey	34722
403	Hacettepe University Medical Faculty	Ankara		Turkey	06230
404	Uludag University Medical Faculty	Bursa		Turkey	16059
405	Trakya Universitesi Tip Fakultesi	Edirne		Turkey	22030
406	Inonu Universitesi Turgut Ozal Medical Center	Malatya		Turkey	44280
407	Oftalmolohycheskyi tsentr "Vzghliad" MTs	Dnipropetrovsk	Dnipropetrovska Oblast'	Ukraine	41100
408	Oftalmolohycheskyi tsentr "Vzghliad" MTs	Dnipropetrovsk	Dnipropetrovska Oblast'	Ukraine	49027
409	Derzhavnyi zaklad, Dnipropetrovska medychna akademiia Ministerstva okhorony zdorovia Ukrainy	Dnipropetrovsk	Dnipropetrovska Oblast'	Ukraine	49102
410	Komumalnyi zaklad, Dnipropetrovska miska bahatoprofilna klinichna likarnia Nº4	Dnipropetrovsk	Dnipropetrovska Oblast'	Ukraine	49102
411	Kyivska klinichna likarnia na zaliznychnomu transporti No3 filii Tsentr okhorony zdorov'ia PAT	Kyiv	Kyivska Oblast'	Ukraine	02096
412	Natsionalnyi medychnyi universytet imeni O.O Bohomltsia, kafedra onkolohii	Kyiv	Kyivska Oblast'	Ukraine	02096
413	Natsionalnyi medychnyi universytet imeni O.O Bohomltsia, kafedra oftalmolohii	Kyiv	Kyivska Oblast	Ukraine	01601
414	Oleksandrivska klinichna likarnia mista Kyieva	Kyiv	Kyivska Oblast	Ukraine	01601
415	Kyivskyi miskyi klinichnyi onkotsentr	Kyiv	Kyivska Oblast	Ukraine	03115
416	Vinnytskyi oblasnyi klinichnyi onkolohichnyi dyspanser, viddilennia khimioterapii	Vinnytsia	Vinnyts'ka Oblast'	Ukraine	21029
417	DVNZ "Uzhhorodskyi natsionalnyi universytet"	Uzhgorod	Zakarpats'ka Oblast'	Ukraine	88000
418	Tsentralna miska klinichna likarnia, Miskyi onkolohichnyi tsentr	Uzhgorod	Zakarpats'ka Oblast'	Ukraine	88000
419	DVNZ "Uzhhorodskyi natsionalnyi universytet"	Uzhhorod	Zakarpatska Oblast	Ukraine	88000
420	TOV "Zakarpatskyi Tsentr Mikrokhirurhii Oka"	Uzhhorod	Zakarpatska Oblast	Ukraine	88000
421	NHS Grampian - Aberdeen Royal Infirmary	Aberdeen	Aberdeenshire Scotland	United Kingdom	AB25 2ZN
422	King Edward V11 Hospital	Windsor	Berkshire	United Kingdom	SL4 3DP
423	Beatson West of Scotland Cancer Centre	Glasglow	Glasglow City, Scotland	United Kingdom	G12 0YH
424	University Hospitals Birmingham NHS Foundation Trust Queen Elizabeth Hospital	Birmingham	WEST Midlands	United Kingdom	B15 2TH
425	Hammersmith Hospital, Imperial College Healthcare NHS Trust	London		United Kingdom	W12 0HS
426	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London		United Kingdom	W12 0HS
427	Sarah Cannon Research Institute UK	London		United Kingdom	W1G 6AD
428	Imperial College Healthcare NHS Trust, Charing Cross Hospital	London		United Kingdom	W6 8RF
429	The Christie NHS Foundation Trust - Christie Hospital	Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

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

Investigators

Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

More Information

Additional Information:

To obtain contact information for a study center near you, click here.

Publications

None provided.

Responsible Party:

Pfizer

ClinicalTrials.gov Identifier:

NCT02928224

Other Study ID Numbers:

ARRAY-818-302
BEACON CRC
2015-005805-35
C4221009

First Posted:

Oct 10, 2016

Last Update Posted:

Mar 16, 2022

Last Verified:

Mar 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Keywords provided by Pfizer

Colorectal cancer

BRAF

BRAFV600E

Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details	Patients were at least 18 years of age with confirmed metastatic colorectal cancer (CRC) whose disease had progressed after 1 or 2 prior regimens in the metastatic setting and whose tumor tissue was BRAF V600E-mutant as previously determined by a local assay at any time prior to Screening
Pre-assignment Detail

Arm/Group Title	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Period Title: Overall Study
STARTED	37	224	220	221
COMPLETED	0	0	0	0
NOT COMPLETED	37	224	220	221

Baseline Characteristics

Arm/Group Title	Combined Safety Lead-in (CSLI)	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm	Total
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.	Total of all reporting groups
Overall Participants	37	224	220	221	702
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	23 62.2%	141 62.9%	137 62.3%	149 67.4%	450 64.1%
>=65 years	14 37.8%	83 37.1%	83 37.7%	72 32.6%	252 35.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (10.34)	59.5 (11.65)	60.2 (11.65)	58.4 (12.07)	59.3 (61)
Sex: Female, Male (Count of Participants)
Female	22 59.5%	119 53.1%	105 47.7%	127 57.5%	373 53.1%
Male	15 40.5%	105 46.9%	115 52.3%	94 42.5%	329 46.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	7 18.9%	20 8.9%	25 11.4%	39 17.6%	91 13%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 2.7%	2 0.9%	0 0%	0 0%	3 0.4%
White	29 78.4%	195 87.1%	183 83.2%	172 77.8%	579 82.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	7 3.1%	12 5.5%	10 4.5%	29 4.1%
Region (Count of Participants)
North America	5 13.5%	30 13.4%	28 12.7%	29 13.1%	92 13.1%
Europe	25 67.6%	150 67%	145 65.9%	125 56.6%	445 63.4%
Rest of World (includes Mexico)	7 18.9%	44 19.6%	47 21.4%	67 30.3%	165 23.5%
Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Baseline (Count of Participants)
0-Fully active	22 59.5%	116 51.8%	112 50.9%	108 48.9%	358 51%
1-Restircted in physically strenuous activity	15 40.5%	108 48.2%	104 47.3%	113 51.1%	340 48.4%
2-Ambulatory and capable of all self-care	0 0%	0 0%	4 1.8%	0 0%	4 0.6%
Primary Tumor Location (Count of Participants)
Left Colon	11 29.7%	79 35.3%	83 37.7%	68 30.8%	241 34.3%
Right Colon	23 62.2%	126 56.3%	110 50%	119 53.8%	378 53.8%
Left and Right Colon	0 0%	8 3.6%	11 5%	22 10%	41 5.8%
Unknown	3 8.1%	11 4.9%	16 7.3%	12 5.4%	42 6%
Primary Tumor Removed (Count of Participants)
Completely Resected	20 54.1%	133 59.4%	123 55.9%	122 55.2%	398 56.7%
Partially Resected/Unresected	17 45.9%	91 40.6%	97 44.1%	99 44.8%	304 43.3%
Number of Organs Involved (Count of Participants)
>=2	16 43.2%	114 50.9%	117 53.2%	123 55.7%	370 52.7%
>=3	21 56.8%	110 49.1%	103 46.8%	98 44.3%	332 47.3%
Sites of Metastases (sites) [Number]
Liver	24	144	134	128	430
Lung	10	86	83	86	265
Lymph Node	17	86	82	88	273
NodePeritoneum/Omentum	17	77	97	93	284

Outcome Measures

1. Primary Outcome

Title	(Safety Lead-in) Number of Participants With Dose-limiting Toxicities (DLTs)
Description
Time Frame	Cycle 1 (up to 28 days)

Outcome Measure Data

Analysis Population Description
The Dose-determining Set (DDS) consisted of all CSLI patients from the Safety Set who either completed a minimum exposure requirement (received ≥ 75% dose intensity of the planned dose for each binimetinib, encorafenib and cetuximab) and had sufficient safety evaluations or experienced a dose-limiting toxicity (DLT).

Arm/Group Title	Combined Safety Lead-in (CSLI)
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Count of Participants [Participants]	5 13.5%

2. Primary Outcome

Title	(Safety Lead-in) Number of Participants With Adverse Events (AEs)
Description	Refer to AE/SAE section for additional data that were measured and analyzed.
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Safety Set consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Patients were analyzed according to treatment received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Count of Participants [Participants]	37 100%

3. Primary Outcome

Title	(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs)
Description
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Safety Set consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Patients were analyzed according to treatment received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Count of Participants [Participants]	26 70.3%

4. Primary Outcome

Title	(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	221
Median (95% Confidence Interval) [months]	9.03	5.42

5. Primary Outcome

Title	(Phase 3) 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
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	111	107
Number (95% Confidence Interval) [percentage of participants]	29 78.4%	2 0.9%

6. Secondary Outcome

Title	(Safety Lead-in) Response Rate (ORR) by Investigator
Description
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Safety Lead-in (SLI) Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Number (95% Confidence Interval) [percentage of participants]	52.8 142.7%

7. Secondary Outcome

Title	(Safety Lead-in) Response Rate (ORR) by BICR
Description	ORR per RECIST, v1.1, defined as the number of patients achieving an overall best response of CR or partial response (PR) divided by the total number of patients
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Number (95% Confidence Interval) [percentage of participants]	41.7 112.7%

8. Secondary Outcome

Title	(Safety Lead-in) Duration of Response (DOR) by Investigator
Description
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Median (95% Confidence Interval) [months]	6.47

9. Secondary Outcome

Title	(Safety Lead-in) Duration of Response (DOR) by BICR
Description	DOR defined as the time from first radiographic evidence of response to the earliest documented disease progression or death due to underlying disease
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Median (95% Confidence Interval) [months]	8.15

10. Secondary Outcome

Title	(Safety Lead-in) Time to Response by Investigator
Description	Time to response defined as the time from first dose to first radiographic evidence of response
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Median (95% Confidence Interval) [months]	1.45

11. Secondary Outcome

Title	(Safety Lead-in) Time to Response by BICR
Description	Time to response defined as the time from first dose to first radiographic evidence of response
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Median (95% Confidence Interval) [months]	1.45

12. Secondary Outcome

Title	(Safety Lead-in) Progression-free Survival (PFS) by Investigator
Description
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Median (95% Confidence Interval) [months]	8.08

13. Secondary Outcome

Title	(Safety Lead-in) Progression-free Survival (PFS) by BICR
Description	PFS defined as the time from first dose to the earliest documented disease progression or death due to any cause
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The SLI Efficacy Set consisted of all CSLI patients in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	36
Median (95% Confidence Interval) [months]	5.59

14. Secondary Outcome

Title	(Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	220	221
Median (95% Confidence Interval) [months]	8.41	5.42

15. Secondary Outcome

Title	(Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	224	220
Median (95% Confidence Interval) [months]	9.03	8.41

16. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	221
Median (95% Confidence Interval) [months]	4.30	1.51

17. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	221
Median (95% Confidence Interval) [months]	4.47	1.58

18. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Doublet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	220	221
Median (95% Confidence Interval) [months]	4.21	1.51

19. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Doublet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	220	221
Median (95% Confidence Interval) [months]	4.27	1.58

20. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	224	220
Median (95% Confidence Interval) [months]	4.30	4.21

21. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	224	220
Median (95% Confidence Interval) [months]	4.47	4.27

22. Secondary Outcome

Title	Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	221
Count of Participants [Participants]	49 132.4%	7 3.1%

23. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	113	107
Number (95% Confidence Interval) [participants]	23 62.2%	2 0.9%

24. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	220	221
Count of Participants [Participants]	31 83.8%	7 3.1%

25. Secondary Outcome

Title	Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	111	113
Number (95% Confidence Interval) [participants]	29 78.4%	23 10.3%

26. Secondary Outcome

Title	Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	224	220
Count of Participants [Participants]	49 132.4%	31 13.8%

27. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	111	107
Median (95% Confidence Interval) [months]	4.80	NA

28. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	111	107
Median (95% Confidence Interval) [months]	4.80	5.75

29. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	113	107
Median (95% Confidence Interval) [months]	6.06	NA

30. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	113	107
Median (95% Confidence Interval) [months]	5.70	5.75

31. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	111	113
Median (95% Confidence Interval) [months]	4.80	6.06

32. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Phase 3 Response Efficacy Set consisted of the first 330 patients randomized into the Phase 3 portion of the study and any additional patients randomized on the same day as the 330th randomized patient.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	111	113
Median (95% Confidence Interval) [months]	4.80	5.70

33. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	50	3
Median (95% Confidence Interval) [months]	1.43	1.45

34. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	49	7
Median (95% Confidence Interval) [months]	1.48	2.63

35. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	36	3
Median (95% Confidence Interval) [months]	1.48	1.45

36. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	31	7
Median (95% Confidence Interval) [months]	1.48	2.63

37. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	50	36
Median (95% Confidence Interval) [months]	1.43	1.48

38. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator
Description
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Measure Participants	49	31
Median (95% Confidence Interval) [months]	1.48	1.48

39. Secondary Outcome

Title	(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet
Description	The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	220	221
Baseline	62.8 (22.18)	60.7 (21.33)	62.8 (21.82)
Cycle 1 Day 1	-2.4 (13.44)	-4.3 (16.27)	-3.4 (15.60)
Cycle 2 Day 1	-1.6 (19.06)	3.8 (18.46)	-1.9 (22.45)
Cycle 3 Day 1	0.7 (18.86)	3.5 (19.96)	-0.2 (24.07)
Cycle 4 Day 1	0.2 (15.63)	4.2 (22.17)	1.4 (21.65)
Cycle 5 Day 1	-1.1 (18.66)	4.3 (22.09)	-2.2 (22.06)
Cycle 6 Day 1	-4.0 (16.76)	5.6 (23.25)	-4.5 (19.43)
Cycle 7 Day 1	-2.5 (16.01)	4.3 (21.77)	1.7 (12.30)
Cycle 8 Day 1	-2.6 (14.83)	4.2 (16.98)	0.0 (27.64)
Cycle 9 Day 1	-5.8 (17.74)	-5.6 (16.44)	-4.8 (12.60)
Cycle 10 Day 1	-3.3 (17.90)	-2.8 (16.97)	2.1 (20.83)
Cycle 11 Day 1	-5.2 (20.38)	3.9 (15.31)	33.3 (NA)
Cycle 12 Day 1	0.0 (22.41)	-4.6 (13.77)	4.2 (53.03)
Cycle 13 Day 1	0.0 (20.41)	-3.2 (14.25)	0.0 (NA)
Cycle 14 Day 1	-1.2 (24.26)	-6.0 (15.00)
Cycle 15 Day 1	3.6 (33.63)	2.8 (8.61)
Cycle 16 Day 1	-16.7 (42.08)	-5.6 (9.62)
Cycle 17 Day 1	-27.8 (20.97)	-2.8 (12.73)
Cycle 18 Day 1	-16.7 (NA)	-8.3 (8.33)
Cycle 19 Day 1	0.0 (NA)	-8.3 (11.79)
Cycle 20 Day 1	-25 (NA)	-8 (NA)
Cycle 21 Day 1	0.0 (NA)	-16.7 (NA)
Cycle 22 Day 1	-16.7 (NA)
Cycle 23 Day 1	0.0 (NA)
End of Treatment	-14.1 (22.66)	-13.1 (21.61)	-15.5 (27.04)
30 Day Follow Up	-17.4 (22.51)	-10.4 (15.96)	-24.6 (24.08)

40. Secondary Outcome

Title	(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
Description	FACT-C is a well-characterized and commonly used questionnaire that belongs to the Functional Assessment of Chronic Illness Therapy Measurement System (FACIT). The FACT-G (G for general) questionnaire (27 questions) constitutes the core of all subscales and is applicable to all tumor types. The FACT-C questionnaire contains 9 additional questions on symptoms specific to CRC, 2 of which are only answered by patients with ostomy appliances. These 9 CRC-specific questions are categorized as "additional concerns" on the questionnaire and constitute the "colorectal cancer subscale" score. The patient self-reports his/her QoL for the previous 7 days. The overall score is calculated across all items and a higher score reflects better quality of life (QoL). The table summarizes the functional well-being subscale, the individual questions are linearly scaled and combined to form the functional well-being subscale score, which ranges from 0-28 (higher is better QoL).
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	220	221
Baseline	16.3 (6.22)	16.2 (5.9)	16.8 (6.07)
Cycle 1 Day 1	-0.2 (3.36)	-0.9 (4.06)	-1.4 (3.32)
Cycle 2 Day 1	-0.3 (4.28)	-0.6 (5.08)	-0.9 (4.48)
Cycle 3 Day 1	-0.2 (5.15)	-0.2 (5.23)	-0.7 (5.03)
Cycle 4 Day 1	0.4 (4.53)	-0.1 (4.66)	-1.8 (6.48)
Cycle 5 Day 1	0.7 (6.4)	-0.2 (4.5)	-1.6 (4.58)
Cycle 6 Day 1	0.7 (6.05)	0.6 (4.56)	-1.9 (5.3)
Cycle 7 Day 1	0.5 (5.85)	-0.1 (4.70)	-0.5 (5.41)
Cycle 8 Day 1	0.9 (6.35)	0.2 (4.24)	-2.1 (4.97)
Cycle 9 Day 1	-1.9 (4.32)	-0.8 (3.74)	-2.6 (2.30)
Cycle 10 Day 1	-1.7 (4.76)	-1.3 (3.59)	0.5 (4.36)
Cycle 11 Day 1	-1.5 (4.47)	-0.5 (4.65)	-4.5 (7.78)
Cycle 12 Day 1	-1.5 (4.93)	-1.1 (4.61)	-4.5 (9.19)
Cycle 13 Day 1	-2.0 (6.76)	-3.2 (5.34)	-8.0 (NA)
Cycle 14 Day 1	-2.4 (5.22)	-4.0 (5.74)
Cycle 15 Day 1	-2.3 (6.85)	-1.5 (4.72)
Cycle 16 Day 1	-4.2 (4.02)	-0.7 (0.58)
Cycle 17 Day 1	-6.7 (5.51)	-0.7 (4.51)
Cycle 18 Day 1	-5.0 (NA)	-3.0 (4.36)
Cycle 19 Day 1	-7.0 (NA)	-6.0 (0.00)
Cycle 20 Day 1	-6.0 (NA)	-5.0 (NA)
Cycle 21 Day 1	-9.0	-5.0
Cycle 22 Day 1	-12.0 (NA)
Cycle 23 Day 1	-9.0 (NA)
End of Treatment	-2.4 (4.84)	-2.2 (5.14)	-3.1 (6.06)
30 Day Follow Up	-3.5 (6.44)	-0.8 (5.42)	-4.2 (6.41)

41. Secondary Outcome

Title	(Phase 3) Change From Baseline in the EuroQol-5D-5L (EQ-5D-5L) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet
Description	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 patient and ranges from 0 to 100 (higher is better quality health).
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	220	221
Baseline	69.0 (19.03)	66.5 (19.51)	68.3 (19.71)
Cycle 1 Day 1	0.8 (10.89)	-0.9 (14.09)	-2.1 (15.02)
Cycle 2 Day 1	1.4 (14.74)	1.9 (14.81)	-2.4 (17.20)
Cycle 3 Day 1	3.0 (13.94)	4.2 (17.32)	-1.4 (17.40)
Cycle 4 Day 1	4.0 (13.06)	5.6 (14.87)	-0.4 (15.14)
Cycle 5 Day 1	3.3 (14.66)	5.1 (15.11)	2.5 (11.17)
Cycle 6 Day 1	1.3 (13.33)	2.9 (16.84)	-3.6 (13.26)
Cycle 7 Day 1	1.4 (13.64)	3.6 (16.71)	2.4 (7.44)
Cycle 8 Day 1	4.1 (10.77)	2.0 (16.11)	-2.8 (12.95)
Cycle 9 Day 1	0.3 (15.16)	-4.0 (12.99)	-8.1 (8.80)
Cycle 10 Day 1	0.2 (13.34)	-8.1 (13.68)	-1.8 (2.36)
Cycle 11 Day 1	0.2 (13.87)	-0.1 (10.15)	4.0 (8.49)
Cycle 12 Day 1	-4.0 (20.11)	-0.6 (11.67)	1.5 (12.02)
Cycle 13 Day 1	-3.0 (17.17)	-4.1 (14.41)	-2.0 (NA)
Cycle 14 Day 1	-4.0 (18.06)	-0.4 (13.99)
Cycle 15 Day 1	-3.4 (14.67)	4.2 (7.36)
Cycle 16 Day 1	-10.4 (24.87)	3.3 (2.89)
Cycle 17 Day 1	-18.3 (20.21)	1.7 (5.77)
Cycle 18 Day 1	7.0 (NA)	-3.3 (2.89)
Cycle 19 Day 1	8.0 (NA)	-5.5 (13.44)
Cycle 20 Day 1	8.0 (NA)	2.0 (NA)
Cycle 21 Day 1	8.0 (NA)	-5.0 (NA)
Cycle 22 Day 1	-5.0 (NA)
Cycle 23 Day 1	-5.0 (NA)
End of Treatment	-8.5 (17.40)	-8.0 (18.99)	-12.7 (21.34)
30 Day Follow Up	-11.1 (20.23)	-5.9 (20.18)	-11.0 (17.51)

42. Secondary Outcome

Title	(Phase 3) Change From Baseline in the Patient Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet
Description	The PGIC is a measure of patients' 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 patient reported outcome (PROs). For this assessment, patients 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."
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all patients who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 patients.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
Measure Participants	224	220	221
Baseline	3.8 (1.30)	3.8 (1.30)	3.9 (1.28)
Cycle 1 Day 1	-0.1 (0.93)	0.1 (1.21)	0.0 (0.90)
Cycle 2 Day 1	-0.7 (1.44)	-0.8 (1.60)	-0.3 (1.52)
Cycle 3 Day 1	-0.9 (1.44)	-1.2 (1.53)	-0.5 (1.56)
Cycle 4 Day 1	-0.9 (1.49)	-1.1 (1.68)	-0.5 (1.35)
Cycle 5 Day 1	-0.9 (1.61)	-1.1 (1.69)	-0.7 (1.41)
Cycle 6 Day 1	-0.8 (1.31)	-1.2 (1.70)	-0.8 (1.39)
Cycle 7 Day 1	-1.1 (1.44)	-1.0 (1.61)	-1.1 (1.07)
Cycle 8 Day 1	-1.2 (1.56)	-1.1 (1.58)	-1.0 (0.71)
Cycle 9 Day 1	-0.8 (1.26)	-0.9 (1.37)	-1.0 (0.71)
Cycle 10 Day 1	-0.5 (1.51)	-0.6 (1.28)	-0.3 (0.58)
Cycle 11 Day 1	-0.9 (1.38)	-1.1 (1.38)	0.0 (0.00)
Cycle 12 Day 1	-0.9 (1.45)	-0.8 (1.36)	-0.5 (0.71)
Cycle 13 Day 1	-1.3 (1.39)	-0.9 (1.52)	-1.0 (NA)
Cycle 14 Day 1	-1.1 (1.46)	-1.5 (1.05)
Cycle 15 Day 1	-1.2 (1.47)	-1.6 (0.89)
Cycle 16 Day 1	-2.0 (0.82)	-0.7 (1.53)
Cycle 17 Day 1	-1.3 (1.53)	-1.0 (1.00)
Cycle 18 Day 1	-2.0 (NA)	-1.0 (1.00)
Cycle 19 Day 1	-3.0 (NA)	-0.5 (2.12)
Cycle 20 Day 1	-3.0 (NA)	-2.0 (NA)
Cycle 21 Day 1	-3.0 (NA)	-2.0 (NA)
Cycle 22 Day 1	-2.0 (NA)
Cycle 23 Day 1	-2.0 (NA)
End of Treatment	0.3 (1.85)	0.1 (1.82)	0.4 (1.58)
30 Day Follow Up	-0.1 (2.08)	0.5 (1.43)	0.7 (1.34)

43. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Cetuximab
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The pharmacokinetics (PK) set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	841000 (22.2)
Cycle 2	970000 (20.6)

44. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Encorafenib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	11300 (61.5)
Cycle 2	6660 (61.7)

45. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Binimetinib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	1960 (43.6)
Cycle 2	1540 (44.7)

46. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve (AUC) for Metabolite of Binimetinib (AR00426032)
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	206 (46.7)
Cycle 2	70.0 (95.5)

47. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	195000 (22.2)
Cycle 2	199000 (26.8)

48. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	3360 (65.1)
Cycle 2	2490 (75.6)

49. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	654 (50.8)
Cycle 2	524 (70.1)

50. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032)
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	59.9 (50.8)
Cycle 2	20.5 (119)

51. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	3.77
Cycle 2	3.05

52. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	2.00
Cycle 2	2.00

53. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	1.98
Cycle 2	1.04

54. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032)
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Cycle 1	2.00
Cycle 2	1.58

55. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	55.3 (61.5)

56. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	18.9 (191)

57. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	55400 (54.8)

58. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-state Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib
Description
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Outcome Measure Data

Analysis Population Description
The PK set included all patients in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Measure Participants	37
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3.41 (68.5)

59. Secondary Outcome

Title	(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib
Description	The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
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.

Outcome Measure Data

Analysis Population Description
The analysis set included all patients in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Phase 3: Triplet, Doublet and Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
Measure Participants	394
Geometric Mean (95% Confidence Interval) [L/h]	16.4

60. Secondary Outcome

Title	(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib
Description	The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
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.

Outcome Measure Data

Analysis Population Description
The analysis set included all patients in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Phase 3: Triplet, Doublet and Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
Measure Participants	181
Geometric Mean (95% Confidence Interval) [L/h]	19.0

61. Secondary Outcome

Title	(Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab
Description	The cross-arm CL/F value is based on the theta determined from a population PK analysis. Data for this Outcome Measure are not reported here because as per plan, the analysis includes pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID for those studies for which results have not yet been posted include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
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.

Outcome Measure Data

Analysis Population Description
The analysis set included all patients in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Patients were analyzed according to the actual treatment and dose received.

Arm/Group Title	Phase 3: Triplet, Doublet and Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
Measure Participants	261
Geometric Mean (95% Confidence Interval) [L/h]	0.0154

Adverse Events

	Combined Safety Lead-in		Phase 3: Triplet Arm		Phase 3: Doublet Arm		Phase 3:Control Arm
Time Frame	Adverse Events (AE) were collected during the study (duration of safety lead-in and phase 3,approximately 12 months (up to 28 days per cycle)), which began in 09Oct2016 and still ongoing.
Adverse Event Reporting Description	An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained.

Arm/Group Title	Combined Safety Lead-in		Phase 3: Triplet Arm		Phase 3: Doublet Arm		Phase 3:Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.		Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.		Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/37 (2.7%)		7/222 (3.2%)		5/216 (2.3%)		11/193 (5.7%)
Serious Adverse Events
	Combined Safety Lead-in		Phase 3: Triplet Arm		Phase 3: Doublet Arm		Phase 3:Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/37 (59.5%)		93/222 (41.9%)		71/216 (32.9%)		71/193 (36.8%)
Blood and lymphatic system disorders
Anaemia	1/37 (2.7%)		4/222 (1.8%)		1/216 (0.5%)		1/193 (0.5%)
Pulmonary embolism	1/37 (2.7%)		8/222 (3.6%)		3/216 (1.4%)		4/193 (2.1%)
Bacteraemia	0/37 (0%)		3/222 (1.4%)		0/216 (0%)		1/193 (0.5%)
Febrile neutropenia	0/37 (0%)		0/222 (0%)		0/216 (0%)		5/193 (2.6%)
Infusion-related reaction	5/37 (13.5%)		1/222 (0.5%)		7/216 (3.2%)		6/193 (3.1%)
Blood creatinine increased	2/37 (5.4%)		2/222 (0.9%)		0/216 (0%)		0/193 (0%)
Neutropenia	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Cardiac disorders
Cardiac arrest	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Cardio-respiratory	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		1/193 (0.5%)
Atrial fibrillation	0/37 (0%)		0/222 (0%)		3/216 (1.4%)		0/193 (0%)
Gastrointestinal disorders
Diarrhoea	1/37 (2.7%)		12/222 (5.4%)		1/216 (0.5%)		10/193 (5.2%)
Vomiting	2/37 (5.4%)		3/222 (1.4%)		2/216 (0.9%)		3/193 (1.6%)
Gastrointestinal perforation	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Ileus	0/37 (0%)		5/222 (2.3%)		3/216 (1.4%)		2/193 (1%)
Intestinal obstruction	0/37 (0%)		6/222 (2.7%)		14/216 (6.5%)		8/193 (4.1%)
Large intestine perforation	1/37 (2.7%)		3/222 (1.4%)		2/216 (0.9%)		2/193 (1%)
Gastrointestinal haemorrhage	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		0/193 (0%)
Subileus	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Abdominal pain	0/37 (0%)		4/222 (1.8%)		3/216 (1.4%)		4/193 (2.1%)
Bile duct obstruction	0/37 (0%)		2/222 (0.9%)		3/216 (1.4%)		2/193 (1%)
Large intestinal obstruction	0/37 (0%)		1/222 (0.5%)		3/216 (1.4%)		0/193 (0%)
Subileus	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		3/193 (1.6%)
Small intestinal obstruction	0/37 (0%)		2/222 (0.9%)		0/216 (0%)		6/193 (3.1%)
Colitis	1/37 (2.7%)		2/222 (0.9%)		0/216 (0%)		0/193 (0%)
Abdominal distention	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Constipation	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		1/193 (0.5%)
Duodenal obstruction	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Dyspepsia	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Gastritis	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Gastrointtestinal perforation	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Haematemesis	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
intestinal perforation	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Melaena	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		0/193 (0%)
Pancreatitis	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		0/193 (0%)
Pancreatitis acute	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Pancreatitis relapsing	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Rectal stenosis	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Rectal ulcer	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Abdominal hernia	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Anal haemorrhage	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		0/193 (0%)
Ascites	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		1/193 (0.5%)
Enterocolitis	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		1/193 (0.5%)
Impaired gastric emptying	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		0/193 (0%)
Large intestine ulcer	1/37 (2.7%)		0/222 (0%)		0/216 (0%)		0/193 (0%)
Proctalgia	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
General disorders
Death	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Pain	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		2/193 (1%)
Asthenia	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		1/193 (0.5%)
Hepatobiliary disorders
Hepatic failure	0/37 (0%)		9/222 (4.1%)		0/216 (0%)		0/193 (0%)
Jaundice	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		1/193 (0.5%)
Immune system disorders
Anaphylactic reaction	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Infections and infestations
Peritonitis	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Respiratory tract infection	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Sepsis	0/37 (0%)		6/222 (2.7%)		2/216 (0.9%)		0/193 (0%)
Abdominal wall abscess	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Biliary tract infection	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		0/193 (0%)
Cholangitis infective	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Endocarditis	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Erysipelas	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Gastrintestinal infection	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Urosepsis	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		0/193 (0%)
Wound abscess	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Abdominal abscess	1/37 (2.7%)		0/222 (0%)		1/216 (0.5%)		0/193 (0%)
Abscess limb	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Anal abscess	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Bacteria sepsis	1/37 (2.7%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Campylobacter gastroenteritis	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Metabolism and nutrition disorders
Nausea	1/37 (2.7%)		12/222 (5.4%)		3/216 (1.4%)		1/193 (0.5%)
General physical health deterioration	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		2/193 (1%)
Asthenia	0/37 (0%)		4/222 (1.8%)		0/216 (0%)		0/193 (0%)
Fatigue	1/37 (2.7%)		2/222 (0.9%)		0/216 (0%)		0/193 (0%)
Dehydration	1/37 (2.7%)		2/222 (0.9%)		1/216 (0.5%)		1/193 (0.5%)
Decreased appetite	1/37 (2.7%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colorectal cancer metastatic	0/37 (0%)		2/222 (0.9%)		0/216 (0%)		0/193 (0%)
Malignant neoplasm progression	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Neoplasm progression	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		1/193 (0.5%)
Colon cancer	1/37 (2.7%)		0/222 (0%)		2/216 (0.9%)		0/193 (0%)
Colon cancer metastatic	0/37 (0%)		0/222 (0%)		2/216 (0.9%)		1/193 (0.5%)
Colorectal cancer	0/37 (0%)		0/222 (0%)		1/216 (0.5%)		1/193 (0.5%)
Cancer pain	0/37 (0%)		1/222 (0.5%)		5/216 (2.3%)		1/193 (0.5%)
Nervous system disorders
Pyrexia	2/37 (5.4%)		4/222 (1.8%)		1/216 (0.5%)		0/193 (0%)
Cerebral ischaemia	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Epilepsy	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Psychiatric disorders
Anxiety	0/37 (0%)		2/222 (0.9%)		0/216 (0%)		0/193 (0%)
Renal and urinary disorders
Acute kidney injury	0/37 (0%)		7/222 (3.2%)		4/216 (1.9%)		1/193 (0.5%)
Urinary tract infection	4/37 (10.8%)		2/222 (0.9%)		5/216 (2.3%)		1/193 (0.5%)
Haematuria	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Hydronephrosis	1/37 (2.7%)		1/222 (0.5%)		0/216 (0%)		1/193 (0.5%)
Nephritis	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Renal failure	2/37 (5.4%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Urinary retention	0/37 (0%)		1/222 (0.5%)		0/216 (0%)		0/193 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration	0/37 (0%)		0/222 (0%)		2/216 (0.9%)		0/193 (0%)
Respiratory distress	0/37 (0%)		0/222 (0%)		0/216 (0%)		1/193 (0.5%)
Respiratory failure	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		3/193 (1.6%)
Other (Not Including Serious) Adverse Events
	Combined Safety Lead-in		Phase 3: Triplet Arm		Phase 3: Doublet Arm		Phase 3:Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/37 (100%)		217/222 (97.7%)		212/216 (98.1%)		188/193 (97.4%)
Blood and lymphatic system disorders
Anaemia	16/37 (43.2%)		80/222 (36%)		35/216 (16.2%)		37/193 (19.2%)
Hypomagnesaemia	6/37 (16.2%)		20/222 (9%)		22/216 (10.2%)		17/193 (8.8%)
Hypokalaemia	3/37 (8.1%)		15/222 (6.8%)		13/216 (6%)		27/193 (14%)
Neutropenia	1/37 (2.7%)		3/222 (1.4%)		1/216 (0.5%)		36/193 (18.7%)
Neutrophil count decreased	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		21/193 (10.9%)
Cardiac disorders
Palpitations	2/37 (5.4%)		3/222 (1.4%)		3/216 (1.4%)		1/193 (0.5%)
Eye disorders
Vision blurred	12/37 (32.4%)		25/222 (11.3%)		8/216 (3.7%)		1/193 (0.5%)
Dry eye	4/37 (10.8%)		6/222 (2.7%)		7/216 (3.2%)		2/193 (1%)
Retinal detachment	2/37 (5.4%)		6/222 (2.7%)		1/216 (0.5%)		0/193 (0%)
Gastrointestinal disorders
Diarrhoea	28/37 (75.7%)		137/222 (61.7%)		72/216 (33.3%)		93/193 (48.2%)
Nausea	22/37 (59.5%)		100/222 (45%)		74/216 (34.3%)		80/193 (41.5%)
Vomiting	18/37 (48.6%)		85/222 (38.3%)		46/216 (21.3%)		56/193 (29%)
Abdominal pain	14/37 (37.8%)		65/222 (29.3%)		49/216 (22.7%)		48/193 (24.9%)
Decreased appetite	14/37 (37.8%)		63/222 (28.4%)		68/216 (31.5%)		52/193 (26.9%)
Constipation	14/37 (37.8%)		55/222 (24.8%)		33/216 (15.3%)		35/193 (18.1%)
Abdominal pain upper	4/37 (10.8%)		20/222 (9%)		19/216 (8.8%)		15/193 (7.8%)
Dyspepsia	4/37 (10.8%)		16/222 (7.2%)		7/216 (3.2%)		7/193 (3.6%)
Flatulence	0/37 (0%)		13/222 (5.9%)		6/216 (2.8%)		3/193 (1.6%)
Rectal haemorrhage	3/37 (8.1%)		12/222 (5.4%)		5/216 (2.3%)		1/193 (0.5%)
Dry Mouth	2/37 (5.4%)		11/222 (5%)		8/216 (3.7%)		7/193 (3.6%)
Gastroesophageal reflux disease	2/37 (5.4%)		11/222 (5%)		4/216 (1.9%)		5/193 (2.6%)
Abdominal distension	2/37 (5.4%)		9/222 (4.1%)		12/216 (5.6%)		8/193 (4.1%)
Intestinal obstruction	0/37 (0%)		8/222 (3.6%)		12/216 (5.6%)		8/193 (4.1%)
General disorders
Chills	4/37 (10.8%)		13/222 (5.9%)		6/216 (2.8%)		3/193 (1.6%)
Malaise	6/37 (16.2%)		6/222 (2.7%)		5/216 (2.3%)		11/193 (5.7%)
Infections and infestations
Pyrexia	15/37 (40.5%)		45/222 (20.3%)		35/216 (16.2%)		27/193 (14%)
Urinary tract infection	7/37 (18.9%)		18/222 (8.1%)		16/216 (7.4%)		6/193 (3.1%)
Paronychia	6/37 (16.2%)		17/222 (7.7%)		8/216 (3.7%)		17/193 (8.8%)
Rash pustular	5/37 (13.5%)		13/222 (5.9%)		4/216 (1.9%)		4/193 (2.1%)
Conjunctivitis	2/37 (5.4%)		10/222 (4.5%)		8/216 (3.7%)		2/193 (1%)
Cystitis	2/37 (5.4%)		6/222 (2.7%)		1/216 (0.5%)		1/193 (0.5%)
Injury, poisoning and procedural complications
Infusion related reaction	3/37 (8.1%)		5/222 (2.3%)		20/216 (9.3%)		13/193 (6.7%)
Investigations
Blood creatine phosphokinase increased	13/37 (35.1%)		20/222 (9%)		1/216 (0.5%)		3/193 (1.6%)
Blood creatine increased	11/37 (29.7%)		18/222 (8.1%)		4/216 (1.9%)		1/193 (0.5%)
Alanine aminotransferase increased	6/37 (16.2%)		15/222 (6.8%)		12/216 (5.6%)		12/193 (6.2%)
Aspartate aminotransferase increased	7/37 (18.9%)		13/222 (5.9%)		8/216 (3.7%)		13/193 (6.7%)
Ejection fraction decreased	5/37 (13.5%)		8/222 (3.6%)		0/216 (0%)		0/193 (0%)
Blood bilirubin increased	3/37 (8.1%)		6/222 (2.7%)		10/216 (4.6%)		8/193 (4.1%)
White blood cell count decrease	0/37 (0%)		1/222 (0.5%)		1/216 (0.5%)		14/193 (7.3%)
Metabolism and nutrition disorders
Fatigue	20/37 (54.1%)		73/222 (32.9%)		65/216 (30.1%)		53/193 (27.5%)
Asthenia	6/37 (16.2%)		55/222 (24.8%)		46/216 (21.3%)		49/193 (25.4%)
Weight decreased	3/37 (8.1%)		24/222 (10.8%)		21/216 (9.7%)		11/193 (5.7%)
Hypomagnesaemia	6/37 (16.2%)		20/222 (9%)		22/216 (10.2%)		17/193 (8.8%)
Hypoalbuminaemia	4/37 (10.8%)		16/222 (7.2%)		5/216 (2.3%)		5/193 (2.6%)
Hyperglycaemia	1/37 (2.7%)		10/222 (4.5%)		7/216 (3.2%)		5/193 (2.6%)
Dehydration	2/37 (5.4%)		9/222 (4.1%)		4/216 (1.9%)		8/193 (4.1%)
Musculoskeletal and connective tissue disorders
PPE syndrome	6/37 (16.2%)		28/222 (12.6%)		9/216 (4.2%)		14/193 (7.3%)
Back Pain	8/37 (21.6%)		25/222 (11.3%)		22/216 (10.2%)		23/193 (11.9%)
Oedema peripheral	6/37 (16.2%)		24/222 (10.8%)		18/216 (8.3%)		13/193 (6.7%)
Arthralgia	9/37 (24.3%)		23/222 (10.4%)		41/216 (19%)		1/193 (0.5%)
Myalgia	7/37 (18.9%)		18/222 (8.1%)		29/216 (13.4%)		4/193 (2.1%)
Pain in extremity	3/37 (8.1%)		15/222 (6.8%)		22/216 (10.2%)		1/193 (0.5%)
Musculoskeletal pain	2/37 (5.4%)		6/222 (2.7%)		27/216 (12.5%)		3/193 (1.6%)
Muscle spasms	2/37 (5.4%)		17/222 (7.7%)		3/216 (1.4%)		4/193 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Pain	4/37 (10.8%)		3/222 (1.4%)		0/216 (0%)		2/193 (1%)
Nervous system disorders
Headache	6/37 (16.2%)		16/222 (7.2%)		42/216 (19.4%)		5/193 (2.6%)
Insomnia	2/37 (5.4%)		11/222 (5%)		24/216 (11.1%)		11/193 (5.7%)
Dizziness	8/37 (21.6%)		13/222 (5.9%)		14/216 (6.5%)		15/193 (7.8%)
Neuropathy peripheral	1/37 (2.7%)		13/222 (5.9%)		8/216 (3.7%)		5/193 (2.6%)
Dysgeusia	6/37 (16.2%)		11/222 (5%)		9/216 (4.2%)		7/193 (3.6%)
Peripheral sensory neuropathy	6/37 (16.2%)		8/222 (3.6%)		4/216 (1.9%)		4/193 (2.1%)
Syncope	2/37 (5.4%)		3/222 (1.4%)		2/216 (0.9%)		0/193 (0%)
Psychiatric disorders
Insomnia	2/37 (5.4%)		11/222 (5%)		24/216 (11.1%)		11/193 (5.7%)
Depression	2/37 (5.4%)		4/222 (1.8%)		4/216 (1.9%)		1/193 (0.5%)
Renal and urinary disorders
Acute kidney injury	1/37 (2.7%)		11/222 (5%)		4/216 (1.9%)		1/193 (0.5%)
Haematuria	2/37 (5.4%)		10/222 (4.5%)		4/216 (1.9%)		4/193 (2.1%)
Respiratory, thoracic and mediastinal disorders
Cough	5/37 (13.5%)		23/222 (10.4%)		16/216 (7.4%)		10/193 (5.2%)
Dyspnoea	12/37 (32.4%)		17/222 (7.7%)		23/216 (10.6%)		17/193 (8.8%)
Pulmonary embolism	2/37 (5.4%)		10/222 (4.5%)		3/216 (1.4%)		8/193 (4.1%)
Epistaxis	1/37 (2.7%)		7/222 (3.2%)		15/216 (6.9%)		7/193 (3.6%)
Dysphonia	1/37 (2.7%)		5/222 (2.3%)		11/216 (5.1%)		3/193 (1.6%)
Rhinnorrhoea	3/37 (8.1%)		5/222 (2.3%)		5/216 (2.3%)		1/193 (0.5%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	25/37 (67.6%)		108/222 (48.6%)		63/216 (29.2%)		76/193 (39.4%)
Dry Skin	19/37 (51.4%)		46/222 (20.7%)		24/216 (11.1%)		13/193 (6.7%)
Rash	3/37 (8.1%)		42/222 (18.9%)		25/216 (11.6%)		27/193 (14%)
Stomatitis	6/37 (16.2%)		31/222 (14%)		12/216 (5.6%)		44/193 (22.8%)
Pruritus	3/37 (8.1%)		28/222 (12.6%)		20/216 (9.3%)		9/193 (4.7%)
Melanocytic naevus	1/37 (2.7%)		1/222 (0.5%)		31/216 (14.4%)		0/193 (0%)
Palmar-planar erythrodysaesthesia	6/37 (16.2%)		28/222 (12.6%)		9/216 (4.2%)		14/193 (7.3%)
Rash maculo-papular	5/37 (13.5%)		18/222 (8.1%)		17/216 (7.9%)		11/193 (5.7%)
Skin fissures	9/37 (24.3%)		15/222 (6.8%)		5/216 (2.3%)		10/193 (5.2%)
Erythema	2/37 (5.4%)		7/222 (3.2%)		10/216 (4.6%)		4/193 (2.1%)
Eczema	2/37 (5.4%)		5/222 (2.3%)		1/216 (0.5%)		1/193 (0.5%)
Skin hyperpigmentation	2/37 (5.4%)		1/222 (0.5%)		16/216 (7.4%)		2/193 (1%)
Skin lesion	0/37 (0%)		1/222 (0.5%)		17/216 (7.9%)		1/193 (0.5%)
Vascular disorders
Hypotension	3/37 (8.1%)		7/222 (3.2%)		9/216 (4.2%)		3/193 (1.6%)
Hypertension	4/37 (10.8%)		6/222 (2.7%)		7/216 (3.2%)		6/193 (3.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of the sponsor's agreements with its investigators may vary. However, the sponsor does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e., data from all sites) in the clinical trials.

Results Point of Contact

Name/Title	Study Director
Organization	Pfizer
Phone	1-800-718-1021
Email	ClinicalTrials.gov_Inquiries@pfizer.com

Responsible Party:

Pfizer

ClinicalTrials.gov Identifier:

NCT02928224

Other Study ID Numbers:

ARRAY-818-302
BEACON CRC
2015-005805-35
C4221009

First Posted:

Oct 10, 2016

Last Update Posted:

Mar 16, 2022

Last Verified:

Mar 1, 2022