Conditions: BRAF V600E-mutant Metastatic Colorectal Cancer
Keywords: Metastatic Colorectal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 95
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of the combination of study drugs encorafenib, binimetinib and cetuximab in patients who have BRAF V600 mutant metastatic colorectal cancer and have not received any prior treatment for their metastatic disease.

Detailed description:
The presence of a BRAFV600E mutation is considered a marker of poor prognosis in subjects with mCRC. The preclinical results and preliminary clinical data together justify the evaluation of this triple combination in the first-line setting of this population. The primary objective of the study is to evaluate the antitumor activity of the combination of encorafenib, binimetinib and cetuximab by assessing the overall response rate in adult subjects with previously untreated BRAFV600E-mutant metastatic colorectal cancer. It will also assess the effect of the triple combination on the duration of response, time to response, progression-free survival and overall survival and assess the effect on quality of life. It will also characterize the safety and tolerability of the triple combination as well as describe the pharmacokinetics (PK) of encorafenib, binimetinib, and cetuximab.

Arms:
arm 1: encorafenib plus binimetinib plus cetuximab

Interventions: intervention 1: encorafenib intervention 2: Binimetinib intervention 3: Cetuximab
Intervention descriptions: intervention 1: 300 mg administered orally once daily (QD) intervention 2: Binimetinib 45 mg administered orally twice daily (BID) intervention 3: Standard of care for the 28 first weeks(\*) and then every 2 weeks (\*\*) :

(\*) 400 mg/m2 administered as a 120-min infusion on Cycle 1 Day 1, followed by 250 mg/m2 administered as a 60-min infusion once weekly (QW) for the first 28 weeks. (\*\*) 500 mg/m2 administered as a 120-min infusion twice weekly (Q2W) from Week 29 (Cycle 8 Day 1) onward.

Following implementation of an Urgent Safety Measure on 26 Mar 2020 due to the outbreak of COVID-19 pandemic, cetuximab infusions could be administered Q2W regardless of the cycle number, after investigator's evaluation of the benefit/risk ratio for the subject, with regards to COVID-19 pandemic.

Protocol document:
Prot_000.pdf: 




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W00090 GE 2 01 
APPROVAL FORM 
Protocol Version 9 – 17JUL2020 
 
 
 
Sponsor’s Representative: 
Clinical Study Physician: 
 
 
 
 
 
 
 
 
 
Date:   
 
 
Signature:  
 
 
Study Coordinating Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:   
 
 
 
 
 
 
Date:   
 
 
 
Signature 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
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W00090 GE 2 01 
COUNTRY COORDINATING INVESTIGATOR  
SIGNATURE FORM 
Protocol Version 9 – 17JUL2020 
 
 
Country: …………………………………….. 
 
Country Coordinating Investigator:  
 
"Name"  
Date:   
 
Signature:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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W00090 GE 2 01 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 9 – X17JUL2020 
 
 
By my signature below, I Dr / Pr"  Name" , hereby confirm that I agree: 
• to conduct the trial described in the protocol W00090 GE 2 01, dated  17 July 2020 in 
compliance with GCP, with applicable regulatory requirements and with the protocol agreed 
upon by the Sponsor Pierre Fabre Medicament and given approval by the Ethics Committee 
/ IRB; 
• to document the delegation of significant study-related tasks and to notify the Sponsor of 
changes in site personnel involved in the study; 
• to comply with the procedure for data recording and reporting; 
• to allow monitoring, auditing and inspection; 
• to retain the trial-related essential documents until the Sponsor informs that these documents 
are no longer needed. 
Furthermore, I hereby confirm that I will have and will use the available adequate resources, 
personnel and facilities for conduct this trial. 
I have been informed that certain regulatory authorities require the Sponsor Pierre Fabre 
Medicament to obtain and supply details about the Investigator’s ownership interest in the Sponsor 
or the study treatment, and more generally about his/her financial relationships with the Sponsor. 
The Sponsor will use and disclose the information solely for the purpose of complying with 
regulatory requirements. 
Hence I agree: 
• to supply the Sponsor with any information regarding ownership interest and financial 
relationships with the Sponsor (including those of my spouse and dependent children); 
• to promptly update this information if any relevant changes occur during the course of the 
study and for 1 year following completion of the study; 
• that the Sponsor may disclose this information about such ownership interests and financial 
relationships to regulatory authorities. 
 
Date:  
 
 
 
 
Signature: 
 
 
 
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TABLE OF CONTENTS OF CLINICAL STUDY PROTOCOL 
 
 
1. 
INTRODUCTION AND STUDY RATIONALE ............................................................ 47 
1.1. 
BACKGROUND INFORMATION ON THE TARGET PATHOLOGY AND 
THERAPY ...................................................................................................................... 47 
1.2. 
INFORMATION ON THE TEST PRODUCT ............................................................... 52 
1.2.1. 
ENCORAFENIB ............................................................................................................. 52 
1.2.2. 
BINIMETINIB ................................................................................................................ 59 
1.2.3. 
CETUXIMAB ................................................................................................................. 64 
1.3. 
STUDY RATIONALE .................................................................................................... 67 
1.4. 
OVERALL RISK AND BENEFIT ASSESSMENT ...................................................... 70 
2. 
STUDY OBJECTIVE AND ENDPOINTS ...................................................................... 71 
2.1. 
PRIMARY OBJECTIVE ................................................................................................ 71 
2.2. 
SECONDARY OBJECTIVES ........................................................................................ 71 
2.3. 
EXPLORATORY OBJECTIVES ................................................................................... 72 
2.4. 
PRIMARY ENDPOINTS ............................................................................................... 72 
2.5. 
SECONDARY ENDPOINTS ......................................................................................... 72 
2.6. 
EXPLORATORY ENDPOINTS: ................................................................................... 73 
3. 
ETHICAL CONSIDERATIONS RELATING TO THE STUDY ................................. 73 
4. 
STUDY DESIGN ................................................................................................................ 74 
4.1. 
OVERALL DESCRIPTION ........................................................................................... 74 
4.2. 
DISCUSSION OF THE STUDY DESIGN .................................................................... 77 
4.2.1. 
Choice of the Study Population ....................................................................................... 77 
4.2.2. 
Choice of the Study Design ............................................................................................. 77 
4.2.3. 
Choice of the Dose and Administration Modalities ........................................................ 78 
4.2.4. 
Choice of sample size ...................................................................................................... 79 
5. 
STUDY POPULATION .................................................................................................... 80 
5.1. 
INCLUSION CRITERIA ................................................................................................ 80 
5.2. 
EXCLUSION CRITERIA ............................................................................................... 82 
5.3. 
LIFESTYLE GUIDELINES ........................................................................................... 85 
5.3.1. 
Contraception .................................................................................................................. 85 
5.3.2. 
Photosensitivity ............................................................................................................... 87 
5.4. 
NUMBER OF SUBJECTS ............................................................................................. 87 
5.5. 
RECRUITMENT MODALITIES ................................................................................... 87 
5.6. 
SUBJECTS IDENTIFICATION ..................................................................................... 88 
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5.7. 
SUBJECT DISCONTINUATION REASONS ............................................................... 88 
5.7.1. 
Treatment Discontinuation for Individual Subject .......................................................... 88 
5.7.2. 
Study Discontinuation for individual Subject ................................................................. 90 
5.8. 
STUDY DISCONTINUATION ...................................................................................... 90 
5.9. 
REPLACEMENT OF SUBJECTS.................................................................................. 90 
5.10. 
POST-STUDY EXCLUSION PERIOD ......................................................................... 90 
5.11. 
SUBJECT CARD ............................................................................................................ 90 
6. 
STUDY TREATMENT(S) ................................................................................................ 91 
6.1. 
SOURCE, PRESENTATION AND COMPOSITION OF INVESTIGATIONAL 
PRODUCT(S) AND ASSOCIATED PRODUCT(S) ..................................................... 92 
6.1.1. 
Encorafenib 75 mg hard capsule ..................................................................................... 92 
6.1.2. 
Binimetinib 15 mg film-coated tablet ............................................................................. 92 
6.1.3. 
Cetuximab solution for infusion ...................................................................................... 93 
6.2. 
PACKAGING AND LABELLING ................................................................................ 94 
6.2.1. 
Packaging ........................................................................................................................ 94 
6.2.1.1. 
Encorafenib 75 mg capsule ......................................................................................... 94 
6.2.1.2. 
Binimetinib 15 mg film coated tablet .......................................................................... 95 
6.2.1.3. 
Cetuximab ERBITUX® 5 mg/mL solution for infusion ............................................. 95 
6.2.2. 
Labelling.......................................................................................................................... 96 
6.3. 
DISTRIBUTION TO CENTERS AND STORAGE ....................................................... 98 
6.4. 
ALLOCATION OF TREATMENTS AND DISPENSATION TO SUBJECTS ............ 99 
6.5. 
TREATMENT ADMINISTRATION ............................................................................. 99 
6.5.1. 
Duration of Treatment ..................................................................................................... 99 
6.5.2. 
Route and Conditions of Administration of Encorafenib and Binimetinib ................... 101 
6.5.3. 
Route and Condition of Administration of Cetuximab ................................................. 102 
6.5.4. 
Dose Modification ......................................................................................................... 103 
6.5.4.1. 
Dose Modification for Encorafenib and/or Binimetinib ........................................... 106 
6.5.4.2. 
Dose Modifications for Cetuximab ........................................................................... 116 
6.6. 
REPLACEMENT PROCEDURE ................................................................................. 117 
6.7. 
BLIND BREAKING PROCESS ................................................................................... 117 
6.8. 
ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
INVESTIGATIONAL PRODUCT(S) AND ASSOCIATED PRODUCT(S) .............. 117 
6.9. 
RECALL OF INVESTIGATIONAL PRODUCT(S) AND RESCUE 
MEDICATION.............................................................................................................. 117 
7. 
CONCOMITANT THERAPY AND THERAPEUTIC / DIAGNOSTIC 
PROCEDURES ................................................................................................................ 118 
7.1. 
PROHIBITED THERAPY AND THERAPEUTIC/DIAGNOSTIC PROCEDURES . 119 
7.2. 
AUTHORIZED THERAPY, THERAPEUTIC AND DIAGNOSTIC 
PROCEDURES ............................................................................................................. 120 
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7.2.1. 
Skin Toxicity Treatments .............................................................................................. 120 
7.2.2. 
Hand-Foot Skin Reaction Treatment............................................................................. 120 
7.2.3. 
Anti-Diarrheal ............................................................................................................... 121 
7.2.4. 
Antiemetics.................................................................................................................... 121 
7.2.5. 
Permitted Concomitant Therapy requiring Caution and/or Action ............................... 121 
7.2.5.1. 
CYP and UGT Substrates and Inhibitors .................................................................. 121 
7.2.5.2. 
Transporter Substrate and Inhibitors ......................................................................... 122 
7.2.5.3. 
Drugs with a Conditional or Possible Risk to Prolong the QT Interval and/or 
Induce Torsade de Pointes ......................................................................................... 122 
8. 
ASSESSMENTS ............................................................................................................... 123 
8.1. 
EFFICACY ASSESSMENTS ....................................................................................... 123 
8.2. 
PHARMACOKINETICS ASSESSMENT ................................................................... 125 
8.2.1. 
Blood Samples Collection ............................................................................................. 125 
8.2.1.1. 
Collection Schedule ................................................................................................... 125 
8.2.1.2. 
Technical Handling ................................................................................................... 129 
8.2.2. 
Samples Handling and shipping .................................................................................... 130 
8.2.3. 
Analytical determination ............................................................................................... 130 
8.2.4. 
Sample Storage .............................................................................................................. 130 
8.3. 
SAFETY ASSESSMENT ............................................................................................. 130 
8.3.1. 
Adverse Events .............................................................................................................. 130 
8.3.2. 
Clinical Safety Laboratory Assessments ....................................................................... 131 
8.3.2.1. 
Schedule .................................................................................................................... 132 
8.3.2.2. 
Parameters ................................................................................................................. 134 
8.3.3. 
Physical Examination .................................................................................................... 136 
8.3.4. 
Vital Signs ..................................................................................................................... 137 
8.3.4.1. 
Schedule .................................................................................................................... 137 
8.3.4.2. 
Technical Procedure and Parameters......................................................................... 137 
8.3.5. 
Electrocardiogram (ECG) and Echocardiogram/Multi-gated Acquisition Scans 
(ECHO/MUGA) ............................................................................................................ 139 
8.3.5.1. 
Schedule .................................................................................................................... 139 
8.3.5.2. 
Technical Procedure and Parameters......................................................................... 139 
8.3.6. 
Ophthalmic Assessments............................................................................................... 140 
8.3.7. 
Dermatologic Evaluations ............................................................................................. 141 
8.3.8. 
ECOG Performance Status ............................................................................................ 142 
8.4. 
TISSUE AND BLOOD BIOMARKER ASSESSMENTS ........................................... 142 
8.4.1. 
Tumor Biomarker Assessments .................................................................................... 142 
8.4.2. 
Blood Biomarker Assessments...................................................................................... 143 
8.4.2.1. 
C-reactive protein ...................................................................................................... 143 
8.4.2.2. 
Tumor markers .......................................................................................................... 143 
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8.4.2.3. 
Circulating DNA (ct-DNA) ....................................................................................... 144 
8.4.3. 
Predictive Biomarkers of Activity................................................................................. 144 
8.4.4. 
Optional tumor biopsy ................................................................................................... 145 
8.4.5. 
Retention of Samples for Future Analysis .................................................................... 146 
8.5. 
CONCOMITANT THERAPY AND THERAPEUTIC / DIAGNOSTIC 
PROCEDURE ASSESSMENT..................................................................................... 147 
8.6. 
QUALITY OF LIFE ASSESSMENT ........................................................................... 147 
8.7. 
HEALTHCARE RESOURCE UTILIZATION ............................................................ 148 
8.8. 
COMPLIANCE ............................................................................................................. 149 
9.
STUDY PROCEDURES ................................................................................................. 150 
9.1. 
MAIN STUDY PERIOD (FROM FIRST SUBJECT SCREENED TO 27 DEC 
2020).............................................................................................................................. 150 
9.1.1. 
VISIT 1 – Screening visit (Day -28 to -1 prior to Cycle 1 Day 1)_ Main study 
period ............................................................................................................................. 150 
9.1.2. 
Cycle 1 - Day 1 _ Main studyperiod ............................................................................. 152 
9.1.3. 
Cycle 1 - Day 8 _ Main study period ............................................................................ 153 
9.1.4. 
Cycle 1 - Day 15 _ Main study period .......................................................................... 154 
9.1.5. 
Cycle 1 - Day 22 _ Main study period .......................................................................... 154 
9.1.6. 
Subsequent Cycles _ Main study period ....................................................................... 155 
9.1.7. 
Subsequent Cycles Day 1 _ Main study period............................................................. 155 
9.1.8. 
Subsequent Cycles - Day 8, Day 15 and Day 22 _ Main study period ......................... 156 
9.1.9. 
End-of-Treatment Visit _ Main study period ................................................................ 157 
9.1.10. Safety Follow-up Visit and Survival Visits _ Main study period ................................. 158 
9.1.10.1. Safety 30 Day-Follow-up Visit _ Main study period ................................................ 159 
9.1.10.2. Survival Visit (every 3 months) _ Main study period ............................................... 160 
9.2. 
STUDY EXTENSION PERIOD (FROM 28 DEC 2020) ............................................. 160 
9.2.1. 
Subsequent Cycles_Study extension period .................................................................. 160 
9.2.2. 
Subsequent Cycles Day 1 _ Study extension period ..................................................... 161 
9.2.3. 
Subsequent Cycles - Day 15 _ Study extension period ................................................. 162 
9.2.4. 
End-of-Treatment Visit _ Study extension period ........................................................ 162 
9.2.5. 
Safety Follow-up Visit and Survival Visits _ Study extension period .......................... 163 
9.2.5.1. 
Safety 30 Day-Follow-up Visit _ Study extension period......................................... 163 
9.2.5.2. 
Survival Visit (every 3 months) _ Study extension period ....................................... 164 
10.
ADVERSE EVENTS: DEFINITION, NOTIFICATION AND REPORTING .......... 166 
10.1. 
ADVERSE EVENTS .................................................................................................... 166 
10.1.1. Definition ...................................................................................................................... 166 
10.1.2. Severity of Adverse Events ........................................................................................... 167 
10.2. 
SERIOUS ADVERSE EVENTS .................................................................................. 168 
10.2.1. Definition ...................................................................................................................... 168 
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10.2.2. Reporting of Serious and non-serious AEs ................................................................... 169 
10.2.3. Follow-up of SAEs ........................................................................................................ 170 
10.2.4. SAEs occurring after the 30-day safety follow-up period ............................................. 170 
10.3. 
REPORTING OF STUDY TREATMENT OVERDOSE TO THE SPONSOR .......... 170 
10.4. 
REPORTING OF PREGNANCY TO THE SPONSOR ............................................... 171 
10.5. 
SPONSOR'S RESPONSIBILITIES FOR SAFETY REGULATORY REPORTING 
PURPOSES ................................................................................................................... 171 
11. 
DATA COLLECTION AND STUDY MONITORING ............................................... 172 
11.1. 
DATA COLLECTION .................................................................................................. 172 
11.1.1. Case Report Forms ........................................................................................................ 172 
11.1.2. Source Documents......................................................................................................... 173 
11.2. 
STUDY MONITORING ............................................................................................... 173 
11.2.1. Monitoring visits ........................................................................................................... 173 
11.2.1.1. Site Preselection Visit ............................................................................................... 173 
11.2.1.2. Initiation Visit ............................................................................................................ 174 
11.2.1.3. Follow-up Visits ........................................................................................................ 174 
11.2.1.4. Closing Visit .............................................................................................................. 175 
11.2.2. Direct Access to Source Documents ............................................................................. 175 
11.3. 
PERIODIC SAFETY DATA REVIEW ........................................................................ 175 
11.4. 
STEERING COMMITTEE ........................................................................................... 176 
11.5. 
IDSMC .......................................................................................................................... 176 
12. 
DATA MANAGEMENT ................................................................................................. 176 
12.1. 
DATA COLLECTION .................................................................................................. 177 
12.1.1. Electronic Case Report Form (e-CRF) .......................................................................... 177 
12.1.2. Pharmacokinetics data ................................................................................................... 177 
12.1.3. Biomarkers .................................................................................................................... 178 
12.1.4. Imaging.......................................................................................................................... 178 
12.2. 
DATA CLEANING ...................................................................................................... 179 
12.3. 
DATA CODING ........................................................................................................... 179 
12.4. 
DATABASE LOCK ...................................................................................................... 179 
12.5. 
DATA STORAGE ........................................................................................................ 180 
13. 
STATISTICAL ANALYSIS ........................................................................................... 180 
13.1. 
GENERAL CONSIDERATIONS ................................................................................ 180 
13.2. 
OUTCOME MEASURES ............................................................................................. 181 
13.2.1. Primary outcome measure ............................................................................................. 181 
13.2.2. Secondary outcome measures ....................................................................................... 181 
13.3. 
SAMPLE SIZE .............................................................................................................. 182 
13.4. 
PROTOCOL DEVIATIONS......................................................................................... 183 
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13.5. 
ANALYSIS SETS ......................................................................................................... 183 
13.6. 
HANDLING OF DROPOUTS AND MISSING DATA .............................................. 184 
13.7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........................ 184 
13.8. 
ANALYSIS OF OUTCOME MEASURES .................................................................. 185 
13.8.1. Analysis of Primary Outcome Measure ........................................................................ 185 
13.8.1.1. Primary Analysis ....................................................................................................... 185 
13.8.1.2. Supportive Analysis .................................................................................................. 185 
13.8.1.3. Exploratory Analysis ................................................................................................. 185 
13.8.2. Analysis of Secondary Outcome Measures ................................................................... 186 
13.9. 
SAFETY ANALYSIS ................................................................................................... 187 
13.9.1. Treatment exposure ....................................................................................................... 187 
13.9.2. Adverse Events .............................................................................................................. 187 
13.9.3. Clinical Safety Laboratory Evaluation .......................................................................... 188 
13.9.4. Other Safety Data .......................................................................................................... 189 
13.10. 
QUALITY OF LIFE ANALYSIS ................................................................................. 189 
13.11. 
EXPLORATORY ANALYSIS ..................................................................................... 189 
13.12. 
CONCOMITANT THERAPIES AND THERAPEUTIC/ DIAGNOSTIC 
PROCEDURE ............................................................................................................... 190 
13.13. 
HEALTHCARE RESOURCE UTILIZATION ............................................................ 190 
13.14. 
PHARMACOKINETICS ANALYSIS ......................................................................... 190 
13.15. 
INTERIM ANALYSIS ................................................................................................. 191 
14. 
GENERAL ETHICAL CONSIDERATIONS ............................................................... 192 
14.1. 
ETHICAL CONDITIONS ............................................................................................ 192 
14.2. 
INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS ............ 192 
14.3. 
SUBJECT’S INFORMATION LEAFLET AND INFORMED CONSENT FORM .... 193 
14.4. 
PERSONAL DATA PROTECTION ............................................................................ 194 
14.5. 
INSURANCE POLICY................................................................................................. 194 
14.6. 
FINANCIAL CONSIDERATIONS .............................................................................. 194 
15. 
ADMINISTRATIVE PROCEDURES ........................................................................... 195 
15.1. 
PROTOCOL AMENDMENTS..................................................................................... 195 
15.2. 
SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE .............................. 195 
15.3. 
END OF STUDY .......................................................................................................... 196 
15.3.1. Definition of the end of study ....................................................................................... 196 
15.3.2. Supply of product after Main study period ................................................................... 196 
15.4. 
AUDIT .......................................................................................................................... 196 
15.5. 
INSPECTION................................................................................................................ 197 
15.6. 
CONFIDENTIALITY ................................................................................................... 197 
15.7. 
CLINICAL STUDY REPORT ..................................................................................... 197 
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15.8. 
STUDY RESULTS COMMUNICATION ................................................................... 197 
15.9. 
STUDY RESULTS PUBLICATION............................................................................ 198 
16. 
REFERENCES ................................................................................................................. 199 
17. 
APPENDICES .................................................................................................................. 206 
17.1. 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
CETUXIMAB-INDUCED, ENCORAFENIB-INDUCED AND/OR 
BINIMETINIB-INDUCED SKIN TOXICITY ............................................................ 206 
17.2. 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
ENCORAFENIB-INDUCED HAND-FOOT SKIN REACTIONS (HFSR) ................ 209 
17.3. 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB-INDUCED DIARRHEA ..................................................................... 211 
17.4. 
SNELLEN EQUIVALENCE (VISUAL ACUITY CONVERSION CHART) ............ 214 
17.5. 
LIST OF CONCOMITANT MEDICATIONS ............................................................. 215 
17.6. 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS RECIST 
VERSION 1.1................................................................................................................ 220 
17.6.1. Measurability of Tumor at baseline .............................................................................. 220 
17.6.2. Specifications by methods of measurements ................................................................ 221 
17.6.3. Tumor Response Evaluation ......................................................................................... 223 
17.6.4. Evaluation of non-target lesion ..................................................................................... 226 
17.6.5. Time point response ...................................................................................................... 229 
17.7. 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB AND CETUXIMAB -ASSOCIATED INTERSTITIAL LUNG 
DISEASE/PNEUMONITIS .......................................................................................... 232 
17.8. 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) ........................................ 234 
 
 
 
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SYNOPSIS 
 
Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Title of the Study: 
Phase II, open-label, single arm, multicenter study of encorafenib, binimetinib plus cetuximab in 
subjects with previously untreated BRAFV600E -mutant Metastatic Colorectal Cancer.  
Study Coordinating 
Investigator: 
 
 
Study Centre(s): 
Approximately 70 centers in Europe, North America and Japan 
Publication(s) / 
Rationale: 
BRAF mutations, which lead to constitutive activation of BRAF kinase and sustained 
RAS/RAF/MEK/ERK pathway signaling resulting in increased cell proliferation and survival occur in 
approximately 10% (range, 5–22%) of the unselected colorectal cancer (CRC) population (Rozek LS et 
al, 2010; Shaukat A et al, 2010; Sorbye et al, 2015) with lower prevalence in more advanced subject 
populations. 
The presence of a BRAFV600E mutation is considered a marker of poor prognosis in subjects with mCRC 
(metastatic ColoRectal Cancer) with a median survival of approximately 12 to 14 months in the first line 
metastatic setting compared to 21 to 25 months for subjects with BRAF wild-type (BRAFwt) tumors (Van 
Cutsem E et al, 2011; Sorbye et al, 2015). 
Preclinical data 
The combination of binimetinib, encorafenib, and cetuximab was tested in a BRAFV600E mutant human 
colorectal xenograft model. The average reduction in tumor volume across all animals was better in the 
group that received the triplet compared to the group that received encorafenib and cetuximab.  
Clinical data 
Consistent with nonclinical data in human colorectal cancer cell models (Corcoran RB et al, 2010; Yang 
H et al 2012), BRAF+MEK+EGFR inhibitors result in greater  activity than a dual combination 
BRAF+EGFR of inhibitors in subjects with BRAFV600E mCRC (Van Cutsem E et al, 2015). 
 
 
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Name of Sponsor: 
Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Publication(s) / 
Rationale: 
There is a large ongoing multicenter randomized phase III study (NCT02928224), the BEACON CRC 
study, evaluating binimetinib + encorafenib + cetuximab vs encorafenib + cetuximab compared with 
Investigator’s choice of irinotecan + cetuximab or FOLFIRI + cetuximab in subjects with BRAFV600E 
mutant mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A total 
of 30 subjects were treated in the safety lead-in (SLI), all of whom received binimetinib (45 mg twice 
day (BID)) + encorafenib (300 mg once daily (QD)) + cetuximab (400 mg/m2 initial dose then 250 mg/m2  
once weekly (QW)). Among the 29 subjects with BRAFV600E mutant tumors (one patient had a BRAF 
non-V600E mutant tumor) the confirmed overall response rate (cORR) was 48% (14/29 patients) and 
was 62% in patients with one previous line of therapy (10/16 patients) including 8 partial responses (PR) 
and 2 complete responses (CR); and in those with two prior lines of therapy the cORR was 31%, (4/13) 
including 3 PR and 1 CR. Preliminary estimate of median progression–free survival (PFS) is 8.0 months 
(95% confidence interval (CI), 5.6–8.5 months), with 7 of 29 patients (24%) still in follow-up and 
progression-free at the cut off date. PFS was similar between patients who had 1 vs 2 previous regimens 
(median, 95% CI, 7.6 [4.0–8.3] vs 8.1 [4.1–10.8] months) (Van Cutsem E et al, 2018). 
 
The confirmed ORR of 48% and median PFS of 8.0 months with the triplet combination of binimetinib 
+ encorafenib+cetuximab exceeds historical standard-of-care and exceeds the ORR of 22% in a phase II 
trial of the doublet of encorafenib + cetuximab (Tabernero J et al, 2016). 
 
The encouraging preliminary efficacy results observed in the SLI part of the BEACON CRC study are 
consistent with the preclinical data and together justify the evaluation of this triple combination in the 
first-line setting of this population, which represents a high-unmet medical need. 
 
 
Main Study Period: Nov 2018 – 27 
Dec 2020 
Clinical Phase: II 
Estimated Study 
Extension Period 
28 Dec 2020 – 
approximately 
Dec 2021 
Study extension 
From 28 Dec 2020, access to study treatment will be provided through a Study 
extension to all subjects whom the investigator considers are continuing to benefit 
from study treatment (i.e. do not experience unacceptable toxicities and none of the 
treatment discontinuation criteria are met) until: 
• 
the last ongoing subject will discontinue study treatments (including 30-
day Safety Follow-Up visit) for any reason (unacceptable toxicity, 
progression of disease, subject’s decision, withdrawal of consent, 
initiation of subsequent anticancer therapy or death),  
• 
or binimetinib/encorafenib are commercially available in the first line 
setting of BRAF V600E mutated mCRC,  
• 
or the binimetinib/encorafenib development program is stopped, 
whichever comes first. 
 
 
Objectives: 
Primary: 
• 
To evaluate the antitumor activity of the combination of encorafenib, binimetinib and cetuximab 
by assessing the confirmed overall response rate (cORR) by local radiologist/investigator 
assessment in adult subjects with previously untreated BRAF V600E-mutant (BRAFV600E) 
metastatic colorectal cancer (mCRC). 
 
 
 
 
Objectives: 
Secondary: 
• 
To evaluate the cORR by central radiologist assessment. 
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Name of Sponsor: 
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Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
• 
To 
evaluate 
the 
ORR 
(for 
confirmed 
and 
unconfirmed 
responses) 
by 
local 
radiologist/investigator and central assessment. 
• 
To assess the effect of the combination of encorafenib, binimetinib and cetuximab on the 
duration of response (DOR). 
• 
To assess the effect of the combination of encorafenib, binimetinib and cetuximab on other time-
related efficacy parameters: time to response (TTR), progression-free survival (PFS) and overall 
survival (OS). 
• 
To characterize the safety and tolerability of the combination of encorafenib, binimetinib and 
cetuximab. 
• 
To assess the effect on quality of life (QoL). 
• 
To explore health care resource utilization. 
• 
To describe the pharmacokinetics (PK) of encorafenib, binimetinib, a metabolite of binimetinib 
(AR00426032) and cetuximab. 
Exploratory: 
• 
To assess the relationship between changes in tumor markers (carcinoembryonic antigen [CEA] 
and carbohydrate antigen 19-9 [CA19-9]) and radiographic response to treatment. 
• 
To assess BRAFV600E status in blood circulating tumor DNA (ctDNA) at baseline. 
• 
To assess the potential predictive significance of the microsatellite instability (MSI) status in 
subjects with BRAFV600E mutant mCRC.  
• 
To assess blood- and tissue-based predictive biomarkers of activity. 
 
Endpoints 
Primary:  
• 
cORR as assessed by local radiologist/investigator review as per Response Evaluation Criteria 
in Solid Tumors (RECIST 1.1).  
Secondary:  
• 
cORR as assessed by central radiologist review as per RECIST 1.1. 
• 
ORR (for confirmed and unconfirmed responses) as per local radiologist/investigator and central 
assessment.  
• 
DOR assessed based on local radiologist/investigator and central review.  
• 
TTR assessed based on local radiologist/investigator and central review. 
• 
PFS assessed based on local radiologist/investigator and central review. 
• 
OS. 
• 
Type and severity of adverse events (AEs) and serious adverse events (SAEs), changes in 
hematology and chemistry values, physical examinations, vital signs, electrocardiogram (ECGs) 
and echocardiogram (ECHO)/ multi-gated acquisition (MUGA) scans and ophthalmological 
examinations graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events v4.03 (NCI-CTCAE v4.03). 
• 
Change from baseline in the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire for Cancer subjects (QLQ-C30), EuroQol-5D-5L (EQ-
5D-5L), and Patient Global Impression of Change (PGIC). 
• 
Resource utilization focused on hospitalizations occurring during the study treatment phase. 
• 
Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) and serum concentration of cetuximab. 
Exploratory: 
• 
Changes from baseline in blood CEA and CA19-9 at the beginning of each cycle and at the end 
of treatment. 
• 
BRAF V600E mutation status in ct-DNA at baseline. 
• 
MSI status in formalin-fixed paraffin-embedded (FFPE) samples via established PCR assays in 
tumor sample versus germline control at screening. 
• 
Genomic and proteomic analysis of tumor tissue at baseline and at end of treatment (optional 
tumor tissue sample at end of treatment). 
• 
Genomic and proteomic analysis of blood samples at baseline. 
 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Methodology: 
This is a multinational, multicenter, open-label, single-arm phase II study to evaluate the combination of 
encorafenib, binimetinib and cetuximab in subjects with BRAFV600E mutant mCRC who have not received 
any prior systemic therapy for metastatic disease.   
Subjects will be eligible for the study based on identification of a BRAFV600E mutation in the tumor tissue 
as determined by local laboratory result obtained at any time prior to Screening. Only polymerase chain 
reaction (PCR) and next generation sequencing (NGS)-based results will be acceptable. The BRAF mutation 
status must be confirmed by central laboratory no later than 30 days after the first dose of study treatment. 
In cases where there is discordance between the local assay and central laboratory results, or if the central 
laboratory is not able to confirm presence of a BRAFV600E mutation due to inadequate or poor sample 
condition or insufficient amount of tumor cells in sample within 30 days of initiating study therapy, subjects 
may only continue treatment if there is no clinical indication of deterioration or disease progression and the 
Investigator determines that the subject is deriving benefit. In such instances, subjects must be informed 
that the BRAF mutation status is unconfirmed and must sign a separate informed consent form (ICF) that 
includes this information and describes alternative treatment options. 
 
Main study period design (treatment phase) 
The Main study period will include two stages according to a two-stage design. 
Stage 1: In the first stage, 40 subjects will be treated. In case of discordance in the results between the local 
assay and the central laboratory (potential false-positive local result), or lack of BRAFV600E confirmation, 
subject will be replaced for the primary analysis of the futility analysis. If there are 11 or fewer confirmed 
responses (CR or PR) in the 40 treated subjects with a centrally confirmed BRAFV600E mutation, the study 
will be stopped. Otherwise, additional subjects will enter stage 2 . Stage 2 may be initiated as soon as 40 
subjects with a centrally confirmed BRAFV600E mutation are treated and confirmed responses are observed 
in at least 12 subjects. 
Stage 2: 50 additional subjects will be treated, for a total of 90 subjects with a centrally confirmed 
BRAFV600E mutation. In case of discordance in the results between the local assay and the central laboratory 
(potential false-positive local result), or lack of BRAFV600E confirmation, subjects enrolled in the stage two 
of the trial will be replaced for the primary analysis.  
If at any time during the study, either in stage 1 or in stage 2, there is discordance between the local assay 
and the central laboratory in 3 subjects (≥ 3% of the total targeted 90 treated subjects) or impossibility to 
confirm the BRAFV600E mutation in 6 subjects (≥ 6% of the total targeted 90 treated subjects), all subsequent 
subjects will be required to have BRAFV600E determined by the central laboratory prior to study treatment 
assignment.For the statistical design, please refer to the statistical section hereunder. 
 
Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, 
withdrawal of consent, initiation of subsequent anticancer therapy or death.   
 
 
An independent Data Safety Monitoring Committee (iDSMC) will review the available safety information 
at regular intervals as defined in the iDSMC charter. 
 
Main study period will end, as initially planned, 1 year after the start of study treatment of the last subject 
enrolled (as the last enrolled subject started study treatment on 27 Dec 2019, Main study period will end 
on 27 Dec 2020). 
 
 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Methodology: 
Study extension period design 
 
After the Main study period (period from first subject screened to 1 year after the start of study treatment 
of the last subject enrolled), access to study treatment will be provided from 28 Dec 2020 through a Study 
extension to all subjects whom the investigator considers are continuing to benefit from study treatment 
(i.e. do not experience unacceptable toxicities and none of the treatment discontinuation criteria are met) 
until:  
• 
the last ongoing subject will discontinue study treatments (including 30-day Safety Follow-Up 
visit) for any reason (unacceptable toxicity, progression of disease, subject’s decision, withdrawal 
of consent, initiation of subsequent anticancer therapy or death),  
• 
or binimetinib/encorafenib are commercially available in the first line setting of BRAF V600E 
mutated mCRC,  
• 
or the binimetinib/encorafenib development program is stopped, whichever comes first. 
 
Number of 
subjects: 
Target: 90 treated*subjects 
Stage 1: 40 treated subjects; Stage 2: 50 treated subjects. 
 
*In case of discordance in the results between the local assay and the central laboratory (potential false-
positive local result), or lack of BRAFV600E confirmation, subject will be replaced. If at any time there is 
lack of confirmation of the BRAFV600E mutation in a total of 6 subjects (≥ 6% of the total targeted 90 treated 
subjects) or discordance between the local assay and thecentral laboratory in 3 subjects (≥ 3% of the total 
targeted 90 treated subjects), all subsequent subjects will be required to have BRAFV600E determined by the 
central laboratory prior to study treatment assignment. 
 
Diagnosis and 
Criteria for 
eligibility 
 
 
Each subject fulfilling all the inclusion criteria and none of the exclusion criteria will be eligible. 
 
Inclusion Criteria  
 
1. 
Provide a signed and dated informed consent document. 
2. 
Male or female ≥ 18 years of age at time of informed consent. 
3. 
Histologically or cytologically confirmed CRC that is metastatic and unresectable at time of study entry (i e. not 
suitable for complete surgical resection at screening). 
4. 
Presence of BRAFV600E mutation in tumor tissue previously determined by a local assay at any time prior to 
screening. 
Notes:  
a. 
Only PCR and NGS-based local assays results will be acceptable. 
 
b. 
If at any time there is lack of confirmation of the BRAFV600E mutation in a total of 6 subjects (≥ 6% of the total 
targeted 90 treated subjects) or discordance between the local assay and the central laboratory in 3 subjects (≥ 
3% of the total targeted 90 treated subjects), all subsequent subjects will be required to have BRAFV600E 
determined by the central laboratory prior to study treatment assignment. 
 
c. 
Central testing cannot be repeated to resolve discordances with a local result once the central laboratory 
delivers a definitive result (positive or negative). 
 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
d. 
If the result from the central laboratory is indeterminate or the sample is deemed inadequate for testing, 
additional samples should be submitted (archival material only). 
 
e. 
If more than 1 discordant result from any local laboratory leads to subject enrollment, subsequent results from 
this local laboratory will not be accepted for further subject enrollment. 
5. 
Eligible to receive cetuximab per locally approved label with regards to tumor RAS status.  
 
e.g.  In agreement with EU label, evidence of wild type RAS (KRAS and NRAS) in EU countries. 
 
6. 
Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly 
obtained) for  testing of BRAF and RAS mutation status. 
 
Note  FFPE tumor tissue block or a minimum of 10 slides, optimally up to 15 slides 
 
7. 
Evidence of measurable disease, as per RECIST 1.1. 
Note  Lesions in areas of prior radiotherapy or other loco-regional therapies are considered measurable only if 
progression has been documented in the region following therapy. 
 
8. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
9. 
Adequate bone marrow function at screening and baseline: 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
ii. 
Platelets ≥ 100 x 109/L. 
iii. 
Hemoglobin ≥ 9.0 g/dL. 
Note  Blood transfusions are allowed provided that the subject has not received more than 2 units of red blood cells in 
the 4 weeks prior to achieve the minimum required hemoglobin level.  
 
10. Adequate renal function at screening and baseline: 
i. 
 Serum creatinine ≤ 1.5x upper limit of normal (ULN) or 
ii. 
Calculated creatinine clearance (CrCl) ≥ 50 mL/min by Cockroft-Gault formula  
11. Adequate electrolytes at screening and baseline, defined as serum potassium and magnesium levels within 
institutional normal limits.  
Note  replacement treatment to achieve adequate electrolytes will be allowed 
 
12. Adequate hepatic function at screening and baseline: 
i. 
Serum total bilirubin ≤ 1.5 x ULN and < 2 mg/dL. Note  Total bilirubin > 1.5 x ULN is allowed if 
direct (conjugated) bilirubin is ≤ 1.5 x ULN (and indirect (unconjugated) bilirubin is ≤ 4.25 x ULN – 
Only applicable for France). 
ii. 
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN, or ≤ 5 x ULN 
in the presence of liver metastases. 
 
13. Adequate cardiac function at screening:  
i. 
Left ventricular ejection fraction (LVEF) ≥ 50% as determined by MUGA scan or ECHO. 
ii. 
Mean triplicate QT interval corrected for heart rate according to Fridericia’s formula (QTcF) value 
≤ 480 msec. 
14. Subject able to take oral medications. 
15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. 
16. Female subjects 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. 
 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Notes  
(a) Precautions to avoid pregnancy must be conducted from screening through 6 months after the last dose of 
cetuximab or through 30 days after the last dose of encorafenib or binimetinib, whichever is later if of childbearing 
potential. 
(b) Permitted methods of contraception as provided (in Section 5.3.1) should be communicated to the subjects and 
their understanding confirmed. For all females, the pregnancy test must be negative at screening and baseline. 
 
17. Male subject must agree to take appropriate precautions to avoid fathering a child  
Notes  
(a) from screening through 6 months after the last dose of cetuximab or through 90 days after the last dose of 
encorafenib or binimetinib, whichever is later. 
(b) permitted methods of contraception as provided (in Section 5.3) should be communicated to the subjects and their 
understanding confirmed.  
 
18. Subjects under guardianship or partial guardianship will be eligible unless prohibited by local laws or by 
local/central ethic committees.  
Note  where allowed, all procedures prescribed by law must be followed. 
 
19. Affiliated to a social security system, or is a beneficiary (if applicable in the national regulation). 
 
 
Diagnosis and 
Criteria for 
eligibility 
Exclusion Criteria 
 
1. 
Prior systemic therapy for metastatic disease. 
Note  previous adjuvant/neoadjuvant therapy is allowed provided that 1) the interval from the end of chemotherapy to 
relapse is >6 months OR 2) in the case of neoadjuvant therapy, complete surgical resection was achieved and the 
interval from the end of chemotherapy to relapse is >12 months. Prior locoregional radiotherapy is allowed. 
 
2. 
Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti-EGFR treatment. 
3. 
Symptomatic brain metastasis. 
Note  subjects previously treated or untreated for these conditions who are asymptomatic in the absence of 
corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks with imaging (e.g. 
brain magnetic resonance imaging [MRI] or computed tomography [CT] demonstrating no current evidence of 
progressive brain metastases at screening). 
 
4. 
Leptomeningeal disease. 
5. 
History or current evidence of Retinal Vein Occlusion (RVO) or current risk factors for RVO. 
Note  Risk factors for RVO are uncontrolled glaucoma or ocular hypertension, history of hyperviscosity syndrome or 
hypercoagulability syndrome. 
 
6. 
Use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or 
inducers of CYP3A4/5 ≤ 1 week prior to the start of treatment. 
7. 
Note  However, subjects who either discontinue moderate or strong inhibitors or inducers of CYP3A4/5 or switch 
to another medication at least 7 days prior to starting study treatment are eligible. Known history of acute or 
chronic pancreatitis within 6 months prior to the start of the treatment. 
8. 
History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention 
(immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to first dose. 
9. 
Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: 
i. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary 
artery bypass graft (CABG), coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment. 
ii. Symptomatic congestive heart failure (Grade 2 or higher), history or current evidence of clinically 
significant arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except 
rate controlled atrial fibrillation and paroxysmal supraventricular tachycardia. 
  
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
10. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic 
blood pressure ≥ 100 mmHg despite optimal therapy. 
11. Impaired hepatic function, defined as Child-Pugh class B or C. 
12. Known history of Gilbert's syndrome or is known to have any of the following genotypes: UDP glucoronosyl 
transferase (UGT)1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28. No more applicable from Protocol 
V6.0/Amendment PA03 
13. Impaired gastrointestinal function or disease* which may significantly alter the absorption of encorafenib or 
binimetinib or recent changes in bowel function suggesting current or impending bowel obstruction. 
*e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection. 
 
14. Previous or concurrent malignancy* within 5 years of study. 
*except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, 
carcinoma in-situ of the cervix or any other malignancy that has been adequately treated and has not recurred within 
3 years prior to study entry. 
 
15. History of thromboembolic* or cerebrovascular events** ≤ 6 months prior to starting study treatment. 
*excluding venous thrombosis related to indwelling catheters and treated with low-grade anticoagulants 
**including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli. 
16. Concurrent neuromuscular disorder that is associated with the potential of elevated Creatine Kinase (CK). 
Note  e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy. 
 
17. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or 
Grade 2 neuropathy. 
18. Known history of human immunodeficiency virus (HIV) infection. 
Note  HIV testing will only be conducted in jurisdictions specifically requiring it. 
 
19. Active hepatitis B or hepatitis C infection. 
20. Known contraindication to receive cetuximab at the planned doses. Refer to the most recent cetuximab summary 
of product characteristics (SPC) or local label as applicable. 
21. Subjects who have any medical condition that would, in the Investigator’s judgment, prevent the subject’s 
participation in the clinical study due to safety concerns or compliance with study procedures. 
22. Any medical or psychiatric condition or laboratory abnormality that may increase the risk with study 
participation or study drug administration or that may interfere with the interpretation of study. 
23. Pregnancy, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test result, or breastfeeding. 
 
24. Is a family member of the Investigator or any associate, colleague, or employee assisting in the conduct of the 
study (secretary, nurse, technician).  
25. Is in a position likely to represent a conflict of interest. 
26. Participation in a clinical study with administration of an investigational product within 4 weeks or five times the 
half-life of the investigational product, whichever is longer, before the first dose of study treatment. 
Is mentally unable to understand the nature, objectives and possible consequences of the trial; or he/she refuses to 
its constraints. 
27. Is mentally unable to understand the nature, objectives and possible consequences of the trial; or he/she refuses to 
its constraints. 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Test Product, 
dose and mode of 
administration:  
Encorafenib: 300 mg PO (oral capsule 4X 75 mg) QD. 
Binimetinib: 45 mg PO (oral tablet 3X 15 mg) BID. 
Cetuximab: 400 mg/m2 intravenous (IV) at Cycle 1 day 1 then 250 mg/m2 IV every week (QW) for the first 
28 weeks. Then, 500mg/m2 IV every two weeks (Q2W) from week 29 (Cycle 8 day 1).  
Since implementation of the Urgent Safety Measure (USM) on 26 Mar 2020, to ensure the subjects’ safety 
in the clinical trial by decreasing the number of clinic visits in the context of COVID-19 pandemic, 
Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 administered as a 120-min 
IV infusion  (i.e. on D1 and D15 of each cycle) regardless of the cycle number, after the investigator has 
evaluated the benefit/risk ratio for the subject with regards to Covid-19 pandemic.  
If there is a dose modification prior to switching to the biweekly schedule, the total dose per cycle should 
be maintained (i.e. 200mg/m2 QW may be changed to a 400mg/m2 Q2W).Cycle duration: 28 days. 
Duration of 
Treatment: 
The treatment will be administered during Main study and Study extension periods until disease 
progression, unacceptable toxicity, subject’s decision, withdrawal of consent, initiation of subsequent 
anticancer therapy or death. After discontinuation of study treatment, there will be a 30-day safety follow-
up period. Subjects will then enter a survival follow-up period. If a subject discontinues the treatment for a 
reason other than progressive disease, tumor assessment must be performed (as per local and central review) 
until the start of new anti-cancer therapy, disease progression, death, lost to follow-up, subject decision or 
withdrawal consent or until the End of the Study. 
Statistical 
Methods: 
Sample Size Determination 
 
The sample size is based on a two-stage design with nominal alpha=2.5% and beta=20%. The null 
hypothesis that the true response rate is 30% (maximum unacceptable probability of response) will be tested 
against a one-sided alternative. In the first stage, 40 subjects will be treated. Subjects in whom the presence 
of  BRAFV600E  is not confirmed by central laboratory will be replaced. If there are 11 or fewer confirmed 
responses in the 40 treated subjects with a centrally confirmed BRAFV600E mutation, inactivity will be 
declared and the study will be stopped for futility.  
The time point for the futility analysis will be after all 40 treated subjects of stage 1 with centrally confirmed 
BRAFV600E mutation had the opportunity to complete four post baseline assessments and after subjects with 
an initial objective response have had an opportunity to have a confirmation scan. However, it will be 
possible to proceed to Stage 2 as soon as 40 subjects with a centrally confirmed BRAFV600E mutation are 
treated and 12 confirmed responses are observed.  
Subjects data that will be analyzed during the futility analysis will be reviewed on an ongoing basis in order 
to determine as soon as possible (even before the inclusion of the 40th subject) whether the criteria for 
continuing to stage 2 (12 confirmed responses ) are satisfied or not. 
 
As it may take several treatment cycles for subjects to achieve a confirmed response, a limited number of 
subjects (maximum 12) from stage 2 may be treated while waiting for all subjects in the initial cohort of 40 
subjects in Stage 1 to be evaluable for a confirmed response providing no safety concern was raised by the 
iDSMC. These additional subjects will not count towards responses in Stage 1 but will be included as part 
of the Stage 2 cohort, should the study move forward into Stage 2. 
If at any time it becomes evident that the threshold of 12 responses is unlikely to be met, then additional 
subjects may not be recruited (eg: 6 or fewer responses among 35 subjects with sufficient follow up 
[potential for at least 2 assessments]). If the study continues to the second stage, 50 additional subjects will 
be treated for a total of 90. Subjects in whom the presence of BRAFV600E mutation is not confirmed by 
central laboratory will be replaced. The null hypothesis will be rejected if 37 or more confirmed responses 
are observed in 90 treated subjects  with a centrally confirmed BRAFV600E mutation. This design yields a 1-
sided type I error rate of 1.6% and power of 80% when the true response rate is 45%. 
The cut-off for stage 2 analysis will be after all 90 treated  subjects of stage 1 and 2 with centrally confirmed 
BRAFV600E mutation had the opportunity to complete four post-baseline tumor assessments, and after 
subjects with an initial objective response have had an opportunity to have a confirmation scan. 
 
 
 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
Statistical 
Methods: 
 
 
Data analysis 
 
The Full Analysis Set (FAS) is composed of all included subjects having received at least one dose of study 
treatment (partial or full).  
The Efficacy Set (ES) is composed of all FAS subjects with a centrally confirmed BRAFV600E mutation.The 
Per-Protocol Set (PPS) will consist of all subjects from the FAS without any major protocol deviations. 
The PK Set will consist of all subjects who receive at least 1 dose of encorafenib, binimetinib or cetuximab 
and who have at least 1 post-dose PK blood collection with associated bioanalytical results. 
 
Efficacy:  
The FAS and ES will be used for all efficacy analyses unless otherwise specified. 
For the main analysis of the primary endpoint, the 95% confidence interval (CI) will be provided on the 
ES. This analysis will be  repeated on the FAS and PPS (supportive analysis). 
OS will be analyzed using the Kaplan-Meier method that will show median time with accompanying 95% 
CI and estimates for OS at several time points (including at least 2, 4, 6, 8, 10 and 12 months after start of 
treatment). Subjects without a death date by the data cut-off date will be censored for OS at their last contact 
date or the cutoff date, whatever is earlier. Analysis of PFS, DOR and TTR will be performed according to 
the Kaplan-Meier method. 95% CIs for the median values will be provided. 
Descriptive methods will be used to present all relevant data: 
- Continuous data will be summarized with: frequency, median, range, mean, standard deviation and 
standard error if relevant. 
- Categorical data will be presented in contingency tables with frequencies and percentages of each modality 
(including missing data modality).  
 
Safety:  
 
FAS will be used for all safety analyses. 
Maximum grade or severity will be tabulated, for each Medical Dictionary For Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term, by cycle and by subject.  
All analyses will be performed in two different ways: regardless or not of the relationship to treatment as 
assessed by the investigator. 
 
QoL: 
 
Results of QoL questionnaires (EORTC QLQ-C30, EQ-5D-5L, PGIC) will be summarized for each visit 
using descriptive statistics on the FAS. Additionally, changes from baseline in the domain scores at the 
time of each assessment will be summarized for EORTC QLQ-C30 and EQ-5D-5L. Further analysis will 
be detailed in the Statistical Analysis Plan. 
 
Pharmacokinetic analyses 
 
Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib (AR00426032) 
and serum concentration of cetuximab will be determined using validated assays. Descriptive statistics of 
concentrations will be reported.  
Ad-hoc PK parameters may be generated by compartmental approaches as appropriate. 
 
 
 
 
 
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Name of Sponsor: Pierre Fabre Médicament represented by the Institut de Recherche Pierre Fabre (IRPF) 
Name of Finished 
Product: 
Encorafenib, Binimetinib, Cetuximab 
End of study 
definition: 
The end of the study is defined as the time point when all treated subjects will have either progressed or 
discontinued study treatments (including 30-day Safety Follow-Up visit) for any other reason (unacceptable 
toxicity, subject’s decision, withdrawal of consent, initiation of subsequent anticancer therapy or death). 
 
 
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a 
Except C1D1, if visit is missed. 
Theoretical cycles dates (7 days ± 3) are kept constant irrespectively of whether the visit is done and/or the product is administered or not. 
If subject doesn´t come for CnD1 visit, the CnD1 assessments will still need to be performed (and shall be recorded on the unscheduled visit in the e-CRF). 
b 
Local urine pregnancy test for women of childbearing potential except serum pregnancy test at EOT.  
c 
Hematology - list of analytes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils/absolute neutrophil count (ANC), platelets, red blood cells (RBC), white blood cells (WBC) 
d 
Clinical Chemistry – list of analytes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (total and direct),albumin, alkaline phosphatase, bicarbonate (HCO3), blood urea nitrogen (BUN)/ 
urea, calcium, chloride, creatine kinase (CK), creatinine, glucose, lactate dehydrogenase (LDH), magnesium, potassium, sodium, total protein, troponin I or T, uric acid, amylase, lipase.  
Calculated creatinine clearance (Cockroft-Gault formula) will be measured at screening  
Bicarbonates (HCO3): not mandatory in Japan  
e 
Coagulation – list of analytes: prothrombin time (PT) or International Normalized Ratio (INR);activated partial thromboplastin time (aPTT)  
f 
Urinalysis – list of analytes: blood, glucose, ketones, leukocytes, hydrogen ion concentration (pH), protein 
g 
Procedure does not have to be repeated if performed within 72 hours prior to Cycle 1 Day 1 (i.e., first day of dosing). 
h 
-Electrocardiograms are to be performed in triplicate after 5 minutes rest predose on Cycle 1 Day 1 (conducted within approximately 5 to 10 minutes total time), followed by a single ECG at 2.0 (+/- 0.5) hours after 
administration of encorafenib and binimetinib and before the start of the cetuximab infusion. 
 -Single ECGs are to be performed on Cycle 2 Day 1 predose and at 2.0 (+/- 0.5) hours after administration of encorafenib and binimetinib and before the start of the cetuximab infusion.  
-Single ECGs are to be performed predose at remaining time points. Electrocardiograms should be performed prior to PK and PD blood collection at equivalent nominal timepoints. 
i 
Visual assessment (General inspection of the eyes, examination of motility and alignment, visual disturbance including diminished central vision, blurred vision or loss of vision) to be performed on site by the 
investigator. 
Full ophthalmic examination by ophthalmologist to be performed at EOT and, if clinically indicated during treatment, including best corrected visual acuity for distance testing, slit lamp examination, intraocular 
pressure and dilated fundoscopy with attention to retinal abnormalities, OCT and/or fluorescein angiography as appropriate. 
A full ophthalmic examination at the 30-day follow up is only required if there was a clinically significant abnormality noted at EOT.  
j 
Dermatologic examinations are to be performed every 8 weeks from Cycle 1 Day 1 (i.e., on Day 1 of Cycles 3, 5, 7…).  
k 
ECHO/MUGA scans are to be performed on Cycle 2 Day 1 and Cycle 5 Day 1, then every 12 weeks and EOT 
l 
Tumor evaluations are to be performed every 6 weeks (±7 days) from first dose for the first 12 weeks, then every 8 weeks (±7 days) until disease progression. The time window allowed for the first tumor  
assessment (i.e. day 42 from first dose) is +7 days. 
m 
If a subject discontinue study treatment for reasons other than disease progression, then tumor assessments must be performed (as per local and central review) every 6 weeks (first 12 weeks) 
 then every 8 weeks  until the start of new anti-cancer therapy, disease progression, death, lost to follow-up, subject’s decision or consent withdrawn. 
n 
PK samples will be collected during Cycle 1 and Cycle 2 only. On Cycle 1 Day 1 postdose at 2 h (± 10 min) and 6 h (± 30 min). PK samples will be collected on Cycle 2 Day 1 predose (just prior to dosing) and 
postdoseat 2 h (± 10 min). PK blood samples for encorafenib/binimetinib and potentially relevant metabolites will be processed to plasma. PK blood samples for cetuximab will be processed to serum. 
o 
Optional tumor sample will be requested only for subjects that discontinue study  drug treatment due to disease progression. 
p 
For subjects who discontinue study treatment due to disease progression, the survival follow up phase will start after the 30-days safety follow up is complete The subject will be contacted by phone for collection of 
information This may be conducted more frequently as needed. 
For subjects who discontinue study treatment due to reasons other than disease progression,  tumor assessment  must be performed until start of new anti cancer therapy,disease progression, death, lost to follow-up, 
subject’s decision or consent withdrawn. 
q 
To be performed 30-day after end of treatment (EOT) , when clinically appropriate, it is recommended subjects be monitored with physical examinations, dermatological examinations and chest CT scans for  
cutaneous and non-cutaneous secondary malignancies for up to 6 months after the last encorafenib dose or until initiation of another antineoplastic therapy.  
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r 
To be performed prior to study treatment administration. Only for vital signs: not to be performed at D8 and D22 starting week 29. 
Complete physical examination to be performed at screening. For all other visits, physical examination should be targeted as clinically indicated 
s 
The questionnaires should be completed by the subjects at the beginning of the study visit prior to receiving any study treatment, prior to any other study assessment or consultation with the Investigator, 
and prior to being informed of their current disease status.  
t 
Cetuximab will be administered as a weekly schedule for the first 28 weeks. Subjects on study will switch to a biweekly schedule starting on week 29 (Cycle 8 day 1).  
Since implementation of the  Urgent Safety Measure on 26 Mar 2020, in order to ensure the subjects’ safety in the clinical trial by decreasing the number of clinic visits in the context of COVID-19 pandemic, 
Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 administered as a 120-min IV infusion (i.e.on D1 and D15 of each cycle) regardless of the cycle number, after the investigator has 
evaluated the benefit/risk ratio for the subject with regards to Covid-19 pandemic. 
 
If there was a dose modification prior to switching to the biweekly schedule, the total dose per cycle should be maintained (i.e. 200mg/m2 QW, may be changed to a 400mg/m2 Q2W).  
 
u 
Information related to the length of stay, hospital facilities used, reasons for hospitalization, and hospital discharge information will be collected 
v 
From Week 29 (cycle 8), D8 and D22 visits will not be performed (biweekly infusions of cetuximab: no cetuximab infusion on D8 and D22) 
Since implementation of the  Urgent Safety Measure on 26 Mar 2020, in order to ensure the subjects’ safety in the clinical trial by decreasing the number of clinic visits in the context of COVID-19 pandemic, 
Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 administered as a 120-min IV infusion (i.e. on D1 and D15 of each cycle) regardless of the cycle number, after the investigator has 
evaluated the benefit/risk ratio for the subject with regards to Covid-19 pandemic. 
If the investigator implements this change, D8 and D22 visits before C8D1 will be performed by phone calls to ensure subject’s safety and will have to be documented in source documents for subjects not having yet 
reached C8D1 at the time of USM implementation. 
Abbreviations:  BSA = body surface area; CA19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative  
Oncology Group Performance Status; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D-5L = EuroQol-5D-5L; HIV= Human immuno deficiency virus; IV 
= intravenous(ly); MRI = magnetic resonance imaging; MSI = microsatellite instability; MUGA = multi-gated a 
cquisition; PD = progressive disease; PGIC = Patient's Global Impression of Change; PK = pharmacokinetic(s). 
 
 
 
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a 
From 28 dec 2020 (start of Study extension period), all treated subjects who are still benefiting from study treatments, will continue, if they consent, to receive study treatment in the Study 
extension period (protocol  amendment 6 – protocol V9). 
After treatment is discontinued (during Main study or Study extension periods), all subjects, if they consent, will be followed for survival until.the End of the Study (defined as the time point 
when all treated subjects will have either progressed or discontinued study treatments (including 30-day Safety Follow-Up visit) for any other reason (unacceptable toxicity, subject’s 
decision, withdrawal of consent, initiation of subsequent anticancer therapy or death). 
b 
Theoretical cycles dates (15 ± 3 days) are kept constant irrespectively of whether the visit is done and/or the product is administered or not. 
If subject doesn´t come for CnD1 visit, the CnD1 assessments will still need to be performed (and shall be recorded on the unscheduled visit in the e-CRF).  
c 
Local urine pregnancy test for women  of childbearing potential except serum pregnancy test at  EOT.  
d 
Hematology - list of analytes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils/absolute neutrophil count (ANC), platelets, red blood cells (RBC), white 
blood cells (WBC) 
e 
Clinical Chemistry – list of analytes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (total and direct), albumin, alkaline phosphatase,, calcium, chloride, 
creatinine, glucose, magnesium, potassium, sodium, total protein,     
 
f 
Urinalysis – list of analytes: blood, glucose, ketones, leukocytes, hydrogen ion concentration (pH), protein 
g 
Blood sample for tumor markers (CEA, CA19-9)  should be collected only  if performed as per clinical routine practice 
h 
 ECGs scans must be performed  every 3 cycles at D1  and at EOT ; and more frequently  if clinically indicated during study .  
ECHO MUGA must be performed every 12 weeks at D1, and at EOT or more frequently if clinically indicated during study 
i 
Visual assessment (general inspection of the eyes, examination of motility and alignment, visual disturbance including diminished central vision, blurred vision or loss of vision) to be 
performed on site by the investigator. 
Full ophthalmic examination by ophthalmologist to be performed at EOT and, if clinically indicated during treatment, including best corrected visual acuity for distance testing, slit lamp 
examination, intraocular pressure and dilated fundoscopy with attention to retinal abnormalities, OCT and/or fluorescein angiography as appropriate. 
A full ophthalmic examination at the 30-day FU is only required if there was a clinically significant abnormality noted at EOT 
j 
Tumor evaluations to be performed  every 12 weeks (±7 days) until disease progression  
k 
If a subject discontinues study treatment for reasons other than disease progression, then tumor assessments should continue to be performed ( per local and central review)  every 12 weeks  
until the start of new anti-cancer therapy, disease progression, death, lost to follow-up, patient decision, consent withdrawn or study end 
l 
For subjects who discontinue study treatment due to disease progression, the survival follow up phase will start after the 30-days safety follow up is complete. The subject will be contacted 
by phone for collection of information every 3 months.  
For subjects who discontinue study treatment due to reasons other than disease progression,  tumor assessment  must be performed until start of new anti cancer therapy,disease progression, 
death, lost to follow-up, subject’s decision, consent withdrawn or study end. 
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m 
To be performed  30-days after end of treatment (EOT).  
When clinically appropriate,as per standard of care it is recommended that subjects  be monitored for physical examinations, dermatological examinations and chest CT scans for cutaneous 
and non-cutaneous secondary malignancies for up to 6 months after the last encorafenib dose or until initiation of another antineoplastic therapy.  
n 
To be performed prior to study treatment administration.  
For Physical examination: examination should be should be targeted as clinically indicated - dermatologic examinations are to be performed every 8 weeks at D1 of the cycle 
o 
Optional tumor sample will be requested only for subjects that discontinue study due to disease progression. 
Abbreviations:  BSA = body surface area; CA19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = 
Eastern Cooperative Oncology Group Performance Status; IV = intravenous(ly); MRI = magnetic resonance imaging;  MUGA = multi-gated acquisition; PD = progressive disease.  
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT  
alanine aminotransferase  
AMP 
Association for Molecular Pathology 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
ASCP 
American Society for Clinical Pathology 
AST  
aspartate aminotransferase  
ATC 
anatomical therapeutic chemical 
AUC 
area under the concentration-time curve 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BP 
blood pressure 
bpm 
beat per minute 
BRAF 
B-RAF proto-oncogene, serine/threonine kinase 
BRAFV600E 
B-RAF proto-oncogene, serine/threonine kinase V600E-mutant 
BRAFwt 
B-RAF proto-oncogene, serine/threonine kinase wild-type 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA 
competent authority 
CA19-9 
carbohydrate antigen 19-9 
CABG 
coronary artery bypass graft  
CAP 
College of American Pathologists 
CEA 
carcinoembryonic antigen 
CI 
confidence interval 
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CK 
creatine kinase 
Cmax 
maximum concentration 
CR 
complete response 
CRA 
clinical research associate 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT DNA 
blood circulating tumor DNA 
CTFG 
Clinical Trials Facilitation Group Guidelines 
CYP 
cytochrome P450 
D 
Day 
DBP 
diastolic blood pressure 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DNA 
desoxyribonucleic acid 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
e-CRF 
electronic case report form 
EDTA 
ethylenediaminetetraacetic acid 
EGFR 
epidermal growth factor receptor 
EGFRI 
EGFR inhibitor 
EMEA 
European Medicines Agency  
EORTC 
European Organization for Research and Treatment of Cancer 
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EOT 
end of treatment 
EQ-5D-5L 
EuroQol-5D-5L  
ERK 
extracellular signal-regulated kinase 
ESMO 
European Society of Medical Oncology 
EU 
European Union 
FA 
folinic acid 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded 
FOLFIRI 
5-fluorouracil/folinic acid/irinotecan 
FOLFOX 
5-fluorouracil/folinic acid/oxaliplatin 
FOLFOXIRI 
5-fluorouracil/folinic acid/oxaliplatin/irinotecan 
FSH 
follicle-stimulating hormone 
5-FU 
5-fluorouracil 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
H1 
histamine receptor 
HC03 
Bicarbonate 
hCG 
human chorionic gonadotropin 
HDPE 
high-density polyethylene  
hERG 
human ether-a-go-go-related gene 
HFSR 
hand-foot skin reaction 
Hg 
Mercury 
HIV 
human immunodeficiency virus 
HR 
hazard ratio or heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
iDSMC 
independent Data Safety Monitoring Committee 
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INR 
international normalized ratio 
IEC 
independent ethics committees 
ILD 
interstitial lung disease 
IRB 
institutional review board 
IRPF 
Institut de Recherche Pierre Fabre 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous(ly) 
KA 
Keratoacanthoma 
KM 
Kaplan-Meier  
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LC/MS-MS 
liquid chromatography-tandem mass spectrometry 
LDH 
lactase dehydrogenase 
LFT 
liver function tests 
LH 
luteinizing hormone 
LLN 
lower limit of the normal reference range 
LOQ 
limit of quantitation 
LVEF 
left ventricular ejection fraction  
mCRC 
metastatic colorectal cancer 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen activated protein kinase kinase 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition  
NaF PET 
sodium fluoride positron emission tomography 
NCCN 
National Comprehensive Cancer Network 
NCI  
National Cancer Institute  
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NGS 
next generation sequencing  
NRAS 
neuroblastoma ras viral oncogene 
NSAID 
nsaids (non-steroidal anti-inflammatory drugs) 
NTI 
narrow therapeutic index 
OAT 
organic anionic transporter 
OATP 
organic anion-transporting peptide 
OCT 
optical coherence tomography 
OCT 
organic cationic transporter 
ORR 
objective response rate / overall response rate 
cORR 
confirmed objective response rate 
OS 
overall survival 
PABA 
para-aminobenzoic acid 
PCR 
polymerase chain reaction 
pERK 
phosphorylated extracellular signal-regulated kinase 
PD 
progressive disease + pharmacodynamic 
PFS 
progression-free survival 
PGIC 
Patient’s Global Impression of Change 
P-gp 
P-glycoprotein 
pH 
hydrogen ion concentration 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PO 
oral(ly) per os 
PP 
Polypropylene 
PPS 
per-protocol set 
PR 
partial response 
PRO 
patient  reported outcome 
PT 
preferred term or prothrombin time 
QD 
once daily 
QLQ-C30 
quality of Life Questionnaire for Cancer Subjects 
QoL 
quality of life  
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QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QW 
once weekly 
Q2W 
every two weeks 
RAF 
raf rapidly accelerated fibrosarcoma I 3K 
RAS 
oncogene rat sarcoma 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
ribonucleic acid 
RNA Seq 
RNA sequencing 
RPED 
retinal pigment epithelial detachment 
RP2D 
recommended Phase 2 dose 
RR 
response rate 
RTQPCR 
real time quantitative polymerase chain reaction 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
steering committee 
SCC 
squamous cell carcinoma 
SD 
stable disease 
SLI 
safety lead in 
SOC 
system organ class 
SPC 
summary of product characteristics 
SPF 
sun protection factor 
SSA 
sessile serrated adenoma 
t1/2 
terminal half-life 
TEAE 
treatment emergent adverse event 
Tmax 
time of maximum concentration 
TdP 
torsade de pointes 
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TSA 
traditional serrated adenoma 
TTR 
time to response 
UGT 
UDP-glucuronosyl transferase 
ULN 
upper limit of normal  
US 
United States 
USM 
Urgent Safety Measure 
V 
Version 
VEGFi 
vascular endothelial growth factor inhibitor 
Wt 
wild-type 
WBC 
white blood cells 
WHO 
World Healh Organization 
 
 
 
 
 
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1. INTRODUCTION AND STUDY RATIONALE 
1.1. BACKGROUND INFORMATION ON THE TARGET PATHOLOGY 
AND THERAPY 
Metastatic colorectal cancer (mCRC) continues to be a serious, life-threatening condition. 
According to GLOBOCAN data, 1.36 million new cases affecting 17.2 individuals per 100000 
population (746000 men and 614000 women) are diagnosed in the world each year, and 693000 
people (373000 men and 320000 women) die from colorectal cancer (CRC), accounting for a yearly 
mortality rate of 8.4 per 100000. In the United States, the American Cancer Society’s estimate for 
the number of colorectal cancer cases for 2017 are 95,520 new cases. In the World Health 
Organisation (WHO) European Region, CRC is the first tumor by incidence, with 471000 new cases 
each year and a mean mortality rate of 28.2 per 100000 population.  
Approximately 25% of subjects present with metastases and 50% eventually develop metastatic 
disease (Van Cutsem et al, 2014).  
Standard therapy in subjects with unresectable mCRC includes combination regimens with 
cytotoxic and targeted agents. In the last decade, substantial advances in the treatment of mCRC 
have resulted in an improvement in overall survival (OS) from 10 to 12 months to more than 20 
months. This improvement is thanks to the addition of irinotecan, oxaliplatin, bevacizumab, 
cetuximab, and panitumumab to the standard treatment with 5-fluorouracil (5 FU)/folinic acid (FA).  
 
BRAFV600E MUTANT COLORECTAL CANCER 
BRAF mutations, which lead to constitutive activation of BRAF kinase and sustained 
RAS/RAF/MEK/ERK pathway signaling resulting in increased cell proliferation and survival, 
occur in approximately 10% (range, 5–22%) of the unselected CRC population (Rozek LS et al, 
2010; Shaukat A et al, 2010).  
 
 
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According to the European Society of Medical Oncology (ESMO) Consensus Guidelines for the 
management of subjects with mCRC (Van Cutsem E et al, 2016), BRAF mutation status should be 
assessed alongside RAS mutation status for prognostic assessment (and/or potential selection for 
clinical trials) [level I, B].  
In the United States (US), the National Comprehensive Cancer Network panel (NCCN) strongly 
recommends genotyping of tumor tissue (either primary tumor or metastasis) in all subjects with 
mCRC, for RAS (KRAS exon 2 and non-exon 2; NRAS) and BRAF upon diagnosis of stage IV 
disease (Benson AB et al, 2017) Testing for the BRAF V600E mutation (BRAFV600E) can be performed 
on formalin-fixed paraffin-embedded (FFPE) tissues and is usually performed by polymerase chain 
reaction (PCR) amplification and direct Deoxyribonucleic Acid (DNA) sequence analysis. 
The presence of a BRAFV600E mutation is considered a marker of poor prognosis in subjects with 
mCRC and is associated (in the first line setting for metastatic disease) with a median survival of 
approximately 12 to 14 months compared to 21 to 25 months for subjects with BRAF wild-type 
(BRAFwt) tumors (Van Cutsem E et al, 2011). Failure to achieve good survival outcomes through 
standard doublet chemotherapy agents in subjects with BRAF V600E mutant mCRC has ignited efforts 
to combine multiple target therapies (Kopetz S el al, 2017; Corcoran RB et al, 2016). 
 
First line treatment options for BRAFV600E mutant mCRC patients 
Currently, there are no agents specifically indicated for subjects with BRAFV600E mutant mCRC. 
However, since BRAF and KRAS mutations are almost always mutually exclusive, subjects with 
BRAFV600E mCRC have typically been treated with standard-of-care regimens for RASwt mCRC. 
Subjects with RASwt mCRC typically receive infusional 5-FU/FA/oxaliplatin (FOLFOX) or (5-
FU/FA/irinotecan (FOLFIRI) with or without bevacizumab (anti VEGF antibody) or cetuximab 
(anti EGFR antibody) as initial therapy. A retrospective study reported no differences in PFS 
irrespective of whether oxaliplatin- or irinotecan-based chemotherapy was administered in the first-
line setting in patients with BRAF mutant CRC (6.4 versus 5.4 months; P=0.99). (Morris V et al, 
2014). There is insufficient evidence to conclude that BRAF is a predictive biomarker for irinotecan 
or oxaliplatin, as patients benefit regardless of their mutational status.  
 
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Some authors have proposed more intensive treatment based on the combination of 5-fluoruracil, 
leucovorin, oxaliplatin, irinotecan and bevacizumab (FOLFOXIRI-Beva) based on a retrospective 
analysis of a prospective phase II trial evaluating this combination, (Loupakis F et al, 2014) which 
included 15 BRAF mutant CRC patients. Results were initially encouraging compared with 
historical controls with median PFS and OS of 11.8 and 24.1 months and a 72% response rate (RR).  
In the follow up phase III trial which randomized a total of 28 patients with BRAF mutant mCRC, 
FOLFOXIRI-Bev had improved results compared with FOLFIRI Bev with respect to OS (median 
19.0 versus10.7 months; HR, 0.84; 95% CI, 0.24–1.2), PFS (median 7.5 versus 5.5 months; HR, 
0.57; 95% CI, 0.27– 1.23), and ORR (55% versus 42%; Odd Ratio, 1.82; 95% CI, 0.38–8.78). 
 
Use of EGFRi with standard chemotherapy in the first line setting for BRAFV600E mutant 
mCRC patients 
Limited data from unplanned retrospective subset analyses of subjects with mCRC treated in the 
first-line setting suggest that, although a BRAFV600E mutation confers a poor prognosis regardless 
of treatment, subjects with disease characterized by this mutation may receive some benefit from 
the addition of cetuximab to front-line therapy (Van Cutsem E et al, 2011; Bokemeyer C et al, 
2012). On the other hand, results from the randomized phase III Medical Research Council (MRC) 
COIN trial suggest that cetuximab may have no effect or even a detrimental one in subjects with 
BRAF-mutated tumors treated with CapeOx (Douillard JY et al, 2013; Maughan TS et al, 2011). 
While data suggest BRAF mutation status has clear prognostic value in mCRC, its predictive value 
for response and benefit from EGFR-directed treatments, such as cetuximab, remain controversial. 
Retrospective analyses of recent trials have suggested that BRAF mutations are not predictive of 
outcome with EGFR-directed therapies (Tol J and Punt CJ, 2010) in certain settings whereas other 
analyses have suggested that cetuximab and panitumumab are most active in subjects with BRAFwt 
mCRC (Di Nicolantonio F et al, 2008; De Roock W et al, 2010). In a recent meta-analysis of 7 
randomized controlled trials in which subjects received panitumumab or cetuximab in different 
lines of therapy, and with a range of background chemotherapy, no significant interaction was noted 
between the benefits of anti-EGFR therapy (measured as OS and PFS) and the presence of BRAF 
mutations. These results suggest that anti-EGFR therapy may have benefit for subjects with 
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BRAFV600E CRC. Consistent with this recent publication, a joint committee of the American Society 
for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Association for 
Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO), issued draft 
guidelines for the evaluation of molecular markers for CRC which stated that there is insufficient 
evidence to recommend BRAFV600E mutation status as a predictive molecular marker for response 
to EGFR directed therapies (see Table 1). 
 
Table 1: First line Phase II and III clinical trials with EGFR and VEGFi and BRAF 
mutational status for metastatic colorectal cancer subjects  
Reference 
No of 
patients 
Treatment 
BRAFm 
(%) 
OS 
(months) 
PFS 
(months 
RR 
NORDIC (Tveit 
KM et al, 2012) 
457 
FLOX+C 
FLOX 
20 
NA 
NA 
19.4% 
21% 
NSS 
CRYSTAL/OPUS 
(Bokemeyer C et 
al, 2012)  
1535 
FOLFIRI/FOLFOX+C 
FOLFIRI/FOLFOX 
8.2 
14.1 
9.9 
HR, 0.62 
P=0.076 
7.1 
3.7 
HR, 0.67 
P=0.23 
21.3% 
13.2% 
OR,1.6 
P=0.46 
COIN (Smith CG 
et al, 2013) 
2445 
FP + Oxaliplatin + C 
FP + Oxaliplatin 
9 
7.2 
10 
HR 1.18 
P=0.46 
NA  
NA 
HR1.25 
P=0.54 
NA 
PRIME (Douillard 
JY et al, 2013) 
 
1183 
FOLFOX + P 
FOLFOX 
10 
10.5 
9.2 
HR0.9 
P=0.76 
6.1 
5.4 
HR0.58 
P=0.12 
NA 
FIRE 3 (Stintzing 
S et al, 2014)  
342 
FOLFIRI + C 
FOLFIRI + Bev 
13.7 
12.3 
13.7 
HR0.87 
P=0.65 
4.9 
6 
HR0.87 
P=0.64 
52.2% 
40% 
OR 1.64 
P=0.29 
TRIBE (Cremolini 
C et al, 2015)  
508 
FOLFIRI + Bev 
FOLFOXIRI+Bev 
5.5 
10.7 
19.0 
HR:0.54 
5.5 
7.5 
HR=0.57 
42% 
56% 
OR:1.82  
(0.38-8.78) 
 
 
 
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Treatment options after first line for BRAFV600E mutant mCRC patients 
In a retrospective analysis of subjects with chemo-refractory mCRC treated with chemotherapy and 
an anti-epidermal growth factor receptor (EGFR) agent, the median progression-free survival (PFS) 
and OS in subjects with BRAF mutant tumors were 2 months and 6.5 months, respectively, 
compared with a median PFS of 6.5 months and a medianOS of 13,5 months  in subjects with 
BRAFwt tumors. In a study evaluating 5-FU/FA/irinotecan (FOLFIRI) plus panitumumab in a pure 
second-line setting, subjects with BRAFV600E mutant mCRC had a median PFS of 2.5 months and a 
median  OS of 4.7 months, compared with a median PFS and a medianOS of 6.9 and 18.7 months, 
respectively, in subjects with BRAFwt tumors. Finally, in 71 subjects with BRAFV600E mutant mCRC 
treated at the MD Anderson Cancer Center between 2003 and 2012, the median PFS with second-
line therapy was 10 weeks in the overall group (n=58) and 12 weeks in subjects who were treated 
with an irinotecan-based regimen (n=39), 28 of whom had received panitumumab or cetuximab 
concomitantly with irinotecan. The median PFS in subjects receiving second- or third-line therapy 
corresponded to the timing of the first restaging scan (Morris V et al, 2014). 
Benefits of combination therapies have been demonstrated in clinical studies of patients with 
mCRC, including: dual inhibition of BRAF + EGFR such as panitumumab + dabrafenib (Corcoran 
RB et al, 2016) and cetuximab + encorafenib (Tabernero J et al, 2016), the ORR reported in these 
studies were 10% and 22%, respectively; or triplet combinations consisting of BRAF + EGFR 
inhibition plus MEK inhibition or chemotherapy such as cetuximab +vemurafenib+ irinotecan 
(Kopetz S el al, 2017) or panitumumab + dabrafenib + trametinib (Corcoran RB et al, 2016), the 
ORR reported in these studies were 16% and 21% respectively . In particular, the phase II study of 
cetuximab + encorafenib demonstrated a median PFS of 4.2 months, and the median overall survival 
exceeded 1 year, which is substantially improved over the historical standard of care for this 
population.   
 
Inhibition of BRAF, MEK, and EGFR in BRAFV600E Colorectal Cancer Cells 
Cancer cells with BRAF mutations are highly dependent on MEK/ERK signaling. As demonstrated 
in melanoma cells, MEK-dependent activation of MAP Kinase (MAPK) signaling occurs following 
BRAF inhibition and near-complete inhibition of phospho-ERK is required for tumor responses. 
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The combination of a BRAF inhibitor and a MEK inhibitor has been shown to be more active than 
either agent alone, presumably due to delaying or preventing resistance (Thakur MD and Stuart 
DD, 2014). Nonclinical studies in CRC cells has shown that BRAF inhibition causes a rapid 
feedback activation of EGFR that supports continued proliferation of BRAFV600E CRC tumor cells 
(Corcoran RB et al, 2012; Prahallad A et al, 2012). Activation of EGFR can be effectively 
prevented by the combination of vemurafenib with anti-EGFR agents such as the small-molecule 
kinase inhibitor, erlotinib, or the monoclonal antibody, cetuximab.  
These reports suggest that activation of EGFR may partially explain the limited therapeutic effect 
of BRAF inhibitor monotherapy in subjects with BRAFV600E mutant mCRC and that this can be 
overcome with concomitant EGFR inhibition. The dependence of BRAF-mutant CRC cells on 
MAPK signaling provides a compelling rationale for inhibiting MEK in addition to BRAF and 
EGFR to achieve more robust inhibition of the pathway. 
1.2. INFORMATION ON THE TEST PRODUCT 
1.2.1. ENCORAFENIB 
Chemical and pharmaceutical characteristics 
Encorafenib (LGX818 or W0090), is a novel oral small-molecule kinase inhibitor with potent and 
selective inhibitory activity against mutant BRAF kinase, a member of the RAF/MEK/ERK MAPK 
pathway, which plays a prominent role in controlling several key cellular functions including 
growth, proliferation and survival. 
For further details, please refer to the current Encorafenib Investigator’s Brochure (Enco IB). 
Non-clinical data 
In 1- to 4-week toxicology studies in rats and cynomolgus monkeys, encorafenib was well tolerated 
at systemic exposures which result in tumor regression in mouse xenograft studies. Findings 
included hyperplasia and hyperkeratosis in the skin (plantar surface of feet) and non-glandular 
stomach in the rat. An absence of the later stages of spermatid maturation in male rats was also 
observed. Significant mortality/morbidity was observed mostly in female rats at the highest dose of 
400 mg/kg/day, a dose well above the maximum tolerated dose (MTD) in rats. 
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In the 13-week toxicology study in monkeys, the only drug-related finding was blister-like lesions 
identified over the macular region of the retina, observed in 2 monkeys treated at a dose of 60 
mg/kg/day. Exposure (maximum area under the concentration–time curve (AUC)0-24 achieved in 
the study at any time point) in the 2 affected monkeys was 5 to 8-fold and 4 to 6-fold greater than 
that achieved at the 300 and 450 mg once daily (QD) dose levels, respectively, in humans at steady 
state in Clinical Study CLGX818X2101. One of the animals with this finding showed evidence of 
recovery after the drug withdrawal. Histopathology examination of the affected eyes suggested that 
the findings were similar to the retinopathy associated with MEK inhibitors. 
Preclinical safety pharmacology data do not indicate a clinical risk for QT interval corrected for 
heart rate (QTc) prolongation, or adverse effects on the CNS or respiratory system. In Good 
Laboratory Practice (GLP) 4- and 13-week oral (gavage) toxicity studies in monkeys and a GLP 
monkey telemetry study, encorafenib had no adverse effect on electrocardiographic (ECG) 
morphology, rhythm or PR, QRS, QT and QTc duration. Using cloned hERG potassium channels 
expressed in mammalian cells, the IC50 for hERG inhibition by encorafenib was determined to be 
73.4 μM indicating that there is unlikely to be an effect of encorafenib on repolarization and QT 
interval.  
The GLP Ames and chromosomal aberration assays as well as a rat micronucleus study indicated 
that encorafenib is not genotoxic.  
Encorafenib was rapidly absorbed in mouse, rat and dog studies. Median Tmax was 2 hours when 
dosed as a suspension and 0.5 hours when dosed as a solution. 
For further details, please refer to the current Encorafenib Investigator’s Brochure (Enco IB). 
Clinical safety 
As of the data cutoff date of 11 May 2017, 1431 patients with advanced cancer have received at 
least one dose of encorafenib, either as a single agent or in combination with other agents in 10 
clinical studies. 
For further details, please refer to the current Encorafenib Investigator’s Brochure (Enco IB). 
 
 
 
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Single-agent encorafenib 
Single-agent encorafenib was evaluated in a first-in-human, Phase I dose-escalation/dose-expansion 
study (Clinical Study CLGX818X2101) in adult patients with BRAFV600E mutant locally advanced 
or metastatic melanoma (dose-escalation and dose-expansion phases) or mCRC (dose-expansion 
phase only). A total of 107 subjects were treated at doses ranging from 50 mg to 700 mg QD. 
In the dose-expansion phase of Study CLGX818X2101, the first 34 patients received encorafenib 
450 mg QD (i.e., MTD). Nine of these subjects experienced a dose-limiting toxicity (DLT) during 
Cycle 1 
 
 
 
 leading to a dose reduction to 300 mg QD in 6 subjects and discontinuation 
of encorafenib for the remaining 3 subjects. Among the patients who did not have a DLT, the 
encorafenib dose was reduced to 300 mg QD in 8 subjects, and 1 subject discontinued due to an 
AE. Based on these findings, 300 mg QD was identified as the recommended Phase 2 dose (RP2D) 
as single agent.  
Eighteen subjects with mCRC received encorafenib in the dose-expansion phase of the study. 
Twelve subjects received encorafenib 450 mg QD and 6 patients received 300 mg QD. 
Doselimiting- toxicities were reported in 3 subjects treated at the 450 mg QD dose and in none of 
the subjects treated at the 300 mg QD dose. The most common (occurring in ≥ 20% of subjects) 
AEs, regardless of causality, observed at the MTD of 450 mg QD and the RP2D of 300 mg QD in 
the mCRC subjects in the dose-expansion phase are shown in Table 2.  
 
 
 
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Encorafenib in combination with an anti EGFR 
Study CLGX818X2103 
Clinical Study CLGX818X2103 is an ongoing phase Ib/II study evaluating the combination of 
encorafenib and cetuximab and the triple combination of encorafenib, cetuximab and alpelisib (a 
PI3Kα inhibitor) in subjects with BRAF-mutant mCRC who experienced disease progression after 
≥ 1 prior standard-of-care regimen or who were intolerant to irinotecan-based regimens. Phase Ib 
has been completed and enrollment to phase II is complete. The aim of the phase Ib portion of the 
study was to determine the MTD and/or RP2D of the dual combination of encorafenib plus 
cetuximab and the triple combination.The phase II portion is an ongoing randomized study (N=102) 
designed to assess the relative clinical efficacy of the dual and triple combinations and to further 
characterize the safety of the two regimens. 
Study CLGX818X2103 Phase Ib 
A total of 26 subjects with locally determined BRAF mutation status (confirmed using Foundation 
Medicine) were treated with the dual combination and 28 patients were treated with triple 
combination. The MTD was not formally reached for either regimen, however, based on general 
tolerability, the RP2D for the triple combination was determined to be encorafenib 200 mg QD, 
alpelisib 300 mg QD in combination with standard dose of cetuximab (initial dose 400 mg/m2 
followed by 250 mg/m2 weekly). The dual combination was studied up to doses of 450 mg QD of 
encorafenib in combination with cetuximab without reaching MTD and with generally acceptable 
toxicity. In order to determine the contribution of alpelisib to the efficacy of the triple combination, 
an equal dose of encorafenib (200 mg QD) in both arms of the phase 2 portion was selected. 
In the 26 subjects treated in the dual combination arm, the median age was 63 years (range 43-80 
years). At baseline, Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 
in 8 (30.8%) subjects, 1 in 16 (61.5%) subjects, and 2 in 2 (7.7%) subjects.  
They had received a median of 2 prior therapies (range 1-5) and 11 (42%) patients had received ≥3 
prior regimens. Four dose levels of encorafenib QD:100 mg QD (n=2), 200 mg QD (n=7), 400 QD 
(n=9), and 450 QD (n=8), and cetuximab (400 mg/m2 initial and 250 mg/m2 weekly) were evaluated 
in the dual combination treatment arm. Complete response (CR) was observed in 1 subject and 
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partial responses (PR) were observed in 5 subjects for an overall response rate (ORR) of 23.1%. All 
except one of the responses (a PR) was confirmed. The median duration of response was 34.7 weeks 
(range 4.1-73.3 weeks). Of the 14 patients with stable disease (SD) as best radiological response, 
tumor regression was observed in 7 (27%). The median PFS was 3.7 months (95% CI, 2.8–10.6 
months) and the activity of the dual combination appeared durable with 8 (30.7%) patients with 
duration of exposure for greater than 1 year with the longest duration being > 88 weeks. 
CLGX818X2103 phase II  
A total of 50 subjects were randomized to the dual combination arm in phase II. The median age 
was 60 years (range 29-76) and ECOG PS was 0/1/2 in 45%/56%/2% of patients. The median 
number of prior treatment regimens was 2 (range 1-6) and 40% had 2 prior regimens and 18% had 
≥3 prior regimens. The ORR was 22% (95% CI: 12-36). The median PFS in the subjects treated 
with encorafenib plus cetuximab was 4.2 months (95% CI, 3.4-5.4). The observed ORR and PFS 
compare favorably to historical controls, which were normally below 10% ORR and generally 2 
months for PFS. The median OS of subjects in the dual combination arm was 12.4 months (95% 
CI, 7.6, not estimable) which compared favorably to historical controls (Tabernero J et al, 2016 ). 
The dual combination was generally well tolerated, as most adverse events observed were Grade 1 
or 2 with few Grade 3 or 4 events. Notably, although rash is observed in the majority of patients 
treated with cetuximab, in the dual combination arm, it was observed in only 7 (14%) patients, all 
of whom experienced Grade 1/2 rash. Summary of adverse events in the dual combination arm are 
summarized in Table 3. 
 
 
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Table 3: Adverse Events (Regardless of Study Drug Relationship) Reported in ≥ 20% of 
Dual-Combination Therapy (encorafenib plus cetuximab) (N=50), by Preferred Term — 
CLGX818X2103, Phase 2 
 
Encorafenib 200mg /  
Cetuximab  
(N=50) 
Preferred Term 
All Grades 
n (%) 
Grade 3/4 
n (%) 
Any Adverse Event 
50 (100) 
31 (62.0) 
Nausea 
23 (46.0) 
0 
Fatigue 
25 (50.0) 
2  (4.0) 
Vomiting 
16 (32.0) 
0 
Abdominal pain 
21 (42.0) 
4  (8.0) 
Diarrhoea 
14 (28.0) 
2  (4.0) 
Decreased appetite 
17 (34.0) 
1  (2.0) 
Arthralgia 
17 (34.0) 
0 
Headache 
16 (32.0) 
0 
Pyrexia 
13 (26.0) 
0 
Dry skin 
9 (18.0) 
0 
Hyperglycaemia 
5 (10.0) 
1  (2.0) 
Rash 
7 (14.0) 
0 
Lipase increased 
15 (30.0) 
11 (22.0) 
Back pain 
12 (24.0) 
1  (2.0) 
Dermatitis acneiform 
9 (18.0) 
0 
Stomatitis 
5 (10.0) 
0 
 
 
 
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1.2.2. BINIMETINIB 
Chemical and pharmaceutical characteristics 
Binimetinib (MEK162 or W0074) is an orally bioavailable, selective and potent mitogen-activated 
protein kinase kinase (MEK) 1 and MEK 2 inhibitor that is active in inhibiting phosphorylated 
extracellular signal-regulated kinase (pERK) and growth of BRAF-mutant cancer cells in the low 
nanomolar range.  
Non-clinical data 
Acute, sub-chronic, chronic and reproductive toxicity, genotoxicity and phototoxicity studies were 
completed in rats and monkeys to support chronic administration of binimetinib to adult subjects. 
There was no evidence of a genotoxic potential in vitro or in vivo. The adverse effects of MEK 
inhibitors in humans are similar to those observed in rats and monkeys, with the exception of ocular 
findings. These adverse effects include gastrointestinal intolerance and diarrhea, rash (skin findings 
in rats only), retinal events (only seen in humans) and retinal vein occlusion (rarely seen in humans). 
In vitro and in vivo phototoxicity studies conducted in mice indicate that binimetinib has a low risk 
of weak phototoxic potential at therapeutic doses. Furthermore, there has been no evidence of 
phototoxicity or photosensitivity in humans treated with binimetinib for cancer or for rheumatoid 
arthritis. 
Given the embryo-lethal effects seen in rats and rabbits and the teratogenic effects seen in rabbits, 
binimetinib should not be used in pregnant women. Women of child-bearing potential must be 
advised to use highly effective contraception methods as described in CTFG 2014 (see Section 
5.3.1 in the protocol). 
For further details, please refer to the current Binimetinib Investigator’s Brochure (Bini IB). 
 
 
 
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Clinical Safety 
As of 20 January 2018, a total of 2816 healthy subjects and patients have received at least 1 dose of 
binimetinib, either as a single agent or in combination with other targeted agents, standard 
chemotherapy agents or immunomodulating agents. These patients constitute the binimetinib safety 
population, which includes 229 healthy subjects, 17 subjects with hepatic dysfunction, 6 subjects 
with renal dysfunction, 164 patients with rheumatoid arthritis and 2400 patients with advanced 
cancer. 
For further details, please refer to the current Binimetinib Investigator’s Brochure (Bini IB).  
Single-agent binimetinib  
Based on two phase I studies (one conducted in subjects with advanced solid tumors, advanced or 
metastatic biliary cancer and KRAS- or BRAF-mutant metastatic CRC (Clinical Study ARRAY-
162-111) and the other conducted in Japanese subjects with advanced solid tumors (Clinical Study 
CMEK162X1101), the recommended single-agent dose of binimetinib is 45 mg twice daily (BID). 
This dose was further confirmed in phase II studies:  (1) conducted in BRAFV600E or NRAS-mutant 
melanoma subjects (Clinical Study CMEK162X2201); (2) in advanced solid tumors (Clinical Study 
CMEK162AUS11); and (3) in Chinese subjects with advanced Neuroblastoma RAS Vital 
Oncogene KRAS/BRAF/NRAS-mutant non-small cell lung cancer (Clinical Study CINC280X2205) 
and in phase III studies: (1) in subjects with NRAS-mutant melanoma (Clinical Study 
CMEK162A2301) and (2) in low grade serous carcinomas of the ovary, fallopian tube or primary 
peritoneum (Clinical Study ARRAY-162-311). 
Available clinical data indicate a predictable safety profile consistent with that reported for other 
allosteric MEK1/2 inhibitors. Frequently reported treatment-emergent AEs in patients receiving 
binimetinib include rash, dermatitis acneiform, nausea, vomiting, diarrhea, peripheral edema, 
fatigue, and creatine kinase (CK) elevation. Other clinically relevant toxicities are retinal events, 
increased blood pressure, decreased ejection fraction, and noninfectious pneumonitis/interstitial 
lung disease, all of which should be monitored closely with appropriate diagnostic evaluations.  
 
 
 
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These observed AEs are generally reversible and manageable by appropriate supportive medical 
care and/or dose modifications. Table 4 describes the safety profile of binimetinib as single agent 
in subjects with NRAS – mutant melanoma (Clinical study CMEK162A2301) [Dummer R et al, 
2017 (NEMO)].  
Table 4: Adverse events regardless of causality in at least 5% (grade 1 or 2) or at least 1% 
(grade 3 or 4) of patients (Clinical study CMEK162A2301) 
 
All patients (N=269) binimetinib 45mg BID 
 
Grade 1-2 
N (%) 
Grade 3 
N (%) 
Grade 4 
N (%) 
Diarrhoea  
104 (39) 
4 (1) 
0 
Oedema peripheral  
96 (36) 
1 (<1) 
0 
Dermatitis acneiform 
88(33) 
7 (3) 
0 
Rash  
87 (32) 
11 (4) 
0 
Nausea 
75 (28) 
4 (1) 
0 
 Blood creatine phosphokinase increased 
61 (23) 
33 (12) 
19 (7) 
Fatigue 
54 (20) 
6 (2) 
0 
Vomiting 
51 (19) 
6 (2) 
0 
Asthenia 
40 (15) 
8 (3) 
0 
Retinal detachement 
39 (14) 
0 
0 
Constipation 
35 (13) 
2 (1) 
0 
Pruritus 
30 (11) 
2 (1) 
0 
Aspartate aminotransferase increased 
29 (11) 
 6 (2) 
0 
Decreased appetite 
29 (11) 
2 (1) 
0 
Pyrexia 
28 (10) 
0 
0 
Skin fissures 
28 (10) 
0 
0 
Dyspnoea 
26 (10) 
3 (1) 
0 
Ejection fraction decreased 
20 (7) 
10 (4) 
0 
Hypertension 
17 (6) 
20 (7) 
0 
Alanine aminotransferase increased 
15 (6) 
7 (3) 
0 
Anaemia 
14 (5) 
4 (1) 
1 (<1) 
Preferred terms are presented by descending order of frequency of grade 1–2 adverse events. A patient with multiple 
occurrences of an adverse event under a preferred term is counted only once for that preferred term. A patient with 
multiple adverse events is counted only once in the total row. As per the study protocol, deaths were not graded and 
therefore were not included in this table; please refer to the (Bini IB) for more detail. 
 
 
 
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Binimetinib in Combination with Anti-EGFR Agents 
The combination of binimetinib and panitumumab was evaluated in patients with mCRC in the 
Phase 1b/2 Clinical Study CMEK162X2116. Ten patients were treated in the Phase 1b portion of 
the study with binimetinib (45 mg BID) and the labeled dose of panitumumab (6 mg/kg IV 
biweekly) which was declared the MTD/RP2D. An additional 40 patients were enrolled in the Phase 
2 portion of the study. In the Phase 2 portion, AEs, regardless of causality, reported in ≥ 15% of 
patients included all grade (%)/Grade 3-4 (%): diarrhea (70.0/12.5), vomiting (55.0/2.5), rash 
(50.0/12.5), nausea (47.5/5.0), fatigue (35.0/5.0), abdominal pain (32.5/2.5), dermatitis acneiform 
(32.5/5.0), blood creatine kinase (CK) increased (27.5/7.5), dry skin (25.0/5.0), anemia (20.0/10.0), 
asthenia (20.0/2.5), constipation (20.0/0), hypokalemia (20.0/12.5), pyrexia (20.0/0), stomatitis 
(20.0/0), AST increased (17.5/5.0), blood creatinine increased (15.0/2.5), chills (15.0/0) and 
hypomagnesemia (15.0/0). 
Combination of encorafenib and binimetinib 
An ongoing Phase 3 (COLUMBUS study - CMEK162B2301), 2-part, randomized, open-label, 
multicenter study = compared the efficacy and safety of the combination of binimetinib + 
encorafenib to single-agent vemurafenib and single-agent encorafenib in patients with BRAF V600-
mutant locally advanced unresectable or metastatic melanoma (Stage IIIB, IIIC and IV per the 
American Joint Committee on Cancer [AJCC]) untreated or have progressed on or after first line 
immunotherapy . 
In Part 1 of the study (Dummer R et al, 2016), patients were to be randomized in a 1:1:1 ratio to 1 
of the 3 treatment arms: binimetinib 45 mg BID + encorafenib 450 mg QD (Combo 450) or single-
agent encorafenib 300 mg QD or single-agent vemurafenib 960 mg BID. In Part 2 of the study 
Dummer R et al, (part 2), patients were to be randomized in a 3:1 ratio to 1 of the 2 treatment 
arms: (1) binimetinib 45 mg BID + encorafenib 300 mg QD (Combo 300) or (2) single-agent 
encorafenib 300 mg QD.  
Enrollment is complete, with a total of 921 patients (577 in Part 1 [192 Combo 450, 194 
encorafenib, 191 vemurafenib] and 344 in Part 2 [258 Combo 300, 86 encorafenib) randomized to 
treatment. A total of 911 patients (577 in Part 1 [192 Combo 450, 192 encorafenib, 186 
vemurafenib] and 344 in Part 2 [257 Combo 300, 84 encorafenib]) received at least 1 dose of study 
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treatment (Combo 450, Combo 300, encorafenib or vemurafenib). The most frequently reported 
AEs (≥ 10.0% of patients in either population) are summarized by preferred term and treatment 
population in Table 5. 
Table 5: Adverse Events Regardless of Causality Reported in ≥ 10.0% of Patients by 
Preferred Term (Pooled Data from Studies of Combo 450 and CMEK162B2301 Part 2 Data 
for Combo 300 in Patients with Melanoma) 
 
Pooled Data* 
Study CMEK162B2301 Part 2 
 
Combo 450 
N = 274 
n (%) 
Combo 300 
N = 257 
n (%) 
Preferred term 
All Grades 
n (%) 
Grade 3/4 
n (%) 
All Grades 
n (%) 
Grade 3/4 
n (%) 
Any AE 
271 (98.9) 
168 (61.3) 
252 (98.1) 
120 (46.7) 
Nausea 
114 (41.6) 
7 (2.6) 
70 (27.2) 
4 (1.6) 
Diarrhoea 
104 (38.0) 
9 (3.3) 
73 (28.4) 
4 (1.6) 
Fatigue 
85 (31.0) 
6 (2.2) 
57 (22.2) 
2 (0.8) 
Vomiting 
77 (28.1) 
6 (2.2) 
39 (15.2) 
1 (0.4) 
Arthralgia 
74 (27.0) 
2 (0.7) 
57 (22.2) 
3 (1.2) 
Blood CK increased 
74 (27.0) 
16 (5.8) 
51 (19.8) 
14 (5.4) 
Constipation 
66 (24.1) 
0 
43 (16.7) 
0 
Headache 
57 (20.8) 
4 (1.5) 
30 (11.7) 
1 (0.4) 
Anaemia 
51 (18.6) 
13 (4.7) 
24 (9.3) 
7 (2.7) 
Pyrexia 
47 (17.2) 
7 (2.6) 
43 (16.7) 
0 
Abdominal pain 
47 (17.2) 
5 (1.8) 
27 (10.5) 
3 (1.2) 
Asthenia 
43 (15.7) 
3 (1.1) 
38 (14.8) 
2 (0.8) 
Vision blurred 
43 (15.7) 
1 (0.4) 
26 (10.1) 
1 (0.4) 
GGT increased 
40 (14.6) 
23 (8.4) 
36 (14.0) 
12 (4.7) 
Alopecia 
38 (13.9) 
0 
33 (12.8) 
0 
Myalgia 
38 (13.9) 
1 (0.4) 
35 (13.6) 
1 (0.4) 
Hyperkeratosis 
37 (13.5) 
1 (0.4) 
25 (9.7) 
0 
Muscle spasms 
37 (13.5) 
1 (0.4) 
18 (7.0) 
1 (0.4) 
ALT increased 
36 (13.1) 
13 (4.7) 
29 (11.3) 
12 (4.7) 
Dry skin 
36 (13.1) 
0 
21 (8.2) 
0 
Oedema peripheral 
35 (12.8) 
3 (1.1) 
28 (10.9) 
0 
Dizziness 
34 (12.4) 
4 (1.5) 
21 (8.2) 
0 
Rash 
34 (12.4) 
2 (0.7) 
18 (7.0) 
2 (0.8) 
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Pooled Data* 
Study CMEK162B2301 Part 2 
 
Combo 450 
N = 274 
n (%) 
Combo 300 
N = 257 
n (%) 
Preferred term 
All Grades 
n (%) 
Grade 3/4 
n (%) 
All Grades 
n (%) 
Grade 3/4 
n (%) 
Hypertension 
31 (11.3) 
15 (5.5) 
21 (8.2) 
9 (3.5) 
Back pain 
30 (10.9) 
2 (0.7) 
36 (14.0) 
2 (0.8) 
Nasopharyngitis 
30 (10.9) 
0 
23 (8.9) 
0 
Pain in extremity 
29 (10.6) 
4 (1.5) 
27 (10.5) 
2 (0.8) 
Abdominal pain upper 
26 (9.5) 
2 (0.7) 
32 (12.5) 
1 (0.4) 
*pooled data from 3 clinical studies of the combination of binimetinib + encorafenib (CMEK162X2110 [Phase 1b/2], CLGX818X2109 
[Phase 2] and CMEK162B2301 Part 1 [Phase 3]) 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatinine phosphokinase; 
Combo = encorafenib plus binimetinib; GGT = gamma-glutamyl transferase; n or N = number 
Preferred terms are sorted in descending frequency of the Combo 450 column 
Data cutoff date CMEK162B2301 (Parts 1 and 2) 09 Nov 2016; CLGX818X2109 30 Dec 2016; CMEK162X2110 31 Dec 2016  
 
 
1.2.3. CETUXIMAB  
Chemical and pharmaceutical characteristics 
Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically 
to the extracellular domain of human EGFR on both normal and tumor cells, and inhibits receptor 
activation by competing with the epidermal growth factor and other ligands. In vitro and in vivo 
assays have shown that binding of cetuximab to the EGFR blocks its dimerization and 
phosphorylation and its consequent activation, resulting in an inhibition of cell growth, induction 
of apoptosis, and decreased matrix metalloproteinase and vascular endothelial factor production. 
Cetuximab exhibits clinical activity as a monotherapy or in combination with chemotherapy and/or 
radiation in head and neck cancer and mCRC (Cunningham D et al, 2004; Baselga J et al, 2005; 
Bonner JA, et al 2006). 
Cetuximab is approved in about 100 countries for the treatment of patients with epidermal growth 
factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer  
• in combination with irinotecan-based chemotherapy,  
• in first-line in combination with FOLFOX,  
• as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and 
who are intolerant to irinotecan (see the locally applicable cetuximab label). 
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Nonclinical data 
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), 
concentrations of cetuximab reach steady-state levels by the third weekly infusion. Cetuximab has 
a long elimination half-life with values ranging from 70 to 100 hours at the target dose. Although 
the US label for Erbitux® indicates that US-licensed cetuximab (Erbitux®) provides approximately 
22% greater exposure relative to cetuximab which is approved in the European Union (EU), the 
dosing and administration guidelines are consistent between the regions. 
 
Clinical data  
In subjects with mCRC whose disease had progressed during or within 3 months after treatment 
with an irinotecan-based regimen, treatment with single-agent cetuximab resulted in an objective 
response rate of 11% and a median time to progression of 1.5 months (Cunningham D et al, 2004). 
In subjects with EGFR-expressing mCRC treated with cetuximab in combination with irinotecan in 
the second-line setting, the median PFS was 4.0 months (95% confidence interval [CI], 3.24.1 
months) and OS was 10.7 months (95% CI, 9.6 -11.3 months) (Sobrero AF et al, 2008). 
In general, cetuximab is well tolerated and does not exacerbate the side effects of irinotecan or 
oxaliplatin. The main side effects are skin reactions, particularly an acne-like rash that is 
characteristic of treatment with many EGFR inhibitors. Such skin reactions are generally 
manageable. Other less frequently observed side effects associated with cetuximab treatment are 
diarrhea, fatigue, and hypomagnesemia (Tabernero J et al, 2008). 
The approved dosing regimen of cetuximab, both as monotherapy and in combination with 
chemotherapy, is an initial i.v. infusion of 400 mg/m2 on day 1 with subsequent weekly doses of 
250 mg/m2.Regarding the first-line treatment, cetuximab plus FOLFIRI, as compared with 
FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer patients with KRAS 
wild-type tumors (Van Cutsem E et al, 2009). 
 
 
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Combination of encorafenib, binimetinib, and cetuximab.  
This triple combination is currently being evaluated in the Phase III BEACON CRC study. A total 
of 30 patients were treated with encorafenib 300 mg QD, binimetinib 45 mg BID and cetuximab 
400 mg/m2 initial dose followed by 250 mg/m2 IV weekly in the Safety Lead-in portion of the study. 
Overall, the observed AEs (Van Cutsem E et al, 2018 – Table 6) were consistent with known 
BRAF, MEK and EGFR inhibitor toxicities. Grade 3/4 adverse events reported in ≥ 10% of patients 
were fatigue, CK increased, AST increased and urinary tract infection (3 patients [10%] each), all 
of which were grade 3 events except for a single grade 4 AST elevation. The only grade 3/4 skin-
related AE reported was rash (grade 3) in 1 patient (3%).  
This rate of severe toxicity is lower than generally observed for cetuximab alone or in combination 
with standard chemotherapy for mCRC (Erbitux® USPI).  
 
Table 6: ARRAY-818-302 (BEACON CRC study) Safety Lead-in: summary of adverse 
events regardless of causality occurring in ≥15% of patients (N=30) 
Event, n (%) 
Any grade 
Grade 3/4 
Any AE 
30 (100) 
19 (63.3) 
Diarrhea 
23 (76.7) 
1 (3.3) 
Dermatitis acneiform 
20 (66.7) 
0 
Fatigue 
19 (63.3) 
4 (13.3) 
Nausea 
19 (63.3) 
2 (6.7) 
Vomiting 
15 (50.0) 
2 (6.7) 
Dry skin 
14 (46.7) 
0 
Anemia 
11 (36.7) 
2 (6.7) 
Blood creatine phosphokinase increased 
11 (36.7) 
3 (10.0) 
Decreased appetite 
11 (36.7) 
2 (6.7) 
Abdominal pain 
10 (33.3) 
1 (3.3) 
Dyspnea 
10 (33.3) 
2 (6.7) 
Constipation 
9 (30.0) 
0 
Pyrexia 
9 (30.0) 
0 
Arthralgia 
8 (26.7) 
0 
Blood creatinine increased 
8 (26.7) 
0 
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Event, n (%) 
Any grade 
Grade 3/4 
Vision blurred 
8 (26.7) 
0 
Skin fissures 
7 (23.3) 
0 
Aspartate aminotransferase increased 
6 (20.0) 
3 (10.0) 
Asthenia 
6 (20.0) 
0 
Palmar-plantar erythrodysesthesia syndrome 
6 (20.0) 
0 
Rash maculopapular 
6 (20.0) 
0 
Dizziness 
5 (16.7) 
0 
Malaise 
5 (16.7) 
1 (3.3) 
Myalgia 
5 (16.7) 
0 
Edema peripheral 
5 (16.7) 
0 
Peripheral sensory neuropathy 
5 (16.7) 
0 
Urinary tract infection 
5 (16.7) 
3 (10.0) 
 
The Triplet combination dose used in the randomized Phase 3 portion of the study for US and EU 
patients (encorafenib 300 mg QD, binimetinib 45 mg BID and cetuximab 400 mg/m2 initial dose 
followed by 250 mg/m2 IV weekly) was subsequently administered to 7 patients enrolled in the 
Japanese Safety Lead-in (JSLI), which was initiated in February 2017. After all patients had 
completed at least 1 cycle of treatment the DMC reviewed the safety from the JSLI and agreed that 
Japanese patients may participate in the randomized portion of the study at the same Triplet regimen 
doses.  Ten Japanese sites have been participating in the randomized Phase 3 portion of the study 
in June 2018. 
 
1.3. STUDY RATIONALE 
BRAF mutations, which lead to constitutive activation of BRAF kinase and sustained 
RAS/RAF/MEK/ERK pathway signaling resulting in increased cell proliferation and survival occur 
in approximately 10% (range, 5–22%) of the unselected colorectal cancer (CRC) population  
(Rozek LS et al, 2010, Shaukat A et al, 2010; Sorbye et al, 2015) with lower prevalence in more 
advanced subject populations. 
The presence of a BRAF mutation is considered a marker of poor prognosis in subjects with mCRC 
and is associated with a median survival of approximately 12 to 14 months relative to 21 to 25 
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months for subjects with BRAFwt tumors (Van Cutsem E et al, 2011; Sorbye et al, 2015). These 
data suggest that improved therapies are urgently needed for patients with BRAFV600E mutant mCRC 
in the first line setting. 
Non clinical experiments have provided compelling evidence that combining a BRAF inhibitor with 
an EGFR inhibitor results in greater anti-tumor effects than either agent alone in BRAFV600E CRC 
cells (Corcoran RB et al, 2012; Prahallad A et al, 2012). Consistent with these observations, the 
combination of the selective BRAF inhibitor, encorafenib and cetuximab resulted in a strong 
synergistic antitumor activity (as shown in Table 1). 
Clinical data 
Consistent with nonclinical data in human CRC cell models (Array data on file), early clinical data 
suggest that the triple combination BRAF + MEK + EGFR inhibitors may result in greater activity 
than a dual combination BRAF + EGFR inhibitor in subjects with BRAFV600E mutant mCRC as 
described below. 
Triple combinations in the second or later line of therapy for the metastatic setting 
The ongoing multicentric, randomized phase III BEACON CRC study (NCT02928224) is 
evaluating encorafenib + binimetinib + cetuximab vs encorafenib + cetuximab compared with 
Investigator’s choice of irinotecan + cetuximab or FOLFIRI + cetuximab in subjects with 
BRAFV600E  mutant mCRC whose disease has progressed after 1 or 2 prior regimens in the 
metastatic setting.  A total of 30 subjects were treated in the SLI, all of whom received encorafenib 
(300 mg QD) + binimetinib (45 mg BID) + cetuximab (400 mg initial dose then 250 mg/m2 QW). 
Among the 29 subjects with BRAFV600E mutated tumors (one patient had a BRAF non-V600E 
mutated tumor) the confirmed overall response rate (ORR) was 48% (14/29) including a complete 
response in 3/29 patients. The ORR was 62% (including 8 PR and 2 CR) in patients with one 
previous line of therapy and 31% including 3 PR and 1 CR in those with two prior lines of therapy. 
Of the 29 patients with a BRAFV600E mutation, the median time on study treatment was 7.9 
months (range, 1.0–11.9 months), and 10 (33%) patients remained on study treatment at the time of 
data cutoff. Preliminary estimate of median PFS is 8.0 months (95% CI, 5.6–8.5 months), with 7 of 
29 patients (24%) still in follow-up and progression-free. Progression-free survival was similar 
between patients who had 1 vs 2 previous regimens (median, 95% CI, 7.6 [4.0–8.3] vs  
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8.1 [4.1–10.8] months) (Van Cutsem E et al, 2018). The confirmed ORR of 48% and median PFS 
of 8.0 months with the triple combination of encorafenib + binimetinib + cetuximab exceeds 
historical standard-of-care and exceeds the ORR of 22% in a phase II trial of the doublet of  
encorafenib + cetuximab (Tabernero J et al, 2016). The BEACON CRC SLI results are also 
improved compared with other recent triple combination including dabrafenib plus trametinib plus 
panitumumab, in which the ORR was 21% (Corcoran RB et al, 2016) and irinotecan, vemurafenib, 
cetuximab, in which the ORR (confirmed plus unconfirmed) was 16% (Kopetz S el al, 2017) in 
patients with previously treated BRAF mutant CRC.  In addition, to being better than other triple 
combinations, the efficacy data from the BEACON CRC SLI is also superior to the ORR of 4% and 
PFS of 2.0 months in patients treated with the irinotecan plus cetuximab, a combination accepted 
as current standard-of-care (Kopetz S el al, 2017). 
The preclinical data and the encouraging preliminary efficacy results observed in the SLI part of 
the BEACON CRC study justify the evaluation of combination of encorafenib, binimetinib and 
cetuximab in the first-line setting of this subject population, which represents a high-unmet medical 
need. 
BRAF inhibition as first line treatment for the metastatic disease in BRAFm mCRC subjects 
Data from retrospective series and post hoc analyses of randomised trials reveal that standard first-
line regimens, including a chemo-doublet and a biologic agent, lead to poor results in terms of PFS, 
ranging from 4 to 6 months (Ince WL et al, 2005). 
BRAF mutation status is a strong predictor for overall survival not only in the metastatic setting but 
also in earlier-stage diagnoses. The BRAF mutation is an early event in the CRC disease 
progression, which is involved in the transformation of epithelia into Traditional Serrated 
Adenomas (TSAs) or Sessile Serrated Adenomas (SSAs). BRAF mutation has also been identified 
as a potential mechanism of resistance to EGFR blockade. Therefore, it could be hypothesized that 
the introduction of a treatment combination including a BRAF inhibitor as first line might be 
effective 1) because of the early onset of the BRAF mutation and 2) as a strategy to prevent the 
resistance to EGFR inhibition.   
On the other hand, less “targeted’ strategies such as an intensive first-line regimen combining 
FOLFOXIRI with bevacizumab, seem to be effective in counteracting BRAF-mutant tumors’ 
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aggressiveness, as it was shown by Cremolini et al in the TRIBE study. It is important to note that 
this treatment combination is reserved to “fit” and young patients and not all patients might be 
eligible to receive such an aggressive treatment. Indeed, (Loupakis F et al, 2014) have reported 
that the treatment combination of FOLFOXIRI and bevacizumab was associated with a significant 
increase in the rates of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia in 
comparison to FOLFIRI and bevacizumab. Therefore new treatment combinations are highly 
awaited for this population in the first line setting. 
The current study is designed in light of the promising non-clinical and early clinical data of the 
combination of encorafenib, binimetinib  and cetuximab in subjects with BRAFV600E mCRC who 
have a poor clinical outcome. 
1.4. OVERALL RISK AND BENEFIT ASSESSMENT 
An independent data monitoring committee (DMC) regularly reviews the safety of the combination 
of binimetinib, encorafenib, and cetuximab in the Safety Lead-in and Phase 3 portions of the 
BEACON CRC trial.  The DMC has not identified any unexpected toxicities and has determined 
that the triple combination data is indicative of an acceptable and manageable tolerability profile. 
The safety profiles of each drug were described (in Section 1.2). Laboratory assessments as well as 
clinical procedures will be performed throughout the conduct of the current study to ensure the 
subjects’ safety.  
The benefit/risk assessment for this phase II study that will be conducted in compliance with the 
protocol, Good Clinical Practices (GCP) and the applicable regulatory requirements, appears 
acceptable for subjects with such an aggressive disease as BRAFm mCRC. 
 
 
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2. STUDY OBJECTIVE AND ENDPOINTS  
2.1. PRIMARY OBJECTIVE  
The primary objective of the study is: 
To evaluate the antitumor activity of the combination of encorafenib, binimetinib and cetuximab by 
assessing the confirmed overall response rate (cORR) by local radiologist/investigator assessment 
in adult subjects with previously untreated BRAFV600E-mutant (BRAFV600E) metastatic colorectal 
cancer (mCRC). 
2.2. SECONDARY OBJECTIVES  
The secondary objectives of the study are: 
• To evaluate the cORR by central radiologist assessment. 
• To evaluate the ORR (for confirmed + unconfirmed responses) by local 
radiologist/investigator and central assessment. 
• To assess the effect of the combination of encorafenib, binimetinib and cetuximab on the 
duration of response (DOR).  
• To assess the effect of the combination of encorafenib, binimetinib and cetuximab on other 
time-related efficacy parameters: time to response (TTR), progression-free survival (PFS) 
and overall survival (OS). 
• To characterize the safety and tolerability of the combination of encorafenib, binimetinib 
and cetuximab.  
• To assess the effect on quality of life (QoL). 
• To explore health care resource utilization. 
• To describe the pharmacokinetics (PK) of encorafenib, binimetinib, a metabolite of 
binimetinib (AR00426032) and cetuximab. 
 
 
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2.3. EXPLORATORY OBJECTIVES 
 
• To assess the relationship between changes in tumor markers (carcinoembryonic antigen 
[CEA] and carbohydrate antigen 19-9 [CA19-9]) and radiographic response to treatment. 
• To assess BRAFV600E status in blood circulating tumor DNA (ctDNA) at baseline. 
• To assess the  potential predictive significance of the microsatellite instability (MSI) status 
in subjects with BRAFV600E mutant mCRC.  
• To assess blood- and tissue-based predictive biomarkers of activity. 
2.4. PRIMARY ENDPOINTS 
• cORR as assessed by local radiologist/investigator review as per Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1).  
2.5. SECONDARY ENDPOINTS 
• cORR as assessed by central radiologist review as per RECIST 1.1. 
• ORR (for confirmed and unconfirmed responses) as per local radiologist/investigator and 
central assessment.  
• DOR assessed based on local radiologist/investigator and central review.  
• TTR assessed based on local radiologist/investigator and central review. 
• PFS assessed based on local radiologist/investigator and central review. 
• OS. 
• Type and severity of adverse events (AEs) and serious adverse events (SAEs), changes in 
hematology and chemistry values, physical examinations, vital signs, electrocardiogram 
(ECGs) and echocardiogram (ECHO)/ multi-gated acquisition (MUGA) scans and 
ophthalmological examinations graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events v4.03 (NCI-CTCAE v4.03). 
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• Change from baseline in the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire for Cancer subjects (QLQ-C30), EuroQol-5D-5L 
(EQ-5D-5L), and Patient Global Impression of Change (PGIC). 
• Resource utilization focused on hospitalizations occurring during the study treatment phase. 
• Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) and serum concentration of cetuximab. 
2.6. EXPLORATORY ENDPOINTS: 
• Changes from baseline in blood CEA and CA19-9 at the beginning of each cycle and at the 
end of treatment. 
• BRAF V600E mutation status in ct-DNA at baseline. 
• MSI status in formalin-fixed paraffin-embedded (FFPE) samples via established PCR 
assays in tumor sample versus germline control at screening. 
• Genomic and proteomic analysis of tumor tissue at baseline and at end of treatment (optional 
tumor tissue sample at end of treatment). 
• Genomic and proteomic analysis of blood samples at baseline. 
3. ETHICAL CONSIDERATIONS RELATING TO THE STUDY 
Some of the ethical considerations that lead to an acceptable risk-assessment have already been 
described in Section 1.2, in the encorafenib and binimetinib Investigator’s Brochures and in the 
Cetuximab  Summary Of Product Characteristics (SPC). The study will be conducted on the basis 
of appropriate clinical and non-clinical data. 
In this study, the treatment will be administered to subjects with mCRC who have received no 
systemic treatment for metastatic disease. They will be included only after they have received 
detailed and complete information about the risks and constraints related to their participation and 
give their written consent for participation in the study. 
They will remain under medical control throughout the duration of the study: as described in the 
assessment and procedures sections. Potential AEs will be reported during all treatment periods, 
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allowing the Investigator to decide whether the subjects can continue to receive study treatment. In 
addition, verification of vital signs, as well as ophthalmologic and dermatologic examinations will 
be performed to detect any safety signals. 
The study will be carried out in accordance with the Declaration of Helsinki and its subsequent 
modifications (the latest in 2013 –Fortaleza), the recommendations for Good Clinical Practice 
(GCP) (ICH E6, R2), and any applicable local regulatory requirement(s). 
The clinical study will start upon receipt of approval from both the relevant independent Ethics 
Committee (IEC) / Institutional Review Board (IRB) and the Competent Authorities. 
4. STUDY DESIGN 
4.1. OVERALL DESCRIPTION 
This two-stage phase II trial will be conducted as a multinational, multicenter, open-label, single-
arm study in 90 subjects. In the first stage 40 subjects will be treated, and an additional 50 subjects 
will be treated during the second stage. Subjects in whom the presence of BRAFV600E is not 
confirmed by central laboratory will be replaced. The second stage may be initiated as soon as 
confirmed responses are observed in at least 12 subjects.  
As it may take several treatment cycles for subjects to achieve a confirmed response, if 12 confirmed 
responses are not observed at the time the 40th subject is treated in Stage 1 a limited number of 
subjects (maximum 12) from stage 2 may be treated while waiting for all subjects in the initial 
cohort of 40 subjects in Stage 1 to be evaluable for a confirmed response providing no safety 
concern was raised by the iDSMC. These additional subjects will not count towards responses in 
Stage 1 but will be included as part of the Stage 2 cohort, should the study move forward into Stage 
2. 
If at any time it becomes evident that the threshold of 12 responses is unlikely to be met, then 
additional subjects may not be recruited (eg: 6 or fewer responses among 35 subjects with sufficient 
followup [potential for at leat 2 assessments]). If the study continues to the second stage, 50 
additional subjects will be treated for a total of 90. Subjects in whom the presence of BRAFV600E is 
not confirmed by central laboratory will be replaced. 
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An iDSMC will review the available safety information at regular intervals to ensure that the overall 
safety remains acceptable during the Main study period (see section 11.5. iDSMC). 
 
For the Main Study period, the treatment will be administered by cycles of 28 days until disease 
progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer 
therapy or death. In each 28-day cycle, subjects will receive: 
From Day 1 to Day 28: Encorafenib: 300 mg PO (oral capsule 4X 75 mg) once daily (QD). 
From Day 1 to Day 28: Binimetinib: 45 mg PO (oral tablet 3X 15 mg) twice daily (BID). 
Initial cetuximab dose Cycle 1, Day 1 400 mg/m2 administered as a 120-min IV infusion followed 
by a 250 mg/m2 dose administered as a 60-min IV infusion once weekly (QW) thereafter until week 
28. Then, 500mg/m2 IV Q2W from week 29 (Cycle 8 day 1).  
Since implementation of the  Urgent Safety Measure on 26 Mar 2020, in order to ensure the 
subjects’ safety in the clinical trial by decreasing the number of clinic visits in the context of 
COVID-19 pandemic, Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 
administered as a 120-min IV infusion (i.e. on D1 and D15 of each cycle) regardless of the cycle 
number, after the investigator has evaluated the benefit/risk ratio for the subject with regards to 
Covid-19 pandemic. 
If there was a dose modification prior to switching to the biweekly schedule, the total dose per cycle 
should be maintained (i.e. 200mg/m2 QW, may be changed to a 400mg/m2 Q2W). 
From 28 Dec 2020, access to study treatment will be provided through a Study extension to all 
subjects whom the investigator considers are continuing to benefit from study treatment (i.e. do not 
experience unacceptable toxicities and none of the treatment discontinuation criteria are met) until:  
• the last ongoing subject will discontinue study treatments (including 30-day Safety Follow-
Up visit) for any reason (unacceptable toxicity, progression of disease, subject’s decision, 
withdrawal of consent, initiation of subsequent anticancer therapy or death),  
• or binimetinib/encorafenib are commercially available in the first line setting of BRAF V600E 
mutated mCRC,  
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• or the binimetinib/encorafenib development program is stopped, whichever comes first.  
The same study treatment doses and schedule as for Main study period will be applicable for the 
Study extension period (including dose modification recommendations). 
After discontinuation of study treatment (during Main study or Study extension periods), there will 
be a 30-day safety follow-up period. Subjects will then enter a survival follow-up period until the 
End of the Study. 
 
BRAF TESTING: 
Because time to treatment initiation is critical for untreated BRAFV600E mCRC subjects, will be 
eligible for the study based on identification of a tumoral BRAFV600E mutation as determined by 
local laboratory result obtained at any time prior to Screening. Only polymerase chain reaction 
(PCR) and next generation sequencing (NGS)-based local assays results will be acceptable.  
The BRAF mutation status must be confirmed by the central laboratory no later than 30 days after 
the first dose of study treatment. In cases where there is discordance between the local assay and 
central laboratory results, or if the central laboratory is not able to confirm presence of a BRAFV600E 
mutation due to inadequate or poor sample condition or insufficient amount of tumor cells in sample 
within 30 days of initiating study therapy, subjects may only continue treatment if there is no clinical 
indication of deterioration or disease progression and the Investigator determines that the subject is 
deriving benefit. In such instances, subjects must be informed that the BRAF mutation status is 
unconfirmed and must sign a separate informed consent form (ICF) that includes this information 
and describes alternative treatment options.  
Central laboratory BRAF mutation tests with a definitive result (positive or negative) cannot be 
repeated to resolve a discordant result. Subjects whose sample is determined to be inadequate or 
who have an indeterminate result on central testing should have samples (archival material only) 
resubmitted for testing until a definite result can be obtained; however, in some cases, the BRAF 
status may remain indeterminate after several attempts to conduct the central test.  
If at any time there is lack of confirmation of the BRAFV600E mutation in a total of 6 subjects (≥ 6% 
of the total targeted 90 treated subjects) or discordance between the local assay and the central 
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laboratory in 3 subjects (≥ 3% of the total targeted 90 treated subjects), all subsequent subjects will 
be required to have BRAFV600E determined by the central laboratory prior to study treatment 
assignment (i.e., local BRAF testing will no longer be accepted for trial eligibility). Information 
regarding sites and laboratories associated with discordant results will be maintained and results 
from laboratories with more than 1 prior discordant result will not be accepted for further subject 
enrollment. It means that further subjects will be treated in this site on the basis of the central 
laboratory only. 
4.2. DISCUSSION OF THE STUDY DESIGN 
4.2.1. Choice of the Study Population 
Refer to Section 1 
4.2.2. Choice of the Study Design 
In clinical practice, the number of mCRC patients receiving therapy (as well as the treatment 
efficacy) decreases with subsequent lines of therapy (Bokemeyer C et al, 2011; Maughan TS et 
al, 2011). Patients with BRAFm mCRC have limited treatment options and currently no targeted 
therapy blocking BRAF has been approved in this patient population.  Standard of Care treatment 
options provide limited number of responses to treatment. As outlined in Section 1, the data from 
retrospective series and post hoc analyses of randomised trials reveal that standard first-line 
regimens, including a chemo-doublet and a biologic agent, lead to poor results in terms of ORR, 
PFS, and OS compared to BRAFwt patients, even when more aggressive and less “targeted” 
approaches are used (Cremolini C et al, 2015). The available data from the SLI of the BEACON 
CRC study provides evidence that the triple combination of encorafenib, binimetinib and cetuximab 
is likely to be at least as effective as the current standard of care in the first line setting. 
The objective and advantage of the current study design is to evaluate the antitumor effect while 
limiting the number of subjects exposed to the triple combination in the frontline setting. The two-
stage design allows for this by providing an opportunity to stop the study early due to futility. 
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4.2.3. Choice of the Dose and Administration Modalities 
In order to optimize the potential for benefit while limiting the potential for toxicity, the dose of 
encorafenib chosen for this study is 300 mg QD, corresponding to its single-agent RP2D.  
The proposed 300 mg dose represents an active dose of encorafenib that has been shown in clinical 
studies to result in tumor regression and clinical responses as a single agent (Dummer R et al, 
2013; Gomez-Roca CA et al, 2014). Non-clinical in vitro and in vivo studies using BRAFV600E 
human melanoma and colon cancer cell lines and xenograft models exploring the relationship 
between dose and efficacy also provide evidence in support of 300 mg being an appropriate starting 
dose in subjects. Using the human melanoma xenograft model A375, which expresses BRAFV600E, 
a 20 mg/kg dose was estimated to reduce tumor volume by 85% compared to untreated animals.  
Based on relative free fraction exposure, the 20 mg/kg steady-state mouse exposure is equivalent to 
the average exposure for subjects receiving 300 mg QD dosing. This is also consistent with the 
observed inhibitory effects of encorafenib in combination with cetuximab using a BRAFV600E CRC 
cell-based system. Inhibition was 70% when studied at a free encorafenib concentration that was 
equivalent to the average daily concentration in subjects receiving 300 mg QD dosing. 
The dose of binimetinib that was chosen corresponds to the single-agent RP2D (45 mg BID). 
The dose of cetuximab corresponds to the approved dose in the US Product Information, Summary 
of the Product Characteristics for Erbitux® and Package Insert respectively in the US, Europe and 
Japan. 
Regarding the use of cetuximab as a biweekly schedule: Tabernero et al. (Tabernero J et al, 2016 
and Tabernero J et al, 2010) showed preliminary pharmacokinetic, pharmacodynamic, efficacy, 
and safety evidence that every-2-weeks administration of cetuximab at a dose of 500 mg/m2 may 
be a potentially convenient alternative to the approved weekly dosing regimen of 250 mg/m2 
(following an initial dose of 400 mg/m2 ) in the treatment of mCRC. In regards to efficacy, an every-
2-weeks dose of 500 mg/m2 of cetuximab in combination with irinotecan gave a strikingly similar 
response rate (23%) and median TTP (4.8 months) (Pfeiffer P et al, 2007) to those of the approved 
dosing regimen plus irinotecan (23% and 4.1 months, respectively) (Cunningham D et al, 2004), 
in patients who had progressed on previous chemotherapy. Based on the pharmacokinetic 
similarities of the two dosing regimens in the first-line setting (Taberno J et al, 2006), it is 
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reasonable to anticipate that the efficacy and safety of the every-2-weeks dosing regimen will also 
be similar to that observed with the approved dosing regimen (Tabernero J et al, 2010). 
The justification to switch to a biweekly schedule is to provide a more convenient schedule of 
administration to subjects who would stay on treatment (and who have not presented any signs of 
PD) for a period of time equivalent as the median PFS reported with SoC in the first line setting. 
Although cetuximab has not been approved for a Q2W dosing schedule, there are several key studies 
supporting the clinical use of this schedule for patients which metastatic CRC in the first line 
(Tabernero J et al, 2010; Bouchahda M et al, 2011) as well as the second and third line setting 
(Roca JM et al, 2010; Martin-Martorell P et al, 2008; Pfeiffer P et al, 2008; Carneiro BA et al, 
2012; Mrabti H et al, 2009; Shitara K et al, 2012). 
Since implementation of the Urgent Safety Measure on 26 Mar 2020, in order to ensure the subjects’ 
safety in the clinical trial by decreasing the number of clinic visits in the context of COVID-19 
pandemic, Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 
administered as a 120-min IV infusion (i.e. on D1 and D15 of each cycle) regardless of the cycle 
number, after the investigator has evaluated the benefit/risk ratio for the subject with regards to 
Covid-19 pandemic.  
As described by Tabernero and colleagues, this change in the Cetuximab administration regimen 
should not impact the pharmacokinetic, pharmacodynamic, efficacy, and safety of Cetuximab in the 
treatment of mCRC (Tabernero J et al, 2016 and Tabernero J et al, 2010). 
In regards to the triple combination, the DMC of BEACON CRC study reviewed the data after the 
first 88 randomized patients, and these have not indicated any safety concerns. The doses of the 
study treatment administered in BEACON CRC study were the same as those that will be used in 
this study. Given that there were no new safety concerns among the 88 subjects randomized, the 
use of the same doses of study treatment in this study is justified. 
4.2.4. Choice of sample size 
Taking into consideration the study primary objective, the study sample size with 40 treated subjects 
with a centrally confirmed BRAFV600E mutation in stage 1, and 50 in stage 2 (if study does not stop 
for futility after stage 1), is considered sufficient to evaluate the antitumor activity of the study 
treatment (see Section 13.3 for more details).  
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5. STUDY POPULATION 
Subjects fulfilling all of the inclusion criteria and none of the exclusion criteria will be eligible. 
5.1. INCLUSION CRITERIA 
 
1. Provide a signed and dated informed consent document. 
2. Male or female ≥ 18 years of age at time of informed consent. 
3. Histologically or cytologically confirmed CRC that is metastatic and unresectable at time of 
study entry (i.e. not suitable for complete surgical resection at screening).  
4. Presence of BRAFV600E mutation in tumor tissue previously determined by a local assay at any 
time prior to screening. 
Notes:  
a. Only PCR and NGS-based local assays results will be acceptable.  
b. If at any time there is lack of confirmation of the BRAFV600E mutation in a total of 6 subjects 
(≥ 6% of the total targeted 90 treated subjects) or discordance between the local assay and 
the central laboratory in 3 subjects (≥ 3% of the total targeted 90 treated subjects), 
discordance or impossibility to confirm the BRAFV600E mutation in 3 subjects, all subsequent 
subjects will be required to have BRAFV600E determined by the central laboratory prior to 
study treatment assignment. 
c. 
Central testing cannot be repeated to resolve discordances with a local result once the 
central laboratory delivers a definitive result (positive or negative). 
d. If the result from the central laboratory is indeterminate or the sample is deemed inadequate 
for testing, additional samples should be submitted (archival material only). 
e. 
If more than 1 discordant result from any local laboratory leads to subject enrollment, 
subsequent results from this local laboratory will not be accepted for further subject 
enrollment. 
 
5. Eligible to receive cetuximab per locally approved label with regards to tumor RAS status.  
e.g.: In agreement with EU label, evidence of wild type RAS (KRAS and NRAS) in EU 
countries. 
 
6. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, 
archival or newly obtained) for  testing of BRAF and RAS mutation status(a). 
(a) FFPE tumor tissue block or a minimum of 10 slides, optimally up to 15 slides. 
 
7. Evidence of measurable disease, as per RECIST 1.1. 
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Note: Lesions in areas of prior radiotherapy or other loco-regional therapies are considered 
measurable only if progression has been documented in the region following therapy. 
 
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
 
9. Adequate bone marrow function at screening and baseline: 
i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
ii. Platelets ≥ 100 x 109/L. 
iii. Hemoglobin ≥ 9.0 g/dL. 
Note: Blood transfusions are allowed provided that the subject has not received more than 2 units 
of red blood cells in the 4 weeks prior to achieve the minimum required hemoglobin level. 
 
10. Adequate renal function at screening and baseline. 
i.  Serum creatinine ≤ 1.5x upper limit of normal (ULN) or 
ii. Calculated creatinine clearance (CrCl) ≥ 50 mL/min  by Cockroft-Gault formula  
 
11. Adequate electrolytes at screening and baseline, defined as serum potassium and magnesium 
levels within institutional normal limits.  
Note: replacement treatment to achieve adequate electrolytes will be allowed 
 
12. Adequate hepatic function at screening and baseline: 
i. Serum total bilirubin ≤ 1.5 x ULN and < 2 mg/dL. Note: Total bilirubin > 1.5 x ULN is 
allowed if direct (conjugated) bilirubin is ≤ 1.5 x ULN (and indirect (unconjugated) 
bilirubin is ≤ 4.25 x ULN – Only applicable for France). 
ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x 
ULN, or ≤ 5 x ULN in the presence of liver metastases. 
13. Adequate cardiac function at screening:  
i. Left ventricular ejection fraction (LVEF) ≥ 50% as determined by MUGA scan or 
ECHO. 
ii. Mean triplicate QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF) value ≤ 480 msec. 
14. Subject able to take oral medications. 
15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other 
study procedures. 
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16. Female subjects 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. 
Notes: 
(a) Precautions to avoid pregnancy must be conducted from screening through 6 months after the 
last dose of cetuximab or through 30 days after the last dose of encorafenib or binimetinib, 
whichever is later if of childbearing potential. 
(b) Permitted methods of contraception as provided (in Section 5.3.1) should be communicated to 
the subjects and their understanding confirmed. For all females, the pregnancy test must be 
negative at screening and baseline. 
 
17. Male subject must agree to take appropriate precautions to avoid fathering a child.  
Notes: 
(a) from screening through 6 months after the last dose of cetuximab or through 90 days after the 
last dose of encorafenib or binimetinib, whichever is later. 
(b) permitted methods of contraception as provided (in Section 5.3.1) should be communicated to 
the subjects and their understanding confirmed.  
 
18. Subjects under guardianship or partial guardianship will be eligible unless prohibited by local 
laws or by local/central ethic committees. 
Note: where allowed, all procedures prescribed by law must be followed. 
 
19. Affiliated to a social security system, or is a beneficiary (if applicable in the national 
regulation). 
5.2. EXCLUSION CRITERIA  
 
1. Prior systemic therapy for metastatic disease. 
Note: previous adjuvant/neoadjuvant therapy is allowed provided that 1) the interval from the end 
of chemotherapy to relapse is >6 months OR 2) in the case of neoadjuvant therapy, complete 
surgical resection was achieved and the interval from the end of chemotherapy to relapse is >12 
months. Prior locoregional radiotherapy is allowed. 
 
2. Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti-EGFR 
treatment. 
 
3. Symptomatic brain metastasis. 
Note: subjects previously treated or untreated for these conditions who are asymptomatic in the 
absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable 
for ≥ 4 weeks with imaging (e.g. brain magnetic resonance imaging [MRI] or computed 
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tomography [CT] demonstrating no current evidence of progressive brain metastases at 
screening). 
 
4. Leptomeningeal disease. 
 
5. History or current evidence of Retinal Vein Occlusion (RVO) or current risk factors for RVO. 
Note: Risk factors for RVO are uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity syndrome or hypercoagulability syndrome. 
 
6. Use of any herbal medications/supplements or any medications or foods that are moderate or 
strong inhibitors or inducers of CYP3A4/5 ≤ 1 week prior to the start of treatment. 
Note: However, subjects who either discontinue moderate or strong inhibitors or inducers of 
CYP3A4/5 or switch to another medication at least 7 days prior to starting study treatment are 
eligible. 
 
7. Known history of acute or chronic pancreatitis within 6 months prior to the start of the 
treatment. 
8. History of chronic inflammatory bowel disease or Crohn’s disease requiring medical 
intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months 
prior to first dose. 
 
9. Impaired cardiovascular function or clinically significant cardiovascular diseases, including 
any of the following: 
i. History of acute myocardial infarction, acute coronary syndromes (including unstable 
angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting) ≤ 6 
months prior to start of study treatment. 
ii. Symptomatic congestive heart failure (Grade 2 or higher), history or current evidence 
of clinically significant arrhythmia and/or conduction abnormality ≤ 6 months prior to 
start of study treatment, except rate controlled atrial fibrillation and paroxysmal 
supraventricular tachycardia. 
 
10. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 
mmHg or diastolic blood pressure ≥ 100 mmHg despite optimal therapy. 
 
11. Impaired hepatic function, defined as Child-Pugh class B or C. 
 
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12. Known history of Gilbert's syndrome or is known to have any of the following genotypes: 
UDP glucoronosyl transferase (UGT)1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28. No 
more applicable from Protocol V6.0/Amendment PA03 
 
13. Impaired gastrointestinal function or disease* which may significantly alter the absorption of 
encorafenib or binimetinib or recent changes in bowel function suggesting current or 
impending bowel obstruction. 
*eg. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small 
bowel resection. 
 
14. Previous or concurrent malignancy* within 5 years of study. 
*except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate 
intraepithelial neoplasm, carcinoma in-situ of the cervix or any other malignancy that has been 
adequately treated and has not recurred within 3 years prior to study entry. 
 
 
15. History of thromboembolic* or cerebrovascular events** ≤ 6 months prior to starting study 
treatment.  
*excluding venous thrombosis related to indwelling catheters and treated with low-grade 
anticoagulants 
**including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or 
pulmonary emboli. 
 
16. Concurrent neuromuscular disorder that is associated with the potential of elevated Creatine 
Kinase (CK). 
Note: e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy. 
 
17. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of 
Grade 2 alopecia or Grade 2 neuropathy. 
 
18. Known history of human immunodeficiency virus (HIV) infection. 
Note: HIV testing will only be conducted in jurisdictions specifically requiring it. 
 
19. Active hepatitis B or hepatitis C infection. 
 
20. Known contraindication to receive cetuximab at the planned doses. Refer to the most recent 
cetuximab summary of product characteristics (SPC) or local label as applicable. 
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21. Subjects who have any medical condition that would, in the Investigator’s judgment, prevent 
the subject’s participation in the clinical study due to safety concerns or compliance with 
study procedures. 
 
22. Any medical or psychiatric condition or laboratory abnormality that may increase the risk with 
study participation or study drug administration or that may interfere with the interpretation of 
study. 
 
23. Pregnancy, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test 
result, or breastfeeding. 
 
24. Is a family member of the Investigator or any associate, colleague, or employee assisting in 
the conduct of the study (secretary, nurse, technician). 
 
25. Is in a position likely to represent a conflict of interest. 
 
26. Participation in a clinical study with administration of an investigational product within 4 weeks 
or five times the half-life of the investigational product, whichever is longer, before the first 
dose of study treatment. 
 
27. Is mentally unable to understand the nature, objectives and possible consequences of the trial; 
or he/she refuses to its contraints. 
5.3. LIFESTYLE GUIDELINES 
5.3.1. Contraception 
Female subjects who are postmenopausal for at least 1 year or are surgically sterile for at least 6 
weeks are considered to be of non-childbearing potential.  
Female subjects of childbearing potential must agree to take appropriate precautions to avoid 
pregnancy from screening through 6 months after the last dose of cetuximab or through 30 days 
after the last dose of encorafenib or binimetinib, whichever is later. 
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Male subjects must agree to take appropriate precautions to avoid fathering a child and prevent 
exposure of seminal fluid to the partner from screening through 6 months after the last dose of 
cetuximab or through 90 days after the last dose of encorafenib or binimetinib, whichever is later.  
The following methods are permitted under this protocol for use by the subject and his/her partner. 
These methods are listed below and should be communicated to the subjects and their understanding 
confirmed. 
Methods that have been determined to be highly effective (i.e., can achieve a failure rate < 1% per 
year when used consistently and correctly) according to the CTFG 2014 (Clinical Trials 
Facilitation Group) include: 
• Complete abstinence from heterosexual intercourse during the entire period of risk 
associated with the study treatments; the reliability of sexual abstinence should be evaluated 
in relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomised partner (considered highly effective provided the vasectomized male has 
received medical assessment of surgical success and that the male is a female subject’s sole 
sexual partner) 
Acceptable birth control methods that result in a failure rate of more than 1% per year (CTFG 2014) 
include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• Male or female condom with or without spermicide 
• Cap, diaphragm or sponge with spermicide 
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NOTE: Due to the potential of encorafenib to induce CYP3A4, hormonal agents (including but not 
limited to birth control patch, vaginal ring, oral, injectable, or implanted contraceptives) are 
permissible only when combined with other highly effective or acceptable methods of 
contraception. 
5.3.2. Photosensitivity 
Subjects should avoid extended exposure to ultraviolet light and, when outdoors, should wear 
occlusive clothing, sunscreen and sunglasses while receiving encorafenib or cetuximab and for 2 
months following the last dose of each agent. 
5.4. NUMBER OF SUBJECTS  
The target of 90 subjects  with centrally confirmed BRAFV600E will be treated in two stages: 
• First stage: 40 subjects will be treated 
• Second stage: if there are at least 12 confirmed responders in the first stage, 50 additional 
subjects will be treated in this second stage .  
In case of discordance in the results between the local assay and the central laboratory (potential 
false-positive local result), or lack of BRAFV600E confirmation, subject will be replaced. 
5.5. RECRUITMENT MODALITIES 
Subjects with confirmed BRAFV600E  mCRC and who have not received any prior systemic therapy 
for the metastatic disease and who fulfill all inclusion and none of the exclusion criteria will be 
recruited. 
Where authorized by local/national regulation, some specific materials may be used to improve 
recruitment including: leaflets, advertising in oncology journals, websites, mailing (paper or e-mail) 
to doctors, subject associations, and subject advocacy groups. Before use of such materials, they 
will be reviewed and approved by the Sponsor and submitted to and approved by the appropriate 
IECs/IRBs. 
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5.6. SUBJECTS IDENTIFICATION 
The Subject’s code will contain 8 digits, corresponding to the country number, the centre number 
and the Subject’s number according to chronological order (once having signed the written 
informed consent). 
5.7. SUBJECT DISCONTINUATION REASONS  
The reasons for a subject’s premature discontinuation from the study may be the following (in all 
cases, available data will be retained for the safety analysis): 
5.7.1. Treatment Discontinuation for Individual Subject  
Subjects may decide to stop participating in the study at any time for any reason without prejudice 
to their future medical care by the physician or at the institution. Wherever possible, the tests and 
evaluations listed for the End of Treatment visit and Safety Follow-up visit should be carried out 
and an effort should be made to continue follow-up. 
If a subject decides to discontinue study treatment, he/she should be asked if he/she is willing to be 
contacted by telephone for monitoring of survival.   
If a subject withdraws consent, the subject’s data collected up to the date of consent withdrawal will 
be included in the analyses. The date, stated reason for and level of consent withdrawal should be 
documented. Any blood or tissue samples collected up to the date of withdrawal of consent will be 
analyzed, unless explicitly prohibited by the subject. 
The Sponsor should be notified of all subjects’ decision to discontinue study treatment and all study 
withdrawals through the designated e-CRFs in a timely manner. 
Subjects meeting any of the following criteria must discontinue study drug treatment: 
• Subject decision to discontinue study treatment (but request agreement to return for end 
of treatment assessments, safety follow-up assessments and/or survival follow-up). 
• Withdrawal of consent: no further participation  
• Lost to follow up: A subject will be considered as lost to follow up, if he/she did not attend 
a scheduled visit and for whom no news can be obtained after three documented attempts 
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with a minimum of 15 days between the first and the last attempt. This status must be dated 
at the latest as the database lock. 
• Investigator decision in the subject’s interest if an SAE occurs and is considered by the 
Investigator liable to threaten the health of the subject or if a serious disease occurs and 
necessitates the prescription of a medication incompatible with the pursuit of the study. The 
Sponsor should immediately be informed by phone or fax or email and a report explaining 
the discontinuation will be forwarded to him as soon as possible. 
•  Progressive disease: at any time (to be taken into account only for treatment 
discontinuation).  
• Unacceptable AE or toxicity (related or not to the study treatment) or failure to tolerate 
the study treatment. 
• Dose interruption of > 28 consecutive days in administration of encorafenib or 
binimetinib, or noncompliance with study drug administration consisting of > 4 missed 
consecutive doses of cetuximab due to an AE or clinically significant laboratory 
abnormality, unless judged by the Investigator and Sponsor Medical Contact or designee to 
be in the best interest of the subject to continue treatment. 
• Death. 
• Female subject becomes pregnant, or begins breastfeeding,  
• Significant protocol deviation that, in opinion of the investigator and/or sponsor, renders 
the subject unsuitable for further study drug administration.  
• Termination of the study by the sponsor. 
Subjects meeting any of the following criteria may be discontinued from study drug treatment if, 
during the course of the study: 
• Is found to have a tumor that is BRAFwt by the central laboratory. 
• Is noncompliant with study procedures or study drug administration in the opinion of the 
investigator. 
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5.7.2. Study Discontinuation for individual Subject  
The subject may be considered discontinued from the study for the following reasons: 
• Withdrawal of consent. 
• Lost to follow-up. 
• Death. 
• Termination of the study by the Sponsor. 
5.8. STUDY DISCONTINUATION 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to all Investigators and 
regulatory authorities and will specify the reason(s) for early termination. The Sponsor/Investigator 
must inform the EC/IRB promptly and provide the reason(s) for the termination. 
The Competent Authority (CA) may suspend or prohibit the study if it considers that the conditions 
of authorisation are not being met or has doubt about the safety or scientific validity of the study. 
5.9. REPLACEMENT OF SUBJECTS  
Withdrawn subjects will not be replaced. 
Subjects with unconfirmed BRAFV600E mutation will be replaced. 
5.10. POST-STUDY EXCLUSION PERIOD  
A post-study exclusion period is not required in this protocol. 
5.11.  SUBJECT CARD 
As soon as consent is signed, the subject will receive from the Investigational Center a personal 
card to be kept throughout the study duration, which provides the following information: subject's 
name, Sponsor's name, study code, (if applicable) EudraCT number, complete address of the 
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Investigating Centre with the name and emergency phone number of the Investigator and a Sponsor 
24/7 phone contact number (French and English languages). 
The delivery date of the card to the study subject will be documented in the electronic case report 
form (e-CRF). 
The preferred contact for the subject in case of need is in all cases the Investigator or his team. The 
card includes the name of the Investigator and the phone number which allows direct contact by the 
subject or the caregiver in case of need. 
 
The card, features an additional phone number which allows, should the need arise, a contact with 
a Sponsor representative able to address any medical and urgent issues. 
The subject is informed that, if a call is necessary, this call will be answered in English / French, 
which allows the subject to take any appropriate measures. 
6. STUDY TREATMENT(S) 
In Europe (EU),  the Investigational Medicinal Product Management Service of the Institut de 
Recherche Pierre Fabre (IRPF) will supply the investigational centers  with labeled and packaged 
encorafenib, binimetinib and cetuximab units necessary for the conduct of the trial. 
In the United States (US), labeled and packaged binimetinib and encorafenib will be supplied to 
investigational centers by Array BioPharma. Cetuximab supply within the US will be supplied 
either locally or by Array BioPharma. Array BioPharma will employ a licensed company 
specializing in packaging, labeling, and distribution of investigational medicinal products. 
In Japan (JAP), labeled and packaged binimetinib, encorafenib and cetuximab will be supplied to 
investigational centers by Array BioPharma via a licensed company specializing in packaging, 
labeling, and distribution of investigational medicinal products via a warehouse facility located in 
Japan.  
 
 
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6.1. SOURCE, PRESENTATION AND COMPOSITION OF 
INVESTIGATIONAL PRODUCT(S) AND ASSOCIATED 
PRODUCT(S) 
6.1.1. Encorafenib 75 mg hard capsule 
Encorafenib will be prepared in oral hard capsules. 
 
Code and name: W0090-Encorafenib for Europe, LGX818-Encorafenib for US and Japan. 
Encorafenib may also be known as ONO-7702 in Japan. 
Pharmaceutical presentation: hard capsule of 75 mg 
 
Composition:  
• Hard capsule 
− Active ingredient: Encorafenib 
− List of Excipients: copovidone, Poloxamer 188, cellulose microcrystalline, succinic acid, 
crospovidone, silica colloidal anhydrous, magnesium stearate of vegetable origin. 
Capsule shell (gelatin, titanium dioxide (E171), iron oxide red (E172), iron oxide yellow 
(E172), iron oxide black (E172), ink capsule shell (Pharmaceutical Glaze, iron oxide black 
(E172), Propylene glycol). 
6.1.2. Binimetinib 15 mg film-coated tablet 
Binimetinib will be prepared in film-coated tablets for oral use. 
 
Code and name: W0074 - Binimetinib for Europe, MEK162 - Binimetinib for US and Japan. 
Binimetinib may also be known as ONO-7703 in Japan. 
Pharmaceutical presentation: film-coated tablet of 15 mg 
 
Composition:  
• Film-coated tablet 
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− Active ingredient: Binimetinib  
− List of excipients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, colloidal silicon dioxide/silica colloidal anhydrous, OPADRY® 
yellow 85F92213 (polyvinyl alcohol – part hydrolyzed, macrogol / PEG 3350, titanium 
dioxide, talc, iron oxide yellow E172, iron oxide black E172)  
 
 
6.1.3. Cetuximab solution for infusion 
Cetuximab is available under different formulations:  
- 1 formulation for Europe and Japan 
- 1 formulation for US 
 
• Europe and Japan formulation: ERBITUX® 5 mg/mL solution for infusion 
Cetuximab solution for infusion will be supplied in labelled packages : single-use vial of 500 mg 
cetuximab (5 mg/mL solution) – vial of 100 mL 
Cetuximab is a colorless solution administered intravenously. 
Cetuximab is a chimeric monoclonal IgG1 antibody produced in a mammalian cell line (Sp2/0) by 
recombinant DNA technology. 
 
Composition: 
−  Active ingredient: Cetuximab 5 mg/mL 
− List of excipients: Sodium chloride, Glycine, Polysorbate 80, Citric acid monohydrate, 
Sodium hydroxide, Water for injection. 
Cetuximab does not contain any antimicrobial preservative or bacteriostatic agents. From a 
microbiological point of view, the product should be used immediately after opening. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 to 8ºC, unless opening has taken place in controlled 
and validated aseptic conditions. 
• US formulation 
Erbitux®(cetuximab) in the US is commercially available and is supplied at a concentration of 2 
mg/mL as a 100 mg/50 ML, single-use vial or as a 200 mg/100 mL, single-use vial as a sterile 
injectable liquid containing no preservatives. 
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Composition: 
Cetuximab is formulated in a solution with no preservatives, which contains: 
− Active ingredient: Cetuximab 2 mg/mL 
−  List of excipients: sodium chloride, sodium phosphate dibasic heptahydrate, sodium 
phosphate monobasic monohydrate, and Water for Injection 
 
6.2. PACKAGING AND LABELLING 
In Europe, the treatment units will be packed and labelled by the Investigational Medicinal Product 
Management Service of IRPF according to the European Directive, local requirements and local 
languages. 
In US, the treatment units will be packed and labelled within US by the sponsor designee and 
comply with the legal requirements of the US. 
In Japan, the treatment units will be packed and labelled by sponsor designee and comply with the 
legal requirements of Japan. 
6.2.1. Packaging 
6.2.1.1. Encorafenib 75 mg capsule 
 
• Europe formulation 
- Primary packaging 
70 hard capsules will be packaged in a bottle 175 cc (HDPE, white, opaque, square) closed 
with a cap (38 mm, polypropylene (PP), white, child-resistant design, cap with induction seal 
liner) and containing a 2 grams silica gel desiccant.  
- Secondary packaging (only for Europe) 
The bottle will be packaged in a sealed box. 
• US and Japan formulation 
- Primary packaging 
70 hard capsules will be packaged in a bottle 175 cc (HDPE, white, opaque, square) closed 
with a cap (38 mm, PP, white, child-resistant design, cap with induction seal liner and opening 
seal ring) and containing a desiccant.  
(Tyvek soft packet, 2 gram silica Gel Desiccant). 
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- Secondary packaging  
No secondary packaging.  
 
6.2.1.2. Binimetinib 15 mg film coated tablet 
 
• Europe formulation 
- Primary packaging 
70 film coated tablets will be packaged in a 120 cc bottle (HDPE, without dessicant, white, 
opaque, square) closed with a cap (38 mm, Polypropylene (PP), white, child-resistant design, 
cap with induction seal liner). 
 
- Secondary packaging  
The bottle will be packaged in a sealed box. 
 
• US and Japan formulation 
- Primary packaging 
70 film coated tablets will be packaged in a 120 cc bottle (HDPE, without desiccant, with 
induction seal, and child-resistant cap) 
 
- Secondary packaging  
No secondary packaging. 
 
 
6.2.1.3. Cetuximab ERBITUX® 5 mg/mL solution for infusion 
• Europe and Japan formulation: Cetuximab ERBITUX® 5 mg/mL solution for infusion 
- Primary packaging 
100 mL of solution in a vial (Type I glass) with a stopper (halobutyl rubber) and a seal 
(aluminium/polypropylene). 
 
- Secondary packaging 
Sealed box of 1 vial: 500 mg. 
 
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• US formulation: Cetuximab ERBITUX® 2 mg/mL solution for infusion 
Erbitux®(cetuximab) in the US is commercially available.  Commercially available vials are 
packed into cartons.   
 
6.2.2. Labelling 
 
• Labelling for Europe Supply: 
Investigational Products will be labelled in compliance with local requirements, according to the 
following rules: 
 
I. 
Treatment unit box labelling:  
The secondary packaging box label (green for binimetinib and white for encorafenib and cetuximab) 
contains the following information: 
(a) Name and address of Sponsor 
(b) Pharmaceutical dosage form, route of administration, quantity of dosage units, the 
name/identifier and strength/potency 
(c) Packaging batch number 
(d) Trial reference code allowing identification of the study (protocol number and EudraCT 
number) 
(e) Treatment number 
(f) Name of the Investigator (will be added when preparing to send)  
(g) Directions for use (reference may be made to the investigator brochure or other 
explanatory document intended for the trial subject or person administering the product) 
(h) “For clinical trial use only” 
(i) Storage conditions 
(j) Expiry date as month/year (MM/YYYY) 
(k) “Keep out of reach and sight of children” except when the product is for use in trials where 
the product is not taken home by subjects 
The box labelling contains a tear-off flap (also green for binimetinib and white for encorafenib and 
cetuximab) with the following information:  
- 
Protocol number 
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- 
Packaging batch number 
- 
Treatment number 
- 
The name/identifier and strength/potency 
Additional mentions will be added according to local authority requirements. 
Symbols or pictograms may be included to clarify certain information mentioned above. Additional 
information, warnings and/or handling instructions may be displayed. 
 
II. 
Treatment bottle/vial labelling:  
The product is supplied in a primary packaging and a secondary packaging which are intended to 
remain together. The following information is included on the label of the primary package 
bottle/vial (green for binimetinib and white for encorafenib and cetuximab): 
(a) 
Name of Sponsor 
(b) 
Pharmaceutical dosage form, route of administration (may be excluded for oral solid 
dose forms), quantity of dosage units, the name/identifier and strength/potency 
(c) 
Packaging batch number 
(d) 
Trial reference code allowing identification of the study (protocol number) 
(e) 
Treatment number 
(f) 
Expiry date as month/year (MM/YYYY) 
• Labelling for US and Japan Supply  
For both encorafenib and binimetinib supplied within the US and Japan, each bottle will be labelled, 
at a minimum, with a unique identifier (medication number), the lot number, contents (number of 
tablets), dosage strength, storage conditions and the name and address of the Sponsor designee. 
Both encorafenib and binimetinib labels will be in the local language and comply with the legal 
requirements of the US and Japan. Site personnel will add the subject number to the label. 
In the US, cetuximab will be supplied either locally or by the Sponsor designee, Array BioPharma. 
If the US cetuximab is locally supplied, then the cetuximab does not require specific labelling. Each 
unit of cetuximab supplied for Japan by the Sponsor designee will be labelled, at a minimum, with 
a unique identifier (medication number), the lot number, contents (number of tablets), dosage 
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strength, storage conditions and the name and address of the Sponsor designee. Cetuximab labels 
will be in local language and comply with the legal requirements of Japan.  
 
6.3. DISTRIBUTION TO CENTERS AND STORAGE 
Before the start of the study, the sponsor or designee will supply the Investigational Centre with the 
necessary treatment units for the study using Interactive Response Technology (IRT).  
Additional treatment supplies will be shipped to the Investigational Centre upon request via IRT 
and according to needs. 
Acknowledgement of receipt of all shipments should be managed according to Pharmacy manual 
process and timelines. 
The Clinical Research Associate (CRA) will ensure during the initiation visit that trial medications 
have been received in good condition and the acknowledgment of receipt has been adequately 
completed and returned. 
In cases of undue delay in study execution, the Pharmacist or Investigator should ensure that the 
expiry date has not been exceeded. If the date has been exceeded, new treatment units will be 
supplied to the investigational center. 
Labeled, packaged encorafenib, binimetinib and cetuximab will be shipped to each centre by the 
Sponsor or designee, as described in the Pharmacy Manual.  
The Investigator or an approved representative (e.g., registered pharmacist) will ensure that all 
encorafenib, binimetinib and cetuximab is stored as outlined in the Pharmacy Manual and in 
accordance with applicable regulatory requirements. The drug storage area at the site must be 
secure, with access limited to authorized personnel. 
Storage conditions will be described on the medication label. Detailed instructions for storage and 
handling of encorafenib and binimetinib will be provided in the Pharmacy Manual. Cetuximab 
should be stored according to the locally approved prescribing information.  
 
 
 
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6.4. ALLOCATION OF TREATMENTS AND DISPENSATION TO 
SUBJECTS  
All subjects who sign an informed consent will be assigned a unique subject number and will be 
able to start screening. A subject will be assigned for study treatments via the IRT system if he/she 
meets all eligibility requirements . 
According to GCP, all eligibility criteria will be checked during the registration procedure. 
Assignment of treatment number will be implemented via IRT. All information regarding this 
process is described in the IRT manual.  
Throughout the Treatment Period (Main study and Study extension periods) the Investigator will 
dispense to the subject the box indicated by IRT (Day 1 of each cycle). 
6.5. TREATMENT ADMINISTRATION 
6.5.1. Duration of Treatment 
During the Main study period, study treatment will be administered until unacceptable toxicity, 
progression of disease, subject’s decision, withdrawal of consent, initiation of subsequent 
anticancer therapy or death. 
During the Study extension period (from 28 Dec 2020), access to study treatment will be provided 
through a Study extension to all subjects whom the investigator considers are continuing to benefit 
from study treatment (i.e. do not experience unacceptable toxicities and none of the treatment 
discontinuation criteria are met) until:  
• the last ongoing subject will discontinue study treatments (including 30-day Safety Follow-
Up visit) for any reason (unacceptable toxicity, progression of disease, subject’s decision, 
withdrawal of consent, initiation of subsequent anticancer therapy or death),  
• or binimetinib/encorafenib are commercially available in the first line setting of BRAF V600E 
mutated mCRC,  
• or the binimetinib/encorafenib development program is stopped, whichever comes first. 
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Dose Schedule 
The investigational products in this study are encorafenib and binimetinib in combination with 
cetuximab. Dose schedule is described in Table 7. 
 
Table 7: Dose and Treatment Schedule 
Study treatment 
Pharmaceutical form and 
route of administration 
Dose 
Frequency 
Encorafenib 
4 × 75 mg oral capsule 
300 mg 
QD 
Binimetinib 
3 × 15 mg oral film-coated 
tablet 
45 mg 
BID 
Cetuximab 
IV infusion 
400 mg/m2 initial 
dose (120-minute 
infusion), then 250 
mg/m2 (60-minutes 
infusion)  
QW for the first 28 
weeks 
500 mg/m2 (120-
minute infusion) 
Q2W (from week 29 - 
C8D1) 
Since implementation of 
the Urgent Safety 
Measure on 26 Mar 
2020, in order to ensure 
the subjects’ safety in the 
clinical trial by 
decreasing the number of 
clinic visits in the 
context of COVID-19 
pandemic, Cetuximab 
infusions can be given 
every two weeks (i.e. on 
D1 and D15 of each 
cycle) regardless of the 
cycle number, after the 
investigator has 
evaluated the benefit/risk 
ratio for the subject with 
regards to Covid-19 
pandemic. 
QD: once daily; BID: twice daily; QW, once weekly; Q2W, every 2 weeks 
 
 
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6.5.2. Route and Conditions of Administration of Encorafenib and 
Binimetinib  
Encorafenib will be administered with a QD schedule and binimetinib will be administered with a 
BID schedule, both PO as a flat-fixed dose, not by body weight or body surface area (BSA).  
Binimetinib and encorafenib can be taken without regard to food. Subjects should be instructed to 
swallow the capsules /tablets whole and not to chew or crush them. Both oral study drugs are to be 
taken together in the morning and only the BID administered drug (binimetinib) is to be taken in 
the evening without regard to food. 
• QD dosing: subjects should be instructed to take encorafenib capsules daily with a large 
glass of water (~250 mL) in the morning (together with the morning intake of binimetinib) 
at approximately the same time every day. Doses of encorafenib that are omitted for AEs or 
any other reason can be taken up to 12 hours prior to the next dose; if less than 12 hours to 
the next dose, the regular dosing schedule must continue and subject should be instructed 
to check with the study doctor. It is forbidden to double the next dose. 
• BID dosing: subjects should be instructed to take binimetinib tablets 12 ± 2 hours apart with 
a large glass of water (~250 mL) in the morning and in the evening at approximately the 
same times every day. Doses of binimetinib that are omitted for AEs or any other reason 
should not be made up later in the day, or at the end of the dosing period and it’s forbidden 
to double the next dose. 
On days when a blood collection is scheduled at the investigational site, subjects will take the 
morning dose of encorafenib and binimetinib at the site under the supervision of the Investigator or 
designee, after any required blood sample collections. The time of dosing and the time of PK 
samples should be recorded on these clinic visit dates. On all other days, subjects will take 
encorafenib and binimetinib at home.  
If a subject vomits at any time after dosing, the dose of study drug should not be re-administered. 
Subjects are prohibited to consume grapefruit, pomegranates, star fruits, Seville oranges or products 
containing the juice of any of these items throughout the entire study and for 7 days before the first 
dose of study drugs, due to potential CYP3A4 interaction with the study drugs. Orange juice is 
allowed.  
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Encorafenib and binimetinib will be administered at least 30 minutes prior to cetuximab without 
regard to when cetuximab premedications are administered. 
The Investigator or responsible site personnel will ensure that the appropriate dose is dispensed and 
will provide the subject with at least the appropriate number of encorafenib capsules and binimetinib 
tablets for the number of doses to be taken prior to the next scheduled visit. The site personnel will 
train the subject and/or the subject’s caregiver on dosing procedures for the study drug. 
Subjects will receive a diary to document self-administered dosings of encorafenib and binimetinib 
for each cycle to include the dose of study drug taken, the date of dosing (and times if applicable), 
and if any doses were missed and the reason for the missed dose. One diary will be provided per 
cycle. Subjects will be instructed to return unused encorafenib and binimetinib and the subject diary 
to the center at the end of each cycle. Drug accountability must be performed on a regular basis. 
The Investigator or responsible site personnel should instruct the subject to take encorafenib and 
binimetinib as per protocol (i.e., promote compliance). The dosage prescribed and dispensed to the 
subject and all dose changes and all missed doses during the study must be recorded in the e-CRF.  
6.5.3. Route and Condition of Administration of Cetuximab 
Cetuximab will be administered IV weekly on Days 1, 8, 15 and 22 (±3 days) of every 28-day cycle 
at the study center for the first 28 weeks then every two weeks from week 29 (Table 7) according 
to institutional standards.  
The initial cetuximab dose on Day 1 of Cycle 1 is 400 mg/m2 administered as a 120-minute IV 
infusion followed thereafter by a 250 mg/m2 dose administered as a 60-minute IV infusion at each 
cycle. Subjects who remain on treatment for 28 weeks will be treated with cetuximab 500 mg/m2 
administered as a 120-min IV infusion once every 2 weeks from week 29 (Cycle 8 day 1).  
Since implementation of the Urgent Safety Measure on 26 Mar 2020, in order to ensure the subjects’ 
safety in the clinical trial by decreasing the number of clinic visits in the context of COVID-19 
pandemic, Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 
administered as a 120-min IV infusion (i.e. on D1 and D15 of each cycle) regardless of the cycle 
number, after the investigator has evaluated the benefit/risk ratio for the subject with regards to 
Covid-19 pandemic. 
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If there was a dose modification prior to switching to the biweekly schedule, the total dose per cycle 
should be maintained (i.e. 200mg/m2 QW, may be changed to a 400mg/m2 Q2W). 
The infusion rate should be consistent with local labelling but should not exceed 10 mg/min (the 
first infusion rate should not exceed 5mg/min). Close monitoring is required during the infusion 
and for at least 1 hour after the end of the infusion. If an infusion reaction occurs while cetuximab 
is being administered, the infusion should be stopped immediately, and the subjects should be 
closely monitored and treated in line with institutional standards. Any re-challenge with cetuximab 
following an infusion reaction should be first discussed with the Sponsor.  
Pre-medication for routine cetuximab infusions may be used in accordance with the label and with 
the national and/or institutional standards, but should preferably be based on a combination of an 
H1 antagonist (e.g., diphenhydramine) and dexamethasone (10 mg IV). This combination is 
mandatory for the first infusion. Pre-medication should be administered no sooner than 1 hour after 
administration of encorafenib and binimetinib (if applicable) and 30 minutes prior to cetuximab 
infusion. According to cetuximab labelling instructions, medications such as corticosteroids and 
antihistamines may be administered at the discretion of the Investigator to treat an existing infusion 
reaction, or as premedication for a subject who has previously experienced an infusion reaction. 
Predose PK samples for cetuximab analysis should be collected just prior the beginning of the 
cetuximab infusion. 
Doses of cetuximab that are omitted for AEs or any other reason should not be made up. If 
cetuximab is discontinued, the frequency of study visits may be decreased after discussion with 
Sponsor.  
6.5.4. Dose Modification 
Subjects will be monitored for AEs. The severity of AEs will be evaluated using the NCI-CTCAE 
v.4.03. 
If a subject develops toxicity, the dose should be modified as outlined in Table 14 and Table 15, 
which include criteria for interruption and reduction of encorafenib, binimetinib and cetuximab. All 
dose modifications should be based on the worst preceding toxicity. All dosing interruptions and 
modifications must be recorded in the e-CRF. 
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If a subject permanently discontinues binimetinib due to an AE or clinically significant laboratory 
value, they may continue to receive encorafenib in combination with cetuximab.  
Due to the lack of efficacy of binimetinib, encorafenib, or cetuximab when used as single agents in 
subjects with BRAF-mutant mCRC, subjects who cannot tolerate these agents in combination with 
at least one other agent, should discontinue study treatment altogether, complete the end of 
treatment visit and continue to be followed for survival (and disease progression, if applicable). 
Cetuximab may be reduced by 2 dose levels to a minimum of 150 mg/m2, due to AEs or laboratory 
abnormalities (Table 8). When a dose reduction is required because of an AE, no subsequent dose 
re-escalation of cetuximab will be permitted for that subject for the duration of study treatment. If 
after resolution of an AE, treatment is resumed at the same dose, and the same toxicity reoccurs 
with the same severity, any re-initiation of treatment must be at the next lower dose level 
irrespective of duration, with some exceptions for skin toxicity.  
In addition, a subject must discontinue study treatment if, after treatment is resumed at a lower 
dose of cetuximab, the same toxicity reoccurs with the same or worse severity.  
If a subject misses > 28 consecutive days of encorafenib or binimetinib, or > 4 consecutive 
cetuximab doses as the result of an AE or clinically significant laboratory abnormality, then the 
respective agent(s) should be discontinued.  
Subjects who discontinue study treatment for a study-related AE or an abnormal laboratory value 
must complete the end of treatment visit and continue to be followed for survival (and disease 
progression). 
 
 
 
 
 
 
 
 
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Table 8: Dose Levels for Dose Modification 
 
Encorafenib 
(mg QD) 
Binimetinib 
(mg BID) 
Cetuximab 
WEEKLY 
(mg/m2)   
 
Cetuximab 
BI-WEEKLY 
(mg/m2)  
 Starting from C8D1 
week 29 Or at any cycle 
since implementation of 
the Urgent Safety 
Measure on 26 Mar 2020 
Starting Dose 
300 
45 
400 mg/m2 cycle 1 day 1   
then 250 mg/m2 
thereafter 
500 
Dose level -1 
225 
30 
200   
400 
Dose level -2 
150 
15 
150 
300 
 
 
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6.5.4.1. Dose Modification for Encorafenib and/or Binimetinib  
Doses of encorafenib and/or binimetinib may be adjusted for AEs throughout the study as described 
inTable 14. In general, doses should not be reduced or interrupted for Grade 1 AEs other than for 
specific ocular AEs referred to in Table 13, but treatment to control symptoms should be provided 
as appropriate, if applicable.  
An individual subject may have their dose of encorafenib and/or binimetinib reduced to the dose 
levels specified in Table 8. 
The lowest permitted dose level of encorafenib is 150 mg QD and the lowest permitted dose level 
of binimetinib is 15 mg BID. 
If the AE causing a dose reduction improves to the subject’s Baseline level and remains stable for 
a minimum of 14 days, the dose can be re-escalated to the next dose level at the discretion of the 
Investigator, provided there are no other concomitant toxicities that would prevent drug re-
escalation. There is no limit to the number of times the subject can have their dose reduced or re 
escalated (in increments specified in Table 8). 
• No dose re-escalation of encorafenib is allowed after a dose reduction due to prolonged 
QTcF ≥ 501 msec  
• No dose re-escalation of binimetinib is allowed after a dose reduction due to LVEF 
dysfunction or prolonged QTcF ≥ 501 msec 
• No dose re-escalation of binimetinib or encorafenib is allowed after a dose reduction due to 
retinal toxicity ≥ Grade 2. 
Refer to Table 14 for recommended dose modifications for encorafenib and/or binimetinib, if 
applicable, based on the occurrence of treatment-related AEs. 
Eye disorders that cannot be specifically graded according to modified NCI-CTCAE, v.4.03, should 
be graded according to Table 9. Serous detachment of the retina should be graded according to 
Table 10.  
 
 
 
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Uveitis should be graded according to NCI-CTCAE, v.4.03 as described in Table 11, Hand-foot 
skin reactions (HFSR) should be graded according to NCI-CTCAE, v.4.03 as described in Table 
12. Diarrhea should be graded according to modified NCI-CTCAE, v.4.03 as described in Table 
13. Furthermore, please refer to Section 17.1 for additional supportive care recommended 
guidelines for the management of: cetuximab-induced, encorafenib-induced and/or binimetinib-
induced skin reaction (Section 17.1), encorafenib-induced HFSR (Section 17.2), binimetinib-
induced diarrhea (Section 17.3) and binimetinib-associated interstitial lung disease/pneumonitis 
(Section 17.7). 
Table 9: Modified NCI CTCAE, Version 4.03 Grading of Eye Disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
3 
Severe or medically significant but not immediately sight threatening; hospitalization or 
prolongation of existing hospitalization indicated; disabling; limiting self-care activities of daily 
living 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the 
affected eye 
 
 
 
Table 10: NCI CTCAE, Version 4.03 Grading of Serous Detachment of the Retina 
Grade 
Description 
1 
Asymptomatic (but with findings in ocular coherence tomography, fundoscopy and/or slit lamp 
biomicroscopy) 
2 
Symptomatic with moderate decrease in visual acuity (20/40a or better); limiting instrumental 
activities of daily living 
3 
Symptomatic with marked decrease in visual acuity (worse than 20/40a); limiting self-care activities 
of daily living  
4 
Blindness (20/200a or worse) in the affected eye 
Note: For rhegmatogenous retinal detachment, grade according to NCI-CTCAE v.4.03 Retinal Detachment. 
a Please refer to (Section 17.3). 
 
 
 
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Table 11: NCI CTCAE, Version 4.03 Grading of Uveitis 
Grade 
Description 
1 
Asymptomatic; clinical or diagnostic observations only 
2 
Anterior uveitis; medical intervention indicated 
3 
Posterior or pan-uveitis 
4 
Blindness (20/200a or worse) in the affected eye 
a Please refer to (Section 17.3). 
 
Table 12: NCI CTCAE, Version 4.03 Grading of Hand-foot Skin Reaction (HFSR)a  
Grade 
Description b 
1 
Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia, paresthesia, 
tingling or hyperkeratosis) without pain 
2 
Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
3 
Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or hyperkeratosis) with 
pain; limiting self-care ADL 
Abbreviations: ADL=activities of daily living. 
a. HFSR or palmar-plantar erythrodysesthesia syndrome, a disorder characterized by redness, marked discomfort, 
swelling, and tingling in the palms of the hands or the soles of the feet; 
b. More specific examples for Grade 1 and Grade 3 are added to facilitate proper grading (from the sorafenib 
package insert; West Haven, CT: Bayer Pharmaceuticals Corporation; 2007). 
 
Table 13: Modified NCI CTCAE, Version 4.03 Grading of Diarrhea 
Grade 
Description 
1 
Increase of < 4 stools per day over Baseline; mild increase in ostomy output compared to 
Baseline 
2 
Increase of 4-6 stools per day over Baseline; moderate increase in ostomy output compared to 
Baseline 
1/2 complicated  
Definition as above (Grade 1/2) with the following complicating signs/symptoms: 
• Moderate to severe cramping 
• Grade ≥ 2 nausea/vomiting 
• Decreased performance status 
• Fever 
• Sepsis 
• Neutropenia 
• Frank bleeding 
• Dehydration 
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Grade 
Description 
• Unresolved diarrhea after 48 hours of treatment with loperamide (including high-dose 
administration) and initiation of second-line treatment 
3 
Increase of ≥ 7 stools per day over Baseline; incontinence; hospitalization indicated; severe 
increase in ostomy output compared to Baseline; limiting self-care activities of daily living 
4 
Life threatening consequences; urgent intervention indicated 
 
Table 14: Recommended dose modifications for Encorafenib-related and/or Binimetinib 
related AEs 
 
Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Eye Disorders - Retinal Events (including serous detachment of the retina), 
Note: Results and images of ocular coherence tomography (OCT) must be made available upon request. 
Any visual acuity impairment at screening should be documented and should be considered as baseline. 
Grade 1 
Maintain dose levels of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days. 
• 
If subject remains asymptomatic (Grade 1), maintain dose level of encorafenib 
and binimetinib and continue the schedule of visual assessments established per 
protocol. 
• 
If subject becomes symptomatic (blurred vision, photophobia, etc.) or visual 
acuity assessment shows Grade 2, follow Grade 2 dose guidelines below. 
Grade 2 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days. 
• 
If resolved to baseline or Grade ≤ 1, resume treatment at current dose level of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol. 
• 
If not resolved to baseline or Grade ≤ 1, resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days: 
• 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol. 
• 
If not resolved to baseline or Grade ≤ 2, continue the interruption and repeat the 
ophthalmic assessment in 10 days. 
. 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib and continue the 
schedule of visual assessments established per protocol 
. 
If remains Grade 3, permanently discontinue encorafenib and 
binimetinib. 
Grade 4 
Permanently discontinue binimetinib and immediate follow-up with ophthalmic 
monitoringc. 
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Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Eye Disorders - Posterior Uveitisc 
Note: Results and images of ocular coherence tomography (OCT) must be made available upon request. 
Any visual acuity impairment at screening should be documented and should be considered as baseline. 
Grade 1 
Maintain dose levels of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days. 
• 
If subject remains asymptomatic (Grade 1), maintain dose level of encorafenib 
and binimetinib and continue the schedule of visual assessments established per 
protocol. 
If subject becomes symptomatic (blurred vision, photophobia, etc.) or visual acuity 
assessment shows Grade 2, follow Grade 2 dose guidelines below. 
Grade 2 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days. 
• 
If resolved to baseline or Grade ≤ 1, resume treatment at current dose level of 
encorafenib and binimetinib and continue the schedule of visual assessments 
established per protocol. 
• 
If not resolved to baseline or Grade ≤ 1, resume treatment at 1 reduced dose 
levelb of encorafenib and current dose of binimetinib and continue the schedule 
of visual assessments established per protocol. 
If posterior uveitis lasts > 6 weeks, permanently discontinue binimetinib and 
encorafenib. 
Grade 3  
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days: 
 
• 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose levelb of 
encorafenib and current dose of binimetinib and continue the schedule of visual 
assessments established per protocol. 
• 
If not resolved to baseline or Grade ≤ 2, continue the interruption and repeat the 
ophthalmic assessment in 10 days. 
• 
If remains Grade 3, permanently discontinue encorafenib and binimetinib. 
Grade 4 
Permanently discontinue encorafenib and binimetinib and immediate follow-up with 
ophthalmic monitoringc. 
Eye Disorder - RVOc(Retinal Vein Occlusion) 
Note: Results and images of ophthalmic examinations should be made available upon request. This includes 
scans/images of fluorescein angiography should a subject be assessed using this technique. 
RVO of any grade 
Permanently discontinue binimetinib and immediately follow-up with ophthalmic 
monitoringc. 
Other Eye Disorders (i.e., Non-Retinal Events) 
Grade 1 – 2 
Maintain dose level of encorafenib and binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or resolution. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and refer subject to ophthalmologist 
within 7 daysc: 
• 
If resolved to Grade ≤ 1 in ≤ 21 days, resume treatment at 1 reduced dose levelb 
of encorafenib and binimetinib. 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue encorafenib 
and binimetinib and close follow-up with ophthalmic monitoring until 
stabilization or resolutionc. 
Grade 4 
Permanently discontinue encorafenib and binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolutionc 
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Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Liver-Related Adverse Events 
Grade 1  
AST or ALT  
> ULN to 3 × ULN 
Maintain dose level of encorafenib and binimetinib. 
Grade 2 
AST or ALT  
> 3 to 5.0 × ULN or  
3 × baseline valued AND  
blood bilirubing  
≤ 2.0 × ULN 
 
 
 
 
 
Maintain dose level of encorafenib and interrupt dosing of binimetinib until resolved to 
Grade ≤ 1 (or Grade ≤ 2 in case of liver metastasis), then: 
• 
If resolved in ≤ 14 days, maintain dose level of encorafenib and binimetinib. 
• 
If not resolved in ≤ 14 days, interrupt dose of encorafenib (in addition to prior 
binimetinib) until resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver 
metastasis), then resume treatment at current dose level of encorafenib and 1 
reduced dose levelb of binimetinib. 
If additional occurrence:  
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or 
Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib. 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment. 
 
 
 
AST or ALT  
> 3.0 to 5.0 × ULN AND  
blood bilirubing 
 > 2.0 × ULN 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1, then: 
• 
If resolved in ≤ 7 days, resume treatment at 1 reduced dose levelb of encorafenib 
and binimetinib. 
• 
If not resolved in ≤ 7 days, permanently discontinue encorafenib and 
binimetinib. 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment. 
Grade 3 
AST or ALT  
> 5.0 to 8.0 × ULN)  
AND  
blood bilirubing  
≤ 2.0 × ULN 
 
 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 
2 in case of liver metastasis), then: 
• 
If resolved in ≤ 14 days, resume treatment at current dose level of encorafenib 
and binimetinib. 
• 
If not resolved in ≤ 14 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib. 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week before 
resuming binimetinib treatment. 
 
If additional occurrence: 
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or 
Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib. 
AST or ALT  
>8 × ULN  
AND blood bilirubing  
≤ 2.0 × ULN 
Permanently discontinue encorafenib and binimetinib. 
AST or ALT  
> 5.0 × ULN 
AND  
blood bilirubing  
> 2.0 × ULN 
Permanently discontinue encorafenib and binimetinib. 
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Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Grade 4  
AST or ALT  
> 20.0 × ULN 
Permanently discontinue encorafenib and binimetinib. 
Cardiac Disorders - Left Ventricular Systolic Dysfunctiona (Dose Adjustment for Binimetinib ONLY). 
Asymptomatic 
absolute decrease of > 10% in 
LVEF compared to baseline and 
the LVEF is below the 
institution’s LLN (e.g., a 
decrease of 60% to 48% is an 
absolute decrease of 12%) 
Interrupt dosing of binimetinib and repeat evaluation of LVEF within 2 weeks. 
• 
If the LVEF recovers (defined as LVEF ≥ 50% or ≥ lower limit of normal (LLN) 
and absolute decrease ≤ 10% compared to baseline) ≤ 21 days, resume treatment 
at 1 reduced dose levelb of binimetinib after approval of the Sponsor’s Medical 
Monitor. Monitor LVEF 2 weeks after resuming binimetinib, every 4 weeks for 
12 weeks and subsequently as per protocol. 
• 
If LVEF does not recover in ≤ 21 days, permanently discontinue binimetinib. 
Closely monitor LVEF until resolution or for up to 16 weeks. 
Grade 3 – 4 
Permanently discontinue binimetinib. Closely monitor LVEF until resolution or up to 
16 weeks. 
Note: Copies of ECHO and/or MUGA scans could be requested for subjects to be 
available to the Sponsor for subjects with absolute decrease of >10% in LVEF 
compared to baseline and LVEF < 50% or LLN. 
CK Elevation  
Grade 1-2 
Maintain dose of encorafenib and binimetinib. Ensure subject is adequately hydrated. 
Closely monitor CK and serum creatinine. 
• 
If total CK ≥ 3 × ULN, measure CK isoenzymes and myoglobin in blood or 
urine. 
Grade 3 
> 5.0 - 10.0 x ULN without  
renal impairment (i.e., serum 
creatinine < 1.5 × ULN or  
1.5 × baseline) 
If asymptomatic, maintain dosing of encorafenib and binimetinib. Ensure subject is 
adequately hydrated. Monitor and measure isoenzymes and myoglobin in blood or urine 
and serum creatinine. 
 
If symptomatic (muscle pain/spasms/muscle weakness), maintain dosing of encorafenib 
and interrupt dosing of binimetinib until resolved to CTCAE Grade ≤ 1 and monitor 
closely, then: 
• 
If resolved in ≤ 21 days, maintain dose of encorafenib and resume treatment at 
1 reduced dose levelb of binimetinib. 
• 
If not resolved in ≤ 21 days, maintain dose of encorafenib and permanently 
discontinue binimetinib. 
Grade 4  
without  
renal impairment (i.e., serum 
creatinine < 1.5 × ULN or  
1.5 × baseline) 
If asymptomatic, maintain dose of encorafenib and interrupt dosing of binimetinib. 
Ensure subject is adequately hydrated. Monitor and measure isoenzymes and 
myoglobin in blood or urine and serum creatinine. 
• 
If resolved in ≤ 21 days, maintain dose of encorafenib and resume treatment at 
1 reduced dose levelb of binimetinib. 
• 
If not resolved in ≤ 21 days, maintain dose of encorafenib and permanently 
discontinue binimetinib. 
If symptomatic (muscle pain/spasms/muscle weakness), maintain dose of encorafenib 
and permanently discontinue binimetinib. 
Grade 3 or 4  
with  
renal impairment 
(i.e., serum creatinine ≥ 1.5 × 
ULN or  
1.5 × baseline) 
Interrupt dosing of encorafenib and binimetinib until resolved to CTCAE Grade < 1 or 
baseline level. Ensure subject is adequately hydrated. Monitor closely and measure 
isoenzymes and myoglobin in blood or urine and serum creatinine, then: 
• 
If resolved in ≤ 21 days, consider resuming treatment at 1 reduced dose levelb of 
encorafenib and binimetinib. 
• 
If not resolved in ≤ 21 days, permanently discontinue encorafenib and 
binimetinib. 
2nd occurrence: 
• 
Permanently discontinue encorafenib and binimetinib. 
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Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Cardiac Investigation – Prolongation of QT interval QTcF value 
QTcF > 500 ms during treatment 
and change from pre-treatment 
value remains ≤ 60 ms 
Subjects should have regular ECG monitoring (continuous where appropriate) until an 
adequately trained physician (such as a cardiologist or internist) has reviewed the data. 
Electrolyte abnormalities including magnesium should be corrected and cardiac risk 
factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be 
controlled. 
1st occurrence:  
• 
Temporarily interrupt dosing of encorafenib and binimetinib until QTcF < 500 
ms. Then resume treatment at 1 reduced dose levelb of encorafenib and 
binimetinib. 
2nd occurrence: 
• 
Temporarily interrupt dosing of encorafenib and binimetinib treatment until 
QTcF < 500 ms. Then resume treatment at 1 reduced dose levelb of encorafenib 
and binimetinib. If a subject restarts binimetinib and encorafenib following 
resolution of Grade 3 QTcF prolongation event, the subject should be evaluated 
with triplicate predose ECGs on Day 1 of the next cycle, followed by a single 
postdose ECG and a single predose ECG on Day 15, as well as single predose 
ECG and a single postdose ECG on Day 1 of the subsequent cycle (2nd cycle 
after the Grade 3 QT prolongation event). 
3rd occurrence:  
• 
Permanently discontinue encorafenib and binimetinib. 
QTcF increase during treatment 
is both > 500 ms and > 60 ms 
change from -pretreatment values  
Subjects should have regular ECG monitoring (continuous where appropriate) until an 
adequately trained physician (such as a cardiologist or internist) has reviewed the data. 
Electrolyte abnormalities including magnesium should be corrected and cardiac risk 
factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be 
controlled. 
• 
Permanently discontinue encorafenib and binimetinib. 
Rash [see cetuximab dose modifications (Table 15) and (Section 17.1). 
Grade 1 
Maintain dose level of encorafenib and binimetinib. 
Initiate Initial Rash Treatment Regimen (see Section 17.1. if it was not already started 
and rash should be closely monitored). 
Grade 2  
1st occurrence:  
• 
Maintain dose level of encorafenib and binimetinib 
• 
Initiate Initial Rash Treatment Regimen if it was not already started and rash 
should be closely monitored 
• 
Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt dosing 
of encorafenib and binimetinib until resolved to Grade ≤ 1. Then resume 
treatment at current dose level of encorafenib and binimetinib. For dermatitis 
acneiform, treatment with encorafenib may be maintained if, in the judgment of 
the Investigator, the rash is considered to be unrelated to encorafenib. If 
treatment with encorafenib was maintained and no improvement within 8 days, 
interrupt dosing of encorafenib. 
2nd occurrence: 
• 
Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt dosing 
of encorafenib and binimetinib until resolved to Grade ≤ 1. Then resume 
treatment at current dose level of encorafenib and 1 reduced dose levelb of 
binimetinib. For dermatitis acneiform rash, treatment with encorafenib may be 
maintained if, in the judgment of the Investigator, the rash is considered to be 
unrelated to encorafenib. If treatment with encorafenib was maintained and no 
improvement within 8 days, interrupt dosing of encorafenib. 
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Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Grade 3 
1st occurrence:  
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. 
Reassess weekly. Then resume treatment at current dose level of encorafenib 
and binimetinib. 
• 
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation. 
2nd occurrence:  
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. 
Then resume treatment at 1 reduced dose levelb of encorafenib and binimetinib. 
Resume treatment with encorafenib at the same dose level if, in the judgment of 
the Investigator, the rash is considered to be unrelated to encorafenib. 
• 
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation. 
Grade 4 
Permanently discontinue encorafenib and binimetinibf 
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndromee (Dose Adjustment for Encorafenib 
ONLY) (See Section 17.2 and Table 12) 
Grade 1 
Maintain dose of encorafenib. Promptly institute supportive measures, such as topical 
therapy, for symptomatic relief. Give instruction on life-style modifications.  
Grade 2  
1st occurrence:  
• 
Maintain dose of encorafenib and HFSR should be closely monitored. Promptly 
institute supportive measures, such as topical therapy, for symptomatic relief. 
Give instruction on life-style modifications. 
• 
If no improvement ≤ 14 days, interrupt dosing of encorafenib until resolved to 
Grade ≤ 1. Resume treatment with encorafenib at current dose level. Continue 
supportive measures, such as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. 
Additional occurrence:  
• 
Treatment with encorafenib may be maintained or interrupted based upon the 
Investigator’s discretion. Continue supportive measures, such as topical therapy, 
for symptomatic relief. Give instruction on life-style modifications. 
• 
If interrupted dosing of encorafenib per Investigator’s judgment, interrupt until 
resolved to Grade ≤ 1. Resume treatment with encorafenib at the same dose level 
or 1 reduced dose levelb based upon the Investigator’s discretion. 
Grade 3 
1st or additional occurrence:  
• 
Interrupt dosing of encorafenib until resolved to Grade ≤ 1. Promptly initiate 
supportive measures, such as topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. Reassess the subject weekly. 
Then resume treatment at one reduced dose levelb of encorafenib 
• 
Consider referral to dermatologist and manage HFSR per dermatologist’s 
recommendation. 
> 3nd occurrence: 
• 
Interrupt dosing of encorafenib until resolved to Grade ≤ 1, decision to resume 
treatment with encorafenib at one reduced dose levelb or permanently 
discontinue encorafenib should be based upon the Investigator’s discretion. 
SCC, KA and any Other Suspicious Skin Lesion (Dose Adjustment for Encorafenib ONLY) 
Grade ≤ 3 
Maintain dose of encorafenib (dose interruptions or modifications are not required). 
Treatment of SCC, KA, and any other suspicious skin lesion (eg, new primary 
melanoma) should occur based upon institutional practice.  
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Worst toxicity 
CTCAE, v.4.03 Grade  
(unless otherwise specifieda) 
Dose Modification for Encorafenib and for Binimetinib  
Diarrhea (See Section 17.3). 
Uncomplicated  
Grade 1-2 
Maintain dose of encorafenib. Consider temporary interruption of binimetinib until 
resolved to Grade ≤ 1. Then resume treatment at current dose level of binimetinib. 
Complicated 
Grade 1-2 
Consider temporary interruption of encorafenib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib 
Interrupt dosing of binimetinib until resolved to Grade ≤ 1. Then resume treatment at 
1 reduced dose levelb of binimetinib. 
Grade 3-4 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib if, in the judgment of the 
Investigator, the toxicity is considered to be unrelated to encorafenib, or at one reduced 
dose levelb. Resume treatment at 1 reduced dose levelb of binimetinib. 
Nausea/Vomiting 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib. Promptly institute antiemetic 
measure.  
Grade 3 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at 1 reduced dose levelb of encorafenib. Resume treatment with 
binimetinib at the current dose if, in the judgment of the Investigator, the toxicity is 
considered to be unrelated to binimetinib, or at 1 reduced dose levelb. 
Note: Interrupt dosing of encorafenib and binimetinib for ≥ Grade 3 vomiting or Grade 
3 nausea only if the vomiting or nausea cannot be controlled with optimal antiemetics 
(as per local practice). 
Grade 4 
Permanently discontinue encorafenib and binimetinibf. 
Interstitial lung disease/pneumonitis - Section 17.7 
Grade 1 
Maintain dose level of encorafenib and binimetinib. Monitor weekly. 
Grade 2 
Maintain dose of encorafenib. Withhold binimetinib for up to 3 weeks. 
If improved to Grade 0 or 1, resume treatment at 1 reduced dose level of binimetinib. 
If not resolved within 3 weeks, permanently discontinue binimetinib. 
Grade 3-4 
Permanently discontinue binimetinib. 
All Other Adverse Events (Suspected To Be Related To Encorafenib and/or Binimetinib) 
Grade 1-2 
If the event is a persistent Grade 2 AE not responsive to a specific therapy, consider 
interruption or reduction of encorafenib and binimetinib, as applicable 
Grade 3 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤1 or to 
pretreatment/baseline level. If the event resolves ≤ 21 days, then study drug may be 
resumed at 1 reduced dose levelb based upon the Investigator’s discretion. 
Grade 4 
Permanently discontinue encorafenib and binimetinibf 
 
a : Not according to NCI-CTCAE 
b : Dose reduction below 150 mg QD for encorafenib, and below 15 mg BID for binimetinib is not allowed. 
c : Ophthalmic monitoring mandated for retinal events, posterior uveitis, RVO: further evaluation with specialized retinal imaging (e.g. 
ocular coherence tomography, fluorescein angiography). Any diagnosis of retinal events must be supported by presence or absence of 
symptoms, visual acuity assessment and findings in OCT. 
d : For subjects enrolled with liver metastases and baseline LFT elevations. 
e : Disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the 
feet. 
f : A subject with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to Grade ≤ 1 within 28 days of 
discontinuing drug and, if in the opinion of the Investigator and Sponsor Medical Monitor, the event is not life-threatening and the subject 
can be managed and monitored for recurrence of AE. Any subjects requiring a treatment interruption of duration > 28 days must 
discontinue study drug permanently. 
g : Refers to total bilirubin. 
 
 
 
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6.5.4.2. Dose Modifications for Cetuximab 
Recommended dose modifications for cetuximab based on the occurrence of cetuximab treatment-
related AEs are summarized in Table 15. Section 17.1 contains recommended guidelines for 
prophylactic and symptomatic treatment of cetuximab-induced rash.   
 
Table 15: Recommended dose modifications for Cetuximab during a cycle of therapy 
Worst toxicity 
CTCAE, v.4.03 Grade 
 
Dose Modification for Cetuximab During a Cycle of Therapy 
Infusion Reaction 
If an infusion reaction occurs while cetuximab is being infused, the infusion 
should be stopped immediately and the subject should be evaluated. 
Grade 1 or 2 
 
Restart and complete the disrupted infusion at the discretion of the 
Investigator. The infusion must be restarted at a reduced rate. Additional 
pre-medications such as antihistamines or low-dose systemic corticosteroids 
may be administered when the infusion is restarted per institutional 
standards. 
All subsequent infusions must also be administered at the reduced rate. 
Grade 3 or 4 
Permanently discontinue cetuximab 
Rash: see encorafenib and/or binimetinib dose modifications (Table 14)] 
Grade 1 or 2 
Maintain dose level; consider initiating appropriate therapy (such as 
antihistamines, topical corticosteroids, and low-dose systemic 
corticosteroids) 
Grade 3, despite therapy 
Omit dose until resolved to ≤ Grade 2, then: 
• If resolved in ≤ 7 days (or ≤ 14 days for acneiform rash), then 
maintain dose level 
• If not resolved in ≤ 7 days despite appropriate skin toxicity therapy 
(or ≤ 14 days for acneiform rash), then permanently discontinue 
cetuximab 
Grade 3 recurrent 
Omit dose until resolved to ≤ Grade 2, then: 
• If resolved in ≤ 7 days (or ≤ 14 days for acneiform rash), then 
decrease 1 dose level 
• If not resolved in ≤ 7 days despite appropriate skin toxicity therapy 
(or ≤ 14 days for acneiform rash), then permanently discontinue 
cetuximab 
• Permanently discontinue cetuximab after 3rd recurrence (i.e., upon 
4th occurrence) 
Grade 4, despite skin toxicity 
therapy 
Permanently discontinue cetuximab 
Interstitial lung disease - Section 17.7: in case of ILD, for all grades, cetuximab must be discontinued 
 
 
 
 
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6.6. REPLACEMENT PROCEDURE  
Not Applicable  
6.7. BLIND BREAKING PROCESS 
Not Applicable  
6.8. ACCOUNTABILITY ON SITE AND RETURN/DESTRUCTION OF 
INVESTIGATIONAL PRODUCT(S) AND ASSOCIATED 
PRODUCT(S) 
The Investigator should maintain accurate written records of treatment received, dispensed, returned 
and any remaining treatment units, on the treatment accountability form. These records should be 
made available for CRA monitoring. The packaging of the medication should remain intact until 
just before the dispensation. 
At each visit, the Investigator will record the number of  capsules and tablets returned by each 
subject. 
At the end of the study, all used and unused treatments including packaging should be noted, and 
will be destroyed at the center (or local warehouse if not possible at the center). A copy of the 
treatment accountability form should be provided by the Investigator to the CRA and a destruction 
certificate should be received by Sponsor. 
6.9. RECALL OF INVESTIGATIONAL PRODUCT(S) AND RESCUE 
MEDICATION 
In cases of recall of investigational products (decided by the Competent Authorities or the Sponsor), 
the Investigator will be immediately informed by the Sponsor. 
The Investigator, in collaboration with the Sponsor representatives (Study Manager, CRA) must 
urgently: 
• stop the delivery of the concerned investigational products to the subjects, 
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• inform the concerned subjects that they must immediately stop taking these investigational 
products and return them to the center. 
The Study Manager/CRA will organize the return of the recalled products to the sponsor or 
designee, or will insure the destruction of the recall products at site under the investigator’s 
responsibility (destruction certificate to be obtained). 
7. CONCOMITANT THERAPY AND THERAPEUTIC / DIAGNOSTIC 
PROCEDURES 
Any existing concomitant therapies (at screening), any new concomitant therapies or change in the 
dosage of an existing concomitant therapy during the course of the study must be recorded on the 
e-CRF (as describe in the e-CRF completion guideline). All non-essential therapies must be stopped 
at screening. 
All medications, whether prescription or nonprescription, and non-drug therapies (e.g., blood 
transfusions) taken within 4 weeks prior to the first administration of study treatment, and all 
concomitant therapy administered during the study must be recorded on the Prior/Concomitant 
Therapies e-CRF page up to 30 days after the last study treatment administration. 
All medications (other than study treatment) and significant non-drug therapies (including physical 
therapy, and blood transfusions) administered during the study must be listed on the concomitant 
therapies e-CRF page. 
For all concomitant therapies taken during the study, the following information must be noted in 
the relevant section(s) of the e-CRF: 
• The name of the treatment / therapy 
• The reason for prescription 
• The route of administration 
• The dose 
• The frequency 
• The duration (start date and end date) 
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Any therapeutic and diagnostic procedures such as endoscopic examinations, diagnostics tests, 
ablation, surgical procedures etc. not planned by the study protocol must also be noted in the e-
CRF. These procedures may be associated with events, in which case the condition that leads to the 
procedure must be reported in the appropriate section of the e-CRF (AEs, medical history).  
For all such procedures that occur during the study, the following information must be noted in the 
relevant section(s) of the e-CRF: 
• 
The name of the procedure 
• 
The indication 
• 
The duration (start date and end date) 
7.1. PROHIBITED THERAPY AND THERAPEUTIC/DIAGNOSTIC 
PROCEDURES 
None of the concomitant therapies and therapeutic/diagnostic procedures listed below are allowed 
during the study period  (except those listed in Section 7.2): 
• 
Anticancer agents such as cytotoxic chemotherapy small-molecule targeted agents, biological 
agents, immune response modifiers or hormonal therapy, 
• 
Local therapies which could interfere with treatment (e.g.  surgical excision or ablation of 
lesions are not permitted without Sponsor approval while subjects are receiving study 
treatment), 
• 
Investigational drugs (other than study drugs) and devices, 
• 
Radiation therapy (not including palliative radiotherapy at focal sites that covers ≤ 10% of the 
bone marrow reserve), 
• 
Herbal preparations/medications. Subjects should stop using herbal medications 7 days prior 
to first dose of study treatment, 
• 
Concomitant moderate or strong systemic CYP3A4 inhibitors or inducers which are likely to 
significantly increase or decrease respectively encorafenib exposure and thus should not be 
used during this study (see Section 17.5). 
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If another therapy and/or therapeutic / diagnostic procedure has to be prescribed in the interests of 
the subject’s health, the decision to discontinue the subject from the study should be taken by the 
Investigator. 
 
7.2. AUTHORIZED THERAPY, THERAPEUTIC AND DIAGNOSTIC 
PROCEDURES 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
subject is permitted, unless otherwise specified. Additional information regarding concomitant 
medications/therapies is provided in the Investigator’s Brochures for encorafenib and binimetinib 
and the cetuximab locally approved labelling. 
Subjects receiving any of the medications listed in Section 17.5 must be used with caution carefully 
monitored for potentiation of toxicity due to any individual concomitant medication and may 
require dose titration of the drug substance. Investigators should use caution when prescribing 
concomitant medications, as clinical experience with these compounds in subjects with cancer is 
often limited. Investigators should contact the Sponsor or designee when they are unsure whether a 
drug should be prescribed to a subject in the clinical study. All concomitant medications/therapies, 
transfusions, procedures and dietary supplements must be documented in the e-CRF.  
7.2.1. Skin Toxicity Treatments 
Subjects should be treated for cetuximab-induced, encorafenib-induced and/or binimetinib-induced 
skin toxicity following the supportive care recommended guidelines for the management of these 
toxicities and prophylaxis measures referred to in Section 17.1.  
7.2.2. Hand-Foot Skin Reaction Treatment  
HFSR has been reported for encorafenib, so it is recommended that subjects are informed prior to 
starting study treatment to avoid activities that can cause friction to the hands and/or feet. In 
addition, supportive measures for prevention and/or management of HFSR should be instituted. 
Clinical judgment and experience of the treating physician should guide the management plan of 
each subject. Subjects receiving encorafenib should be treated for encorafenib-induced HFSR 
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following the supportive care recommended guidelines for the management of these toxicities 
(Section 17.3).  
7.2.3. Anti-Diarrheal  
Subjects should be treated for diarrhea as per institutional guidelines, and/or as indicated in the 
locally approved prescribing information, or for subjects receiving binimetinib, per the supportive 
care recommended guidelines for the management of binimetinib-induced diarrhea (Section 17.3). 
7.2.4. Antiemetics  
Prophylactic antiemetics should only be administered if the subject experiences nausea or vomiting 
and at the discretion of the Investigator. It is recommended that subjects use drugs that do not cause 
QT prolongation. Note that some antiemetics have a known risk for Torsade de Pointes (TdP) 
(Section 17.5). 
7.2.5. Permitted Concomitant Therapy requiring Caution and/or Action 
7.2.5.1.  CYP and UGT Substrates and Inhibitors 
Encorafenib is a reversible inhibitor of CYP2B6, CYP2C9, CYP3A4 and UGT1A1. It is also a time-
dependent inhibitor of CYP3A4. Likewise, binimetinib is also a reversible inhibitor of CYP2B6. 
Permitted medications to be used with caution in this study include those that are sensitive substrates 
of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and UGT1A1 or those substrates that have 
a narrow therapeutic index (Section 17.5). 
There is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness of 
hormonal contraception methods. Therefore, the use of at least one form of non-hormonal 
contraception is required during participation in this study (See Section 5.3 for use of contraception 
methods required for this study). Caution should be used in subjects receiving concomitant 
treatment with other drugs that are substrates of CYP3A4 as the efficacy of these drugs could be 
reduced when administered with encorafenib. 
Encorafenib has been identified in vitro to be metabolized by CYP3A4 and to a lesser extent by 
CYP2C19. The use of strong inhibitors of CYP3A4 is prohibited. Concomitant use of moderate 
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CYP3A4 inhibitors while on study should be avoided. If use of moderate CYP3A4 inhibitors is 
unavoidable and no alternatives are available, short-term use (≤ 30 days) following discussion with 
the Sponsor may be permitted with accompanying dose reduction to one-half of the encorafenib 
dose prior to use of moderate CYP3A4 inhibitors (or as close as can be achieved without exceeding 
the target dose). The encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor may 
be resumed after the inhibitor has been discontinued for 3 to 5 elimination half lives. Strong 
inhibitors of CYP2C19 should be used with caution when co-administered with encorafenib.  
Binimetinib has been identified to be primarily metabolized by glucuronidation. It is advised that 
strong inhibitors of UGT1A1 should be used with caution when co-administered with binimetinib 
(Section 17.5).  
Subjects should be closely monitored for the occurrence of AEs. 
7.2.5.2. Transporter Substrate and Inhibitors 
In vitro data showed that both encorafenib and binimetinib are substrates of the transporter P-
glycoprotein (P-gp). Binimetinib is also a substrate of BCRP. Encorafenib is a BCRP inhibitor. 
Thus, the use of drugs that are known to inhibit or induce P-gp or BCRP should be used with caution. 
Encorafenib is also a potent inhibitor of the renal transporters, organic anionic transporter OAT1, 
OAT3 and organic cationic transporter (OCT) 2, and the hepatic transporter organic anion-
transporting peptide (OATP1)B1 and OATP1B3. The co-administration of drugs that are known to 
be sensitive or narrow therapeutic index substrates of BCRP, P-gp, OAT1, OAT3, OCT 2, 
OATP1B1 and OATP1B3 should be used with caution (Section 17.5). 
 
7.2.5.3. Drugs with a Conditional or Possible Risk to Prolong the QT Interval 
and/or Induce Torsade de Pointes 
Investigators should use caution when administering encorafenib or binimetinib with concomitant 
medications with a known, conditional or possible risk to prolong the QT interval and/or induce 
TdP (Section 17.5). Subjects receiving such medications must be carefully monitored for 
potentiation of toxicity due to any individual concomitant medication, and may require dose 
titration of the concomitant medication. 
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8. ASSESSMENTS 
8.1. EFFICACY ASSESSMENTS 
Tumor response will be evaluated locally by the Investigator according to RECIST, v1.1 (Section 
17.6). 
All potential sites of tumor lesions will be assessed at screening, the following should be performed: 
• A CT scan with IV contrast of chest, abdomen and pelvis is the preferred technique. If there 
is concern about radiation exposure, an MRI may be used instead of a CT. 
• In subjects with a history of asymptomatic brain metastases, a brain MRI or CT scan 
• If clinically indicated, a whole-body bone scan (i.e., if bone metastases are suspected or 
known at baseline). A whole-body bone imaging method may be used per local standard of 
care (e.g., Tc99m bone scan, fluorodeoxyglucose-positron emission tomography [FDG-
PET], sodium fluoride-positron emission tomography [NaF PET] scan or whole-body bone 
MRI).  
Skeletal lesions identified on a whole-body bone scan at baseline, which are not visible on the chest, 
abdomen, or pelvis CT (or MRI) scan should be imaged at baseline using localized CT, MRI, or X-
ray.  
As far as possible, the same method of assessment of each lesion should be used at screening and 
for all visits, for consistent comparison. 
During the Main study period, all post-screening assessments should be performed every 6 weeks 
(±7 days) from the first dose for the first 12 weeks of treatment; except for first tumor evaluation 
for which the time-window allowed is day 42 +7 days from first dose. Then, every 8 weeks 
thereafter until disease progression, subject decision, withdrawal of consent, initiation of 
subsequent anticancer therapy, subject is lost to follow-up, death or defined end of study as 
described in Section 5.7. 
During the Study extension period, all assessments should be performed every 12 weeks (±7 days), 
until disease progression, subject decision, withdrawal of consent, initiation of subsequent 
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anticancer therapy, subject is lost to follow-up, death or defined end of study as described in Section 
5.7. 
 
If a subject discontinues study treatment for reasons other than disease progression, tumor 
assessments must continue to be performed (as per local and central review) every 6 weeks (first 12 
weeks) then every 8 weeks during the Main study period and every 12 weeks during the Study 
extension period (as per local review), until the start of new anti-cancer therapy, disease 
progression, death, lost to follow-up, subject decision or withdrawal consent. 
Regardless of whether study treatment is discontinued, the following should be performed: 
• Chest, abdomen, and pelvis CT (or MRI) scans  
• Brain MRI or CT scan, if metastases were documented at baseline 
• Skeletal lesions identified at baseline should continue to be imaged at subsequent scheduled 
visits using localized CT, MRI, or X-ray (using the same method used at baseline for all 
visits for any given lesion). After baseline, whole body bone scans need not be repeated, 
unless clinically indicated. 
• Additional imaging evaluations may be performed if there is symptomatic evidence 
suggesting the possibility of disease progression based on clinical symptoms or physical 
examination at any time. 
If off-schedule imaging evaluations are performed or if progression is suspected, every effort should 
be made to perform subsequent imaging evaluations in accordance with the original imaging 
schedule.  
All CT scans should be performed with IV contrast. If a subject is known to have a medical 
contraindication to the contrast agent or develops a contraindication during the study, a CT scan 
without IV contrast of the chest and MRI with IV contrast, if possible, of the abdomen and pelvis 
may be performed. A CT scan of the brain, preferably with IV contrast, may be performed if MRI 
is contra-indicated. 
Chest X-ray or ultrasound should not be used for tumor response assessments in this study. 
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Any lesions that have been subjected to loco-regional therapies (e.g., radiotherapy, ablation, etc.) 
should not be considered measurable, unless they have clearly progressed since that therapy. 
Previously treated lesions that have not progressed should be considered non-measurable and 
therefore, assessed as non-target lesions. 
While FDG-PET scans are not required for this study, sites may perform combined PET/CT scans 
per their local standard of care, provided the CT is of similar diagnostic quality as a CT scan 
performed without PET, including the use of oral and IV contrast media. If acquired according to 
local standard of care, FDG-PET may be relied upon to document progressive disease (PD) in 
accordance with RECIST.  
When possible, each center should have a designated radiologist responsible for the interpretation 
of scans and response evaluations for study subjects. At a minimum, a single radiologist should 
perform all evaluations for an individual subject. 
Transmission for central review 
All imaging data acquired for efficacy purposes during the Main study period will be transmitted to 
an imaging vendor for central review. Image transmission to the imaging vendor should be 
accomplished according to the imaging vendor manual.  Full details of the central reading process 
are included in the Independent Review Charter.  
8.2. PHARMACOKINETICS ASSESSMENT  
8.2.1. Blood Samples Collection 
8.2.1.1. Collection Schedule 
Blood samples (4 mL/time point) for determination of encorafenib, binimetinib and the active 
metabolite of binimetinib (AR00426032) plasma levels will be collected, during Cycle 1 and Cycle 
2, at the following times. 
Cycle 1: 
• Day 1: T2h (±10 min) and T6h (±30 min) post encorafenib/ binimetinib dose.  
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Dosing and sampling information will consist of the date and time of the first encorafenib and 
binimetinib dose, the encorafenib and binimetinib dose amount administered, and exact date and 
time of the PK samples; 
Cycle 2: 
• Day 1: predose (T0) (just prior to the dose of encorafenib/ binimetinib), T2h (±10min) post 
encorafenib/ binimetinib dose.  
Dosing and sampling information will consist of: 
− For predose sample:  
. date and time of the last two previous binimetinib doses (morning/evening) and the 
current day’s binimetinib dose, including the dose amounts taken and exact date and 
time of the PK samples.  
. date and time of the last previous encorafenib dose and the current day’s encorafenib 
dose, including the dose amounts taken and exact date and time of the PK samples 
 
− For T2h sample:  
. date and time of the current day’s first encorafenib and binimetinib dose, including the 
dose amounts administered, and exact date and time of the PK samples. 
Blood samples (4 mL per time point) for determination of cetuximab serum levels will be collected, 
during Cycle 1 and Cycle 2, only at the following times:  
Cycle 1: 
• Day 1: T2h (± 10 min) and T6h (± 30 min) after the beginning of cetuximab infusion.  
− Post dose infusion information should include date, dose, start time, and infusion duration. 
Any eventual infusion interruptions should also be documented. 
Cycle 2: 
• Day 1: predose (T0) (just prior the infusion), T2h (± 10 min) after the start of cetuximab 
infusion.  
Dosing and sampling information will consist of: 
− Predose sample: collection should occur before the beginning of cetuximab infusion. 
Information should include date, dose, start time, and infusion duration of the last previous 
dose of cetuximab and exact date and time of the PK sample. 
− For T2h: include the current day’s date, dose, start time, and infusion duration of the 
infusion and exact date and time of the PK sample. Any eventual infusion interruptions 
should also be documented. 
Blood sample collection times are presented in (Table 16) and (Table 17): 
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Table 16: Pharmacokinetic sampling times for Encorafenib, Binimetinib and AR0042603 
 
Cycle 1 Day 1 
Cycle 2 Day 1 
Time after encorafenib/ binimetinib dosing 
on designated dosing days (h) 
 
2 
6 
0 
(Pre-dose) 
2 
PK sample for encorafenib, binimetinib 
and AR00426032 (4 mL per time point) 
 
x 
x 
x 
x 
Abbreviations: h = hours; PK = pharmacokinetic 
PK samples will be collected on Cycle 1 Day 1 postdose (encorafenib/binimetinib) at 2 h (± 10 min) and 6 h (± 30 min). PK samples will be 
collected on Cycle 2 Day 1 predose (just prior to encorafenib/binimetinib dose) and postdose at 2 h (± 10 min). Blood samples for 
encorafenib/binimetinib PK will be processed to collect plasma. 
 
 
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Table 17: Pharmacokinetic sampling times for Cetuximab 
 
 
Cycle 1 Day 1 
Cycle 2 Day 1 
Time after the start of 
cetuximab infusion on 
designated dosing days (h) 
2 
6 
0 
(Pre-infusion) 
2 
PK sample for cetuximab (4 
mL per time point) 
x 
X 
x 
X 
Abbreviations: h = hours; PK = pharmacokinetic 
PK samples will be collected on Cycle 1 Day 1 post-infusion (cetuximab) at 2 h (± 10 min) and 6 h (± 30 min). PK samples will be collected on 
Cycle 2 Day 1 pre-infusion (just prior to infusion of cetuximab) and post-infusion at 2 h (± 10 min). Blood samples for cetuximab PK will be 
processed to obtain serum. Time points are based on the start of infusion. 
 
The total number of blood samples for analytical determination will be 8 per subject, making the 
total volume of collected blood for pharmacokinetics approximately 32 mL per subject. 
If a subject receiving any of the treatments defined in this protocol experiences an AE that results 
in an unscheduled visit or meets the criteria for an SAE, a blood sample for measurement of 
concentrations of drug-related analytes should be collected, if feasible, if less than 24 hours have 
elapsed since the last dose of study drug. 
Study visits for PK sampling should be scheduled in the morning so that correct predose and 
postdose PK blood samples can be collected. On the PK visit days, the morning doses of encorafenib 
and binimetinib, if applicable, should be taken at the study site, only after collecting the predose 
PK sample (for cycle 2). A graphic representation of blood PK sampling for plasma and serum is 
provided in Figure 1. 
 
 
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Figure 1: Graphic representation for pharmacokinetic sampling plan* 
 
*Predose PK samples for cetuximab analysis should be collected just prior the beginning of the cetuximab infusion, 
regardless of the pre-medication that may be used prior to cetuximab infusion. 
If a vomiting episode occurs within the first 4 hours post-dosing of binimetinib and encorafenib 
during the day of the last dose prior to collection of PK samples, the exact time (whenever possible) 
must be noted in the e-CRF. In addition, on Day 1 of cycles 1 and 2 when postdose PK samples are 
collected, if vomiting occurs, the exact time of the first vomiting episode within the first 4 hours 
post-dosing on that day must be noted.  
 
8.2.1.2. Technical Handling 
Complete instructions for sample processing, handling and shipment will be provided in a separate 
Laboratory Manual. 
Each blood sample will be drawn by direct venipuncture or via an indwelling catheter. Each sample 
will be 4 mL (according to the Collection Schedule Table 16, Table 17). 
Important points for blood collection:  
• Blood sampling from a central venous line is not allowed if this line was used to infuse 
cetuximab, 
• If an indwelling catheter is used for blood collection, approximately 1 mL will be drawn 
and discarded before sampling, 
• Blood samples must be collected from the body side contralateral to the site of the cetuximab 
infusion, 
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• Care must be taken to collect blood slowly without causing hemolysis 
 
8.2.2. Samples Handling and shipping 
Complete instructions for sample labelling, handling, storage and shipping to the central laboratory  
will be provided in a separate Laboratory Manual. The samples will be stored in the central 
laboratory until transfer to the bioanalytical center for analytical determination.  
8.2.3. Analytical determination 
Analytical determination of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) in plasma will be carried out at a designated CRO laboratory using validated 
LC/MS-MS methods. 
Analytical determination of cetuximab in serum will be carried out at a designated CRO laboratory 
using a validated method. 
8.2.4. Sample Storage 
Biological samples dedicated to analytical determination will not be discarded before the final 
clinical study report (CSR) is released and without prior notification to the study manager and 
authorization of the head of the PK/PD Department of IRPF. 
8.3. SAFETY ASSESSMENT 
8.3.1. Adverse Events 
At screening, any concomitant diseases will be reported as medical history in the e-CRF. At each 
subsequent visit, the occurrence of AEs since the last visit will be determined by the subject’s 
spontaneous reporting, the Investigator’s non-leading questioning and his/her clinical evaluation.  
The severity of AEs will be evaluated using the NCI-CTCAE, v.4.03. 
All AEs that occur after signature of informed consent through 30 days after the last dose of study 
drug must be recorded on the AE e-CRF, irrespective of their etiology and relationship to study 
treatment. Assessment and reporting of AEs is described in detail in Section10 and will be 
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completed at the time points specified in the study flow chart (Main study period and Study 
extension period flow charts). 
 
8.3.2. Clinical Safety Laboratory Assessments  
The local clinical center’s laboratory will analyze and report all laboratory safety tests performed 
at the center to the Investigator who will ensure they are entered in the e-CRF. Clinical laboratory 
tests will be performed according to the laboratory procedures and the latest updated references. 
Ranges from the laboratory will be used to identify abnormal values.  
Assessments including clinical chemistry, hematology, urinalysis, coagulation, and pregnancy tests 
do not have to be repeated if performed within 72 hours prior to the first dose on Cycle 1 Day 1.  
Additional clinical laboratory tests may be obtained at any time during the study at the Investigator’s 
discretion. 
 
 
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8.3.2.2. Parameters 
Table 20: Summary of Clinical Laboratory Tests_Main study period 
Hematology 
Chemistry 
Urinalysis 
Coagulation 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Monocytes 
Neutrophils/ANC 
Platelets 
RBC 
WBC 
ALT 
AST 
Bilirubin [total and direct 
(and indirect – only 
applicable for France)]a 
Albumin 
Alkaline phosphatase 
Bicarbonate (HCO3) 
BUN/urea 
Calcium 
Chloride 
CKb 
Creatinine 
Glucose 
LDH 
Magnesium 
Potassium 
Sodium 
Total protein 
Troponin I or T 
Uric acid 
Lipase 
Amylase  
Serum CK isoenzymes b 
Myoglobinb 
Blood 
Glucose 
Ketones 
Leukocytes 
pH 
Protein 
Myoglobinb 
PT or INR 
aPTT 
Other 
At Screening only: 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• CRP 
• Calculated creatinine 
clearance (Cockroft-
Gault formula)  
• LH, FSH and/or 
estradiol (if 
applicable) 
• HIV (if required) 
• At Screening and 
EOT  
• Serum pregnancy test 
(if applicable) 
 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; CK = creatine kinase; CRP = C-reactive protein; FSH = follicle-stimulating hormone; INR = International Normalized Ratio; LDH = 
lactate dehydrogenase; LH = luteinizing hormone; pH = hydrogen ion concentration; PT = prothrombin time; aPPT = activated partial 
thromboplastin time; RBC = red blood cell(s); WBC = white blood cell(s); HIV = Human  Immuno deficiency Virus. 
a Direct bilirubin (and indirect – only applicable for France) will be measured at screening only if total bilirubin values are abnormal; for the 
purposes of determining eligibility to participate in the study.  
b For Grade 2 total CK that is also > 3 × ULN or asymptomatic Grade 3 total CK: measure CK, CK isoenzymes and myoglobin in blood or 
urine weekly for 3 weeks. If total CK remains above the grade that led to the increased monitoring, continue to assess CK, CK isoenzymes and 
myoglobin, along with regularly scheduled clinical chemistry assessments, until normalization or improvement to Grade 1. When CK is 
elevated, ensure the subject is adequately hydrated. 
 
 
 
 
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Table 21: Summary of Clinical Laboratory Tests_Study extension period 
Hematology 
Chemistry 
Urinalysis 
Other 
 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Monocytes 
Neutrophils/ANC 
Platelets 
RBC 
WBC 
ALT 
AST 
Bilirubin [total and 
direct (and indirect – 
only applicable for 
France)] 
Albumin 
Alkaline phosphatase 
Calcium 
Chloride 
Creatinine 
Glucose 
Magnesium 
Potassium 
Sodium 
Total protein 
 
Blood 
Glucose 
Ketones 
Leukocytes 
pH 
Protein 
 
At EOT  
Serum pregnancy test (if 
applicable) 
 
 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = pH = hydrogen ion concentration; RBC = red blood 
cell(s); WBC = white blood cell(s) 
 
 
 
 
Hematology, Coagulation and Clinical Chemistry: 
Blood samples for the hematology, coagulation and chemistry laboratory tests listed in Table 
Summary of Clinical Laboratory Tests (Table 20) will be collected at the time points specified in 
Table Laboratory Schedule (Table 18) for Main study period. 
For the Study extension period, blood samples for the hematology and chemistry laboratory tests 
listed in Table Summary of Clinical Laboratory Tests (Table 21) will be collected at the time points 
specified in Table Laboratory Schedule (Table 19). 
 
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Blood sample collections occurring on dosing days must be performed prior to study drug 
administration. Laboratory test results required to make decisions regarding potential dose 
modifications (as specified in Section 6.5.4) should be reviewed prior to study treatment 
administration. 
Additional tests may be done at the Investigator’s discretion, in the subjects’ best interest. 
Urinalysis  
Urine samples for the laboratory tests listed in Summary of Clinical Laboratory Tests (Table 20) 
for Main study period will be collected at the time points specified in Table Laboratory Schedule 
(Table 18). 
Urine samples for the laboratory tests for the Study extension period listed in Summary of Clinical 
Laboratory Tests (Table 21) will be collected at the time points specified in Table Laboratory 
Schedule (Table 19). 
 
All urine collections occurring on dosing days must be performed prior to study treatment 
administration. 
Pregnancy and Assessment of Fertility 
For Main study and Study extension periods, all females of childbearing potential are required to 
undergo a local serum pregnancy assessment at Screening and end of treatment (EOT) and local 
urine pregnancy assessments at time points specified in Table Laboratory Schedule (Table 18 and 
Table 19) 
Any positive pregnancy tests will result in immediate cessation of study treatment 
administration.Female subjects of non-childbearing potential (as defined in Section 5.3) do not 
require pregnancy tests.  
 
8.3.3. Physical Examination 
A physical examination will be carried out for each body system at the screening visit and on Day 
1 of every cycle (for Main study and Study extension periods). 
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At Screening, the physical examination should include general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular 
and neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast and pelvic examinations will be performed; body weight will be measured as part of the 
physical examination. Height will only be measured at Screening. 
For subsequent visits, the physical examinations should be targeted as clinically indicated. 
The physical examination will be globally evaluated prior to study drug administration as 
“normal/abnormal”. Further target inspection will be undertaken for any abnormal finding and will 
be recorded as AEs. 
 
8.3.4. Vital Signs  
8.3.4.1. Schedule 
Vital signs include Heart Rate (HR), systolic and diastolic blood pressure (SBP, DBP), respiration 
rate, and temperature. They will be assessed at the time points indicated in the study flow chart 
(please refer to the flow-chart corresponding to the current period: Main study or Study extension). 
8.3.4.2. Technical Procedure and Parameters 
 
SBP and DBP, expressed in mmHg,and HR expressed in beat per minute (bpm) will be measured  
per institutional standards.  
Limits for abnormal values for SBP and DBP should be graded according to NCI-CTCAE, v.4.03 
as described in tables below (Table 22 and Table 23).  
 
 
 
 
 
 
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 Table 22: Modified NCI CTCAE, Version 4.03 Grading for Hypertension   
Grade  
Description  
Grade 1  
Prehypertension (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg ) 
Grade 2 
Stage 1 hypertension (systolicBP 140 - 159 mm Hg or 
diastolic BP 90 - 99 mm Hg); medical intervention indicated; 
recurrent or persistent (>=24hrs); symptomatic increase by>20 mm Hg 
(diastolic) or to>140/90 mm Hg if previously 
WNL; monotherapy indicated  
Grade 3 
Stage 2 hypertension (systolic BP >=160 mm Hg or diastolic 
BP >=100 mm Hg); 
 Medical intervention indicated; more than one drug or more intensive 
therapy than previously used indicated 
Grade 4  
Life-threatening consequences (e.g., malignant hypertension, 
Transient or permanent neurologic deficit, hypertensive crisis); urgent 
intervention indicated 
 
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 
90 mm Hg. 
 
 
Table 23: Modified NCI CTCAE, Version 4.03 Grading for Hypotension 
Grade  
Description  
Grade 1  
Asymptomatic, intervention not indicated 
Grade 2 
Non-urgent medical intervention indicated 
Grade 3 
Medical intervention or hospitalization indicated 
Grade 4  
Life-threatening and urgent intervention indicated 
 
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual  in a given environment. 
 
An institutional thermometer will be used to measure body temperature.  
All vital sign measurements occurring on dosing days must be performed prior to study treatment 
administration. 
Any treatment-emergent abnormal findings will be recorded as AEs.  
 
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8.3.5. Electrocardiogram (ECG) and Echocardiogram/Multi-gated 
Acquisition Scans (ECHO/MUGA) 
8.3.5.1. Schedule 
ECG and ECHO/MUGA will be assessed as indicated in the study flow chart (please refer to the 
flow-chart corresponding to the current period: Main study or Study extension). 
ECGs for which abnormal results are collected after study treatment initiation should be repeated 
until the values return to normal or to a stable status. The frequency with which such checks should 
be made will be defined by the Investigator according to the degree of abnormality.  
 
8.3.5.2. Technical Procedure and Parameters 
• Electrocardiogram 
An ECG will be recorded as described on the flowchart (please refer to the flow-chart corresponding 
to the current period: Main study or Study extension) using the internationally recognized 12-lead 
cardiograph. An institutional cardiograph will be used.  
Prior to performing the 12-lead ECG, subjects should rest in the supine position for at least 5 
minutes. The ECG measurement performed at the Screening Visit will be used to determine 
eligibility. The mean of the triplicate ECG measurements recorded pre-dose on Cycle 1 Day 1 will 
serve as the subject’s Baseline value for all postdose comparisons. The ECG measurement at any 
time point should be used for AE grading and recommended dose modifications. 
When an ECG is to be performed at the same time point as a blood collection, the ECG is to be 
performed first.  
Interpretation of the tracing, Heart Rate (HR), QTcF interval (Fridericia’s correction formula), PR 
and QRS complex should be made by a qualified physician and evaluated as normal or abnormal . 
All data should be documented in the e-CRF.  
Clinically significant abnormalities present when the subject signed the Screening informed consent 
should be reported in the e-CRF. New or worsened clinically significant findings occurring after 
the informed consent must be recorded in the e-CRF.  
 
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• Echocardiogram/Multi-gated Acquisition Scans 
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA scans as described on 
the flowchart (please refer to the flow-chart corresponding to the current period: Main study or 
Study extension). The same method should be used throughout the study.  
Subjects who develop signs/symptoms of congestive heart failure at any point during the study are 
required to have an evaluation of LVEF measurement by ECHO or MUGA.  
 
8.3.6. Ophthalmic Assessments 
During the Main study period, visual assessment must be performed by investigator, to assess 
general inspection of the eyes, examination of motility and alignment, visual disturbance including 
diminished central vision, blurred vision or loss of vision at each Day 1, if clinically indicated at 
D8, D15, D22 during treatment and at 30-days follow-up visit.  
During the Study extension period, visual assessment must be performed by investigator, to assess 
general inspection of the eyes, examination of motility and alignment, visual disturbance including 
diminished central vision, blurred vision or loss of vision at each Day 1, if clinically indicated at 
D15 during treatment and at 30-days follow-up visit. 
At screening, EOT, if clinically indicated, during treatment, and at safety 30 day-follow-up visit in 
case of ocular clinical event at EOT visit, a full ophthalmic examination will be performed by an 
ophthalmologist (during Main study and Study extension periods).  
The full ophthalmic examination includes:  
• Best corrected visual acuity for distance testing, slit lamp examination, intraocular pressure 
and dilated fundoscopy (with attention to retinal abnormalities, especially retinal pigment 
epithelial detachment (RPED), serous detachment of the retina and RVO).  
• OCT will be performed systematically at screening and if clinically indicated during 
treatment and at EOT. 
• Fluorescein angiography will be performed only if clinically indicated from screening to 
EOT. 
 
 
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For all subjects, ophthalmic assessments may be performed more frequently per standard of care or 
if clinically indicated for evaluation of any visual signs or symptoms. Subjects with clinical 
suspicion of retinal abnormalities (i.e., RPED, posterior uveitis, serous detachment of the retina, 
RVO, photopsia, metamorphopsia, impairment of visual acuity, etc.), must complete at least one of 
the following additional assessments: 
• For non-vascular abnormalities: OCT of the macula (spectral domain OCT recommended). 
• For vascular abnormalities: fluorescein angiography of the central 30 degrees.  
Images/results of the ophthalmic examinations (at a minimum, OCT and/or fluorescein 
angiography) should be sent to the study site and be maintained in the subject’s source document 
file. These images/results may be requested to be sent to the Sponsor or designee.  
8.3.7. Dermatologic Evaluations  
Dermatologic evaluations will be performed at the site by the Investigator to monitor for the 
possible development of keratoacanthoma (KA) and/or squamous cell carcinoma (SCC), as these 
have been reported to occur with selective BRAF inhibitor treatment. This assessment can be done 
predose or postdose and will be performed at the time points specified in the Flowchart (please refer 
to the flow-chart corresponding to the current period: Main study or Study extension).  
In case of occurrence of KA or SCC, subjects will undergo complete surgical excision of the skin 
lesion following institutional standards. The evaluation can be done by the dermatologist if 
clinically indicated. 
It is recommened that dermatological examination should be performed every two months for up to 
6 months following discontinuation of encorafenib.  
 
 
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8.3.8. ECOG Performance Status 
Assessment of ECOG PS will be performed at the time points specified in the Flow Chart (please 
refer to the flow-chart corresponding to the current period: Main study or Study extension). ECOG 
PS should be obtained on the scheduled day, even if study treatment is being held (see Table 24). 
 
Table 24: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
 
8.4.  TISSUE AND BLOOD BIOMARKER ASSESSMENTS 
All tissue and blood biomarker assessments are described in Table 25 for the Main study period. 
All tissue and blood biomarker assessments are described in Table 26 for the Study extension 
period 
 
8.4.1.  Tumor Biomarker Assessments 
 
- 
BRAF testing 
Subjects will be eligible for the study based on identification of a BRAFV600E mutation in the tumor 
as determined by local laboratory result obtained any time prior to Screening. Only PCR and NGS-
based local assays results will be acceptable. The BRAF mutation status must be confirmed by the 
central laboratory no later than 30 days from first dose of study treatment.  
In cases where there is discordance between the local assay and central laboratory results, or if the 
central laboratory is not able to confirm presence of a BRAFV600E mutation due to inadequate or 
poor sample condition or absence of available material within 30 days of initiating study therapy, 
subjects may only continue treatment if there is no clinical indication of deterioration or disease 
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progression and the Investigator determines that the subject is deriving benefit. In such instances, 
subjects must be informed that the BRAF mutation status is unconfirmed (negative or indeterminate) 
and must sign a separate informed consent form (ICF) that includes this information and describes 
alternative treatment options.  
If the result from the central laboratory is indeterminate or the sample is deemed inadequate for 
testing, additional samples should be submitted (archival material only). 
This analysis will be performed on an archival FFPE tumor sample or fresh biopsy provided at 
screening and may also be performed on an optional biopsy obtained at End of Treatment. 
 
- 
Other assessments in tumor tissue samples 
The tissue source submitted to the central laboratory will also be used for retrospective testing of 
MSI status and RAS mutation status. Information regarding tissue specimen requirements, sample 
handling and shipment will be provided in the Laboratory Manual. 
This test will analyze tumor mutations representative of the mutational load. Germline DNA 
obtained via a blood sample (MSI germline control) will also be required (10mL) for the Main study 
period (see Table 25). 
These biomarker analysis will be exploratory and will not be part of the CSR. 
 
8.4.2.  Blood Biomarker Assessments 
8.4.2.1. C-reactive protein 
A blood sample (3.5 mL) for analysis of C-reactive protein (CRP), a biomarker of inflammation, 
will be collected during Screening. Complete instructions for sample collection, processing, 
handling and shipment to the central laboratory will be provided in the Laboratory Manual. 
8.4.2.2. Tumor markers 
Blood samples (10 mL of each) for analysis of tumor markers CEA and CA 19-9 will be collected 
at screening, predose on day 1 of cycle 1 if more than 72 hours after screening and pre-dose on day 
1 of each subsequent cycles,and at the EOT visit (Main study period). This measurement will 
provide a surrogate marker of response to treatment. 
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During the Study extension period, blood samples (10 mL of each) for analysis of tumor markers 
(CEA and CA 19-9) will be collected at pre-dose on day 1 of each cycle,and at the EOT visit, only 
if as per routine clinical practice. 
The analysis of these blood samples will be performed by the local laboratory. 
 
 
8.4.2.3. Circulating DNA (ct-DNA) 
ctDNA will be analyzed at baseline in a plasma sample (2 blood samples of 10 mL). BRAFV600E 
mutational status will be explored and compared to the BRAFV600E mutational status observed in the 
local test used for inclusion and for retrospective tumor mutation analysis. In addition to BRAFV600E, 
other cancer genes may be explored in order to identify biomarkers for sensitivity or resistance to 
treatment. 
All blood biomarker analysis will be exploratory and will not be part of the CSR. 
 
8.4.3.  Predictive Biomarkers of Activity 
Further exploratory biomarker research may be conducted on collected blood and tumor samples. 
These studies would extend the search for other potential biomarkers relevant to the effects of the 
drugs given in combination in this study, and/or prediction of these effects, and/or resistance to the 
treatment, and/or safety, and these additional investigations would be dependent upon clinical 
outcome, reagent and sample availability. Samples used for these analyses will be: 
- 
Remaining tumor tissue (Section 8.4.1): retrospective analyses may include and not limited to: 
expression of proteins by immunohistochemistry or gene expression by RNA analysis 
(RNAseq, nanostring, RT-Q PCR, etc). 
- 
Remaining blood samples (Section 8.4.2.3): remaining blood samples collected at baseline may 
be analyzed for potential genomic or proteomic predictive markers of activity.  
Complete instructions for sample collection, processing, handling and shipment to the central 
laboratory will be provided in the Laboratory Manual.  
These analyses will be exploratory and will not be part of the CSR. 
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8.4.4.  Optional tumor biopsy 
If the subject consents, optional fresh tumor samples may be collected at the time of progression in 
subjects with accessible lesions. Accessible lesions are defined as tumor lesions which are easily 
biopsied with minimum risk to the subject. Lesions with the greatest change in dimensional size are 
the recommended lesions to be excised at the time of PD. Whenever possible, biopsies at 
progression should be performed within 3 days of study drug discontinuation (during the Main study 
or Study extension periods). The tissue from these biopsies will be used to determine possible 
mechanisms of resistance. Subjects will be asked (in a specific section of the main ICF) if they 
agree to provide this tumor sample.  
All blood biomarker analysis will be exploratory and will not be part of the CSR. 
 
Table 25: Biomarker samples_Main study period 
 
(a) 
 
Optional tumor sample will be requested only for subjects that discontinue study due to disease progression. 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle/Period
Visit
Screening
C1        
D8
C1         
D15
C1         
D22
Cn         
D1
Cn         
D8
Cn        
D15
Cn        
D22
End of 
treatment 
Safety Follow-
Up
q (EOS)
Survival
(Every x Months)
Cycle Days
D-28 to D-1
D8
D15
D22
D1
D8
D15
D22
Dxx
Dxx
Dxx
Epochs
FOLLOW-UP
LONG-TERM 
FOLLOW-UP
Pre-Dose
Post-Dose
Procedures
Blood sample for tumor markers (CEA, 
CA19-9)
X
X
X
X
A tumour sample (archival or fresh) 
should be send to central laboratory to 
test   for BRAFV600E and RASwt status 
and MSI testing
X
Blood samples for ctDNA analysis (i.e. 
BRAFV600)
X
Blood sample for MSI testing (control)
X
Tumor biopsy (optional) 
X
a
Subsequent Cycles
Cycle 1
C1
D1
D1
SCREENING 
TREATMENT 
± 3-day window for procedures/assessments
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Table 26: Biomarker samples_Study extension period 
Cycle/Period 
Subsequent Cycles during study 
extensiona,b 
  
  
  
Visit 
CnD1 
CnD15 
End of treatment  
Safety Follow-Up  
(EOS)m 
Survival 
(Every 3 Months) 
Cycle Days 
D1 
D15 
Dxx 
Dxx 
Dxx 
Epochs 
TREATMENT 
FOLLOW-UP 
LONG-TERM 
FOLLOW-UP 
Procedures 
  
Blood sample for tumor 
markers (CEA, CA19-9)a 
X 
  
X 
  
  
Tumor biopsy (optional) b 
  
  
X 
  
  
 
(a) 
(b) 
Blood sample for tumor markers (CEA, CA19-9) should be collected only if performed as per routine clinical practice 
Optional tumor sample will be requested only for subjects who discontinue study due to disease progression. 
 
 
 
8.4.5.  Retention of Samples for Future Analysis 
If the subject agrees, and in accordance with local laws, any tumor (archival or fresh), blood and 
plasma samples remaining after determination of BRAFV600E status may be stored for up to 10 years 
after the final CSR of the study is released. The samples may be further analyzed to address 
scientific questions and/or development of biological tests related to administration of encorafenib 
+ cetuximab + binimetinib and/or cancer. The decision to perform such exploratory biomarker 
research studies would be based on outcome data from this study or from new scientific findings 
related to the drug class or disease, as well as reagent and assay availability.  
The Sponsor will be the exclusive owner of any data and discoveries resulting from this study. 
 
 
 
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8.5. CONCOMITANT THERAPY AND THERAPEUTIC / DIAGNOSTIC 
PROCEDURE ASSESSMENT 
Concomitant therapies and therapeutic / diagnostic procedures will be evaluated at each cycle at 
D1, D8, D15, D22 and starting Cycle 8, at D1 and D15 and at EOT/30-day Safety Follow Up (Main 
study period). 
Since implementation of the Urgent Safety Measure on 26 Mar 2020, in order to ensure the subjects’ 
safety in the clinical trial by decreasing the number of clinic visits in the context of COVID-19 
pandemic, Cetuximab infusions can be given every two weeks at the dose of 500 mg/m2 
administered as a 120-min IV infusion (i.e. on D1 and D15 of each cycle) regardless of the cycle 
number, after the investigator has evaluated the benefit/risk ratio for the subject with regards to 
Covid-19 pandemic.  
For the subjects moving to this every two weeks regimen before C8D1, concomitant therapies and 
therapeutic / diagnostic procedures will be evaluated at each cycle at D1 and D15 and at EOT/30-
day Safety Follow Up.  
During the Study extension period, concomitant therapies and therapeutic / diagnostic procedures 
will be evaluated at each cycle at D1 and D15 and at EOT/30-day Safety Follow Up. 
Requirements relating to subject’s concomitant therapies and therapeutic / diagnostic procedures 
before entry or throughout the trial can be found in Section 7.  
8.6. QUALITY OF LIFE ASSESSMENT  
Patient reported outcome (PRO) assessments will be collected during Main study period using the 
QoL questionnaires EORTC QLQ-C30 ,EQ-5D-5L and Patient Global Impression of Change 
(PGIC) at the time points specified in Study Flow Chart (Main study period Flow Chart). 
These questionnaires will be used to explore PRO measures of health-related QoL, functioning, 
cancer symptoms, and treatment-related side effects. 
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The QLQ-C30 EQ-5D-5L and PGIC are recognized reliable and valid measures in the treatment of 
cancer subjects.  
The questionnaires should be administered to subjects in the subjects’ local language at the 
beginning of the study visit prior to receiving any study treatment, prior to any other study 
assessment or consultation with the Investigator, and prior to being informed of their current disease 
status.  
Attempts should be made to collect all questionnaires for all subjects, including those who 
discontinue prior to the EOT visit. However, if the subject refuses to complete the questionnaires, 
this should be documented in study source records. Subject refusal to complete study questionnaires 
is not a protocol deviation. 
Subjects should be given sufficient space and time to complete all study questionnaires, and all 
administered questionnaires should be reviewed for completeness. If missing responses are noted, 
subjects should be encouraged to complete any missing responses. 
Completed questionnaires, including both responses to the questions and any unsolicited comments 
written by the subject, should be reviewed by the Investigator or designee to ensure every question 
has been answered and that there is only one response for each question. If omissions or double 
responses occur, they should be brought to the attention of the subject. Investigators must not 
encourage the subject to change responses reported in questionnaires.  
In addition, the completed questionnaires should be reviewed and assessed by the Investigator for 
responses which may indicate potential AEs or SAEs. This review should be documented in study 
source records.  
8.7. HEALTHCARE RESOURCE UTILIZATION 
Hospitalization data of interest will focus on those hospitalizations reported as Serious Adverse 
Events as required in Section 10.2.1 
Healthcare resource utilization data regarding hospitalizations should be captured continuously 
through-out the Main study period treatment phase starting on the date of first study treatment 
administration until 30 days after the last administration dose, as described in the Study Flow Chart 
(during the Main study period only).  
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Information related to the length of stay, hospital facilities used, reasons for hospitalization, and 
hospital discharge information will be evaluated. 
 
 
8.8. COMPLIANCE 
The subject will be reminded regularly to bring back to the site at each study visit any remaining 
encorafenib and binimetinib blisters and boxes (used or unused). 
Compliance will be evaluated at each cycle on Day 1 and at EOT by reviewing subject diary entries, 
accounting of returned study drug and subject interviews (Main study and Study extension periods). 
Cetuximab will be administered intravenously per protocol in the clinic by study personnel. 
Information regarding individual study drug infusions is to be documented as described in Section 
6.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. STUDY PROCEDURES 
Details of schedule, technical procedures and parameters per assessment/exam are described in 
Section 8. 
Starting Cycle 1 Day 1 and during the whole treatment period, (during the Main study and the Study 
extension periods), all procedures/assessments should take place in a + 3 day-window from the 
corresponding visit, unless otherwise specified. 
Except C1D1, the visit can be missed. Theoretical cycles dates (7 days ± 3) are kept constant 
irrespectively of whether the visit is done and/or the product is administered or not. If subject 
doesn´t come for CnD1 visit, the CnD1 assessments will still need to be performed (and shall be 
recorded on the unscheduled visit in the e-CRF). 
Study procedures section is divided in 2 main sub-sections:  
-1 for the study visits and procedures during the Main Study period (until 27 Dec 2020) 
-1 for the study visits and procedures during the Study extenstion period (from 28 Dec 2020)  
9.1. MAIN STUDY PERIOD (FROM FIRST SUBJECT SCREENED TO 27 
DEC 2020) 
 
9.1.1. VISIT 1 – Screening visit (Day -28 to -1 prior to Cycle 1 Day 1)_ Main 
study period 
The subject considered eligible for screening by the Investigator will be informed of the 
characteristics and the consequences of the trial both verbally and by reviewing the subject's 
information sheet and ICF (see Section 14.3). If he/she accepts to participate in the study, he/she 
will sign the informed consent and will keep a copy. 
All screening procedures to determine eligibility must be performed within specific time windows 
prior to the first dose of protocol treatment. 
The subject will be assessed for the following: 
• Demographic characteristics (gender, age, race, ethnicity) 
• Medical history 
• Prior medications/therapies/procedures   
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• Physical examination (incl. height, weight) 
• Vital signs 
• ECOG PS  
• Concomitant medications/therapies (authorized, disallowed) 
• Twelve-lead single ECG (after 5-min rest in supine position) 
• Full ophthalmic examination 
• Dermatologic examination 
• ECHO/MUGA  
• Serum pregnancy test (for females of childbearing potential only) 
• LH, FSH and/or estradiol measurements (for females who are post-menopausal) 
• Hepatitis B surface antigen, hepatitis C antibody 
• HIV (if required) 
• Hematology  
• Clinical chemistry 
• Coagulation 
• Urinalysis 
• Blood sample for CRP 
• Blood sample for tumor markers (CEA, CA19-9) 
• A tumor sample (archival or fresh) should be sent to central laboratory to test for BRAFV600E 
and RASwt status and for MSI testing 
• Tumor assessments (CT scan, MRI) as defined by RECIST 
• The Investigator will inform the Sponsor of the screening using IRT. 
 
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9.1.2. Cycle 1 - Day 1 _ Main studyperiod 
If the subject still fulfills the eligibility criteria during the screening period and/or the results of 
additional examinations, the Investigator will dispense to the Subject the box number indicated by 
the IRT. Eligibility is determined using results of screening assessments performed before the first 
dose of study treatment and up to and including Cycle 1 Day 1. 
If the following study procedures were not performed within 72 hours before Day 1, they must be 
repeated on Cycle 1 Day 1 (i.e., first day of dosing): 
• Physical examination, including measurement of body weight 
• Dermatologic examination 
• Obtain blood samples for hematology, coagulation, clinical chemistry  
• Obtain blood samples for tumor markers (CEA and CA19-9)  
• Obtain urine sample for urinalysis and for pregnancy test for females of childbearing 
potential  
• Assess ECOG PS  
 
All of the following study procedures are to be performed on Cycle 1 Day 1: 
• Visual assessment by investigator: general inspection of the eyes, examination of motility 
and alignment, visual disturbance including diminished central vision, blurred vision or loss 
of vision  
• QOL questionnaires (EORTC QLQ-C30, EQ-5D-5L, PGIC)  
• Assess vital signs (blood pressure, pulse, temperature and respiratory rate)  
• Calculate BSA predose 
• Obtain 3 serial, resting and supine 12-lead ECGs conducted within approximately 5 to 
10 minutes total time and prior to the first dose, followed by a single ECG 2.0 (+/- 0.5) 
hours following administration of encorafenib + binimetinib and before the start of the 
cetuximab infusion. ECGs should be performed prior to the 2-hour post-dose PK blood 
collection. 
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• Verify inclusion/exclusion criteria 
• Collect blood samples for: 
− MSI germline control 
− ctDNA for BRAF testing  
− PK plasma level determination of encorafenib, binimetinib and AR00426032: 2h (± 10 min) 
and 6 hours (± 30 min) after administration of encorafenib and binimetinib. 
− PK serum level determination of cetuximab: 2h (± 10 min) and 6 hours (± 30 min) after the 
start of cetuximab infusion 
 
• Administer dose of encorafenib and binimetinib with water  
• Administer cetuximab premedication according to SPC (antihistaminic and corticosteroïd 
pretreatment are mandatory for the the first infusion) 
• Administer cetuximab as an IV infusion  
• Document prior (pre-dose) and concomitant medications/therapies 
• Assess AEs 
• Dispense the treatment number using IRT 
• Dispense a 4-week supply of encorafenib and binimetinib along with a monthly dosing 
diary. Review dosing instructions with the subject.  
 
9.1.3. Cycle 1 - Day 8 _ Main study period 
The subject will be assessed for the following: 
• Physical examination if clinically indicated 
•  Visual assessment by investigator if clinically indicated (in case of any abnormalities a full 
ophthalmic examination must be performed by an ophthalmologist) 
• Assess vital signs (blood pressure, pulse, temperature and respiratory rate)  
• Administer cetuximab premedication according to institutional standards  
• Administer cetuximab as an IV infusion  
• Review concomitant medications/therapies 
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• Assess AEs since previous visit  
• Obtain information on Healthcare Resource Utilization in case of hospitalization  since 
previous visit (see Section 8.7) 
9.1.4. Cycle 1 - Day 15 _ Main study period 
• Physical examination if clinically indicated  
•  Visual assessment by investigator if clinically indicated (in case of any abnormalities a full 
ophthalmic examination must be performed by an ophthalmologist) 
• Assess vital signs (blood pressure, pulse temperature and respiratory rate) 
• Obtain blood samples for hematology and clinical chemistry  
• Obtain single ECG (predose)  
• Administer cetuximab premedication according to institutional standards  
• Administer cetuximab as an IV infusion  
• Review concomitant medications/therapies 
• Assess AEs since previous visit  
• Obtain information on Healthcare Resource Utilization in case of hospitalization since 
previous visit (see Section 8.7) 
9.1.5. Cycle 1 - Day 22 _ Main study period 
• Physical examination if clinically indicated 
• Visual assessment by investigator if clinically indicated (in case of any abnormalities a full 
ophthalmic examination must be performed by an ophthalmologist) 
• Assess vital signs (blood pressure, pulse  temperature, and respiratory rate)  
• Obtain a blood sample for hematology  
• Administer cetuximab premedication according to institutional standards  
• Administer cetuximab as an IV infusion  
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• Review concomitant medications/therapies 
• Assess AEs since previous visit  
• Obtain information on Healthcare Resource Utilization in case of hospitalization  since 
previous visit (see section 8.7) 
9.1.6. Subsequent Cycles _ Main study period 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of disease) 
are to be performed every 6 weeks (±7 days) from the first dose for the first 12 weeks, then every 8 
weeks (±7 days) thereafter until disease progression, subject decision, withdrawal of consent, 
initiation of subsequent anticancer therapy, subject is lost to follow-up, or death, regardless of 
whether study treatment is discontinued.  
The time-window allowed for the first tumor assessment (i.e. day 42 from first dose) is +7 days. 
Information on Healthcare Resource Utilization will be obtain in case of hospitalization and during 
the whole treatment period until 30 days after the last administration of study treatment. (see Section 
8.7) 
 
9.1.7. Subsequent Cycles Day 1 _ Main study period 
• QOL questionnaires (EORTC QLQ-C30, EQ-5D-5L, PGIC) 
• Weight  
• Calculate BSA  
• Physical examination  
• Assess vital signs (blood pressure, pulse temperature, and respiratory rate)  
• Assess ECOG PS 
• Single ECG are to be performed pre-dose at D1 of each subsequent cycle. At Cycle 2 only: 
obtain a single ECG predose and 2.0 hours (+/- 0.5 hour) after administration of encorafenib 
+ binimetinib and before the start of the cetuximab infusion. ECGs should be performed 
prior to the 2-hour post-dose PK blood collection. 
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• Visual assessment by investigator (in case of any abnormalities a full ophthalmic 
examination must be performed by an ophthalmologist)  
• Dermatologic examination every 8 weeks from Cycle 1 Day 1 (i.e., Day 1 of Cycles 3, 5, 7, 
etc.)  
• ECHO/MUGA scans Cycle 2 Day 1 and Cycle 5 Day 1, then every 12 weeks  
• Collection of blood samples for:  
− PK: Cycle 2 only:  
. Plasma level determination of encorafenib, binimetinib and AR00426032: predose (just 
prior to encorafenib/binimetinib dose) and 2 hours (± 10 min) following administration 
of encorafenib and/or binimetinib 
. Serum level determination of cetuximab: predose (just prior to cetuximab infusion) and 
2 hours (± 10 min) after the start of cetuximab infusion 
 
− Hematology, coagulation and clinical chemistry  
− Tumor markers (CEA and CA19-9) 
 
• Obtain a urine sample for urinalysis and urine pregnancy testing for women of childbearing 
potential 
• Administer dose of encorafenib and binimetinib with water  
• Administer cetuximab premedication according to institutional standards  
• Administer cetuximab as an IV infusion  
• Assess compliance of encorafenib and/or binimetinib dosing and use of dosing diary.  
• Review concomitant medications/therapies 
• Assess AEs since previous visit 
• Dispense a 4-week supply of encorafenib and binimetinib along with a monthly dosing 
diary. Review dosing instructions with the subject.  
9.1.8. Subsequent Cycles - Day 8, Day 15 and Day 22 _ Main study period 
• Physical examination if clinically indicated 
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• Visual assessment by investigator if clinically indicated (in case of any abnormalities a full 
ophthalmic examination must be performed by an ophthalmologist) 
• Assess vital signs (blood pressure, pulse, temperature, and respiratory rate). Vitals signs do 
not need to be done at D8 and 22 starting week 29 (when the Q2W schedule is in place) 
• Administer cetuximab premedication according to institutional standards 
• Administer cetuximab as an IV infusion 
• Review concomitant medications/therapies 
• Assess AEs since previous visit 
From week 29 the D8 and D22 visits will not be performed (biweekly infusion of cetuximab: no 
cetuximab infusion on D8 and D22).  
Since implementation of the Urgent Safety Measure on 26 Mar 2020, if the investigator implements 
this change, each D8 and D22 visit (before C8D1) for subjects having not yet reached C8D1 at the 
time of USM implementation will be performed by phone calls and will have to be documented in 
source documents to ensure subject’s safety.  
 
 
9.1.9. End-of-Treatment Visit _ Main study period 
At the time of study treatment discontinuation, the EOT visit should be completed for all subjects 
as soon as possible after the last dose of study drug, and every effort should be made to perform the 
procedures listed below. This visit should take place as soon as possible and ≤ 14 days after the last 
dose of study treatment. An e-CRF should be completed, giving the date and reason for stopping 
the study treatment. All subjects will enter the follow-up period  
If a subject withdrawal occurs or if the subject fails to return for visits, the Investigator must 
determine the primary reason for a subject’s discontinuation from the study and record this 
information on the relevant page of the e-CRF. 
Subjects will be assessed for the following: 
• QOL questionnaires (EORTC QLQ-C30, EQ-5D-5L, PGIC)  
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• Physical examination including weight    
• Full ophthalmic examination 
• Vital signs (blood pressure, pulse, temperature and respiratory rate)  
• ECOG PS 
• Single ECG  
• Dermatologic examination  
• ECHO/MUGA 
• Serum pregnancy test (for females of childbearing potential only) 
• Collection of blood samples for: 
− Hematology, coagulation and clinical chemistry 
− Tumor markers (CEA and CA19-9) 
 
• Obtain a urine sample for urinalysis 
• Optional tumor biopsy sample (only if discontinuation due to disease progression) 
• Assess compliance of encorafenib and/or binimetinib dosing and use of the dosing diary. 
Collect all remaining bottles of study drugs. 
• Review concomitant medications/therapies 
• Assess AEs since previous visit 
• Obtain information on Healthcare Resource Utilization in case of hospitalization  since 
previous visit (see Section 8.7) 
9.1.10. Safety Follow-up Visit and Survival Visits _ Main study period 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of disease) 
should continue to be performed every 6 weeks (±7 days) for the first 12 weeks, then every 8 weeks 
(±7 days) thereafter until disease progression, initiation of subsequent anticancer therapy, subject is 
lost to follow-up, subject decision, withdrawal of consent or death. 
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When clinically appropriate, it is recommended that subjects be monitored with physical 
examinations, dermatological examinations and CT scans for cutaneous and non‑cutaneous 
secondary malignancies for up to 6 months after the last encorafenib dose or until initiation of 
another antineoplastic therapy.  
9.1.10.1. Safety 30 Day-Follow-up Visit _ Main study period 
All subjects will return for a Safety Follow-up visit approximately 30 days after the last dose of 
study drug, or prior to the initiation of subsequent anticancer therapy, whichever occurs first.  
Information related to AEs (including concomitant medication taken for ongoing AEs) and ongoing 
antineoplastic treatments will be collected for 30 days after the last dose of study drug.  
The following study procedures will be performed, completed or reported: 
• QOL questionnaires (EORTC QLQ-C30, EQ-5D-5L, PGIC)  
• Physical examination including weight  
• Vital signs (blood pressure, pulse, temperature and respiratory rate)  
• ECOG PS 
• Single ECG  
• Visual assessment by investigator (full ophthalmic examination by an ophthalmologist only 
in case of ocular clinical event at the EOT visit) 
• Urine pregnancy test 
• Hematology, coagulation and clinical chemistry 
• Urinalysis 
• Survival Status 
• Documentation of subsequent anticancer therapy 
• Obtain information on Healthcare Resource Utilization in case of hospitalization  since 
previous visit (see Section 8.7) 
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9.1.10.2. Survival Visit (every 3 months) _ Main study period 
The Survival follow-up period will start after the completed 30 days safety follow up, until the End 
of Study.  
If a subject discontinues the treatment for a reason other than progressive disease, tumor assessment 
must be performed (as per local and central review) until the start of a new anti-cancer therapy, 
disease progression, death, lost to follow-up, subject decision or withdrawal of consent. Subjects 
who discontinue the treatment will be contacted by phone every 3 months (or more frequently as 
needed) for collection of information during the survival follow-up period: 
• Survival status 
• Documentation of subsequent anticancer therapy 
• Documentation of the date of progressive disease following the initiation of subsequent 
anticancer therapies 
 
9.2. STUDY EXTENSION PERIOD (FROM 28 DEC 2020) 
 
9.2.1. Subsequent Cycles_Study extension period 
Written information and consent form addendum related to Study extension period must be 
submitted to the subject with an oral explanation. It must be agreed and signed by the subject before 
any Study extension-related procedure starts. 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of disease) 
are to be performed every 12 weeks (±7 days) until disease progression, subject decision, 
withdrawal of consent, initiation of subsequent anticancer therapy, subject is lost to follow-up, or 
death, regardless of whether study treatment is discontinued.  
 
 
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9.2.2. Subsequent Cycles Day 1 _ Study extension period 
 
• Weight  
• Calculate BSA  
• Physical examination  
• Assess vital signs (blood pressure, pulse, temperature, and respiratory rate)  
• Assess ECOG PS 
• ECGs scans must be performed every 3 cycles at D1 D1 or more frequently if clinically 
indicated 
• Visual assessment by investigator (in case of any abnormalities a full ophthalmic examination 
must be performed by an ophthalmologist)  
• Dermatologic examination every 8 weeks   
• ECHO/MUGA scans every 12 weeks or more frequently if clinically indicated 
• Collection of blood samples for:  
o Hematology and clinical chemistry  
o Tumor markers (CEA and CA19-9) – only if as per routine clinical practice  
• Obtain a urine sample for urinalysis and urine pregnancy testing for women of childbearing 
potential 
• Administer dose of encorafenib and binimetinib with water  
• Administer cetuximab premedication according to institutional standards  
• Administer cetuximab as an IV infusion  
• Assess compliance of encorafenib and/or binimetinib dosing and use of dosing diary.  
• Review concomitant medications/therapies 
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• Assess AEs since previous visit 
• 
Dispense a 4-week supply of encorafenib and binimetinib along with a monthly dosing diary. 
Review dosing instructions with the subject.  
9.2.3.  Subsequent Cycles - Day 15 _ Study extension period 
• Physical examination if clinically indicated 
• Visual assessment by investigator if clinically indicated (in case of any abnormalities a full 
ophthalmic examination must be performed by an ophthalmologist) 
• Assess vital signs (blood pressure, pulse, temperature, and respiratory rate). 
• Administer cetuximab premedication according to institutional standards 
• Administer cetuximab as an IV infusion 
• Review concomitant medications/therapies 
• Assess AEs since previous visit 
9.2.4.  End-of-Treatment Visit _ Study extension period 
At the time of study treatment discontinuation, the EOT visit should be completed for all subjects 
as soon as possible after the last dose of study drug, and every effort should be made to perform the 
procedures listed below. This visit should take place as soon as possible and ≤ 14 days after the last 
dose of study treatment. The e-CRF should be completed, giving the date and reason for stopping 
the study treatment. The e-CRF should be completed, giving the date and reason for stopping the 
study treatment. All subjects will then enter the follow-up period until the End of Study. 
If a subject withdrawal occurs or if the subject fails to return for visits, the Investigator must 
determine the primary reason for a subject’s discontinuation from the study and record this 
information on the relevant page of the e-CRF. 
Subjects will be assessed for the following: 
• Physical examination including weight    
• Full ophthalmic examination 
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• Vital signs (blood pressure, pulse, temperature and respiratory rate)  
• ECOG PS 
• Single ECG  
• Dermatologic examination  
• ECHO/MUGA 
• Serum pregnancy test (for females of childbearing potential only) 
• Collection of blood samples for: 
o Hematology and clinical chemistry 
o Tumor markers (CEA and CA19-9) if as per routine clinical practice  
• Obtain a urine sample for urinalysis 
• Optional tumor biopsy sample (only if discontinuation due to disease progression) 
• Assess compliance of encorafenib and/or binimetinib dosing and use of the dosing diary. Collect 
all remaining bottles of study drugs. 
• Review concomitant medications/therapies 
• Assess AEs since previous visit 
9.2.5.   Safety Follow-up Visit and Survival Visits _ Study extension period 
Tumor assessments (i.e., appropriate radiological scans to document all suspected sites of disease) 
should continue to be performed every 12 weeks (±7 days) thereafter until disease progression, 
initiation of subsequent anticancer therapy, subject is lost to follow-up, subject decision, withdrawal 
of consent or death. 
When clinically appropriate, it is recommended that subjects be monitored for physical 
examinations, dermatological examinations and CT scans for cutaneous and non‑cutaneous 
secondary malignancies for up to 6 months after the last encorafenib dose or until initiation of 
another antineoplastic therapy.  
9.2.5.1. Safety 30 Day-Follow-up Visit _ Study extension period 
 
All subjects will return for a Safety Follow-up visit approximately 30 days after the last dose of 
study drug, or prior to the initiation of subsequent anticancer therapy, whichever occurs first.  
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Information related to AEs (including concomitant medication taken for ongoing AEs) and ongoing 
antineoplastic treatments will be collected for 30 days after the last dose of study drug.  
 
The following study procedures will be performed, completed or reported: 
• Physical examination including weight  
• Vital signs (blood pressure, pulse, temperature and respiratory rate)  
• ECOG PS 
• Single ECG  
• Visual assessment by investigator (full ophthalmic examination by an ophthalmologist only in 
case of ocular clinical event at the EOT visit) 
• Urine pregnancy test 
• Hematology and clinical chemistry 
• Urinalysis 
• Survival Status 
• Documentation of subsequent anticancer therapy 
9.2.5.2. Survival Visit (every 3 months) _ Study extension period 
 
The Survival follow-up period will start after completion of the 30 days safety follow up visit, and 
all subjects will be followed until the End of the study, i.e. until the last subject will have either 
progressed or discontinued study treatments (including 30-day Safety Follow-Up visit) for any other 
reason (unacceptable toxicity, subject’s decision, withdrawal of consent, initiation of subsequent 
anticancer therapy or death). 
If a subject discontinues the treatment for a reason other than progressive disease, tumor assessment 
must be performed (as per local review) until the start of a new anti-cancer therapy, disease 
progression, death, lost to follow-up, subject decision or withdrawal of consent. Subjects who 
discontinue the treatment will be contacted by phone every 3 months (or more frequently as needed) 
for collection of information during the survival follow-up period: 
• Survival status 
• Documentation of subsequent anticancer therapy 
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• Documentation of the date of progressive disease following the initiation of subsequent 
anticancer therapies 
 
 
 
 
 
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10. ADVERSE EVENTS: DEFINITION, NOTIFICATION AND 
REPORTING 
10.1. ADVERSE EVENTS 
10.1.1. Definition 
An AE is any untoward medical occurrence, including the exacerbation of a pre-existing condition, 
in a patient or clinical investigation subject administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product (ICH-Guideline for GCP). 
Any new or worsening adverse event that is assessed by the investigator as related to the disease 
progression must be reported as an AE. 
The relationship to disease progression must be captured as specified in e-CRF. 
If the AE meets the seriousness definition and thus becomes SAE, it should be notified to the 
Sponsor Pharmacovigilance Department by the investigator as soon as he/she is informed of the 
event and no later than 24 hours after knowledge. 
Note:  Disease progression documented solely by medical imaging techniques with no new or 
worsening symptoms will not require to be reported as an AE nor notified as SAE to the Sponsor 
Pharmacovigilance Department but documented as progression of disease in the tumor assessments 
(RECIST) e-CRF forms. 
All laboratory tests, vital signs, ECGs collected after study treatment initiation for which abnormal 
results meet the criteria for AE  are collected after study treatment initiation should be repeated until 
the values return to normal or to a stable status and recorded into the e-CRF.  
The frequency with which such checks should be made will be defined by the investigator according 
to the degree of abnormality.  
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For any of the following reasons, an abnormal result should be considered as clinically significant 
and reported as an AE. : 
- 
A symptomatic value. 
- 
A value or a change that requires active management (e.g., study treatment dose modification, 
discontinuation of study treatment, more frequent follow-up assessments, corrective 
treatment …). 
- 
Any value judged by the investigator as clinically significant. 
Laboratory abnormalities that meet the criteria for AEs should be followed until they have returned 
to normal or baseline, or per Investigator discretion. 
10.1.2. Severity of Adverse Events 
The severity rating of an AE refers to its intensity. The severity of each AE will be determined by 
the Investigator using the NCI-CTCAE, v4.03. For any term that is not specifically listed in the 
CTCAE scale, intensity should be assigned a Grade of 1 through 5 using the following CTCAE 
guidelines: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Fatal 
To avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, 
the following note of clarification is provided:  
- 
- “Severe” is used to describe the intensity of a specific AE, which may be of relatively minor 
medical significance. 
- 
- “Seriousness” is based on the regulatory definition supplied below (see Section 10.2.1) 
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10.2. SERIOUS ADVERSE EVENTS 
10.2.1. Definition  
A serious adverse event (SAE) includes but is not necessarily restricted to any event which: 
- 
results in death (whatever may be the cause) 
Death is an outcome of an SAE and not an SAE in itself. Death should only be reported as an SAE 
term when no additional information is known about a fatal event. When death is an outcome, the 
event(s) resulting in death should be reported (e.g., “pulmonary embolism” with a fatal outcome) 
and assigned severity Grade 5. 
- 
is life-threatening  
- 
results in persistent or significant disability/incapacity 
- 
requires the subject’s in-patient hospitalisation or prolongation of current hospitalisation* 
- 
is a congenital anomaly or birth defect  
- 
is serious for other reason: medical and scientific judgment should be exercised in other 
situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardize the patient or may require intervention to 
prevent one of the outcomes described in the definition above. These should also usually be 
considered serious.  
In addition, for all subjects with COVID-19 (with critical symptoms and/or hospitalization), a 
Serious Adverse Event should be declared.  
*Note that any hospitalisation, or prolongation of hospitalisation due to the circumstances listed 
below will not be notified as an SAE to the Sponsor by the Investigator: 
- 
a visit to the emergency room, or outpatient observation that does not result in admission,  
- 
 preparation for routine health assessment/procedure (e.g. routine colonoscopy), 
- 
planned medical/surgical admission (planned prior to entry into study trial, appropriate 
documentation required), 
- 
administrative or social reasons (e.g. lack of housing, economic inadequacy, care-giver respite, 
family circumstances). 
 
 
 
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10.2.2. Reporting of Serious and non-serious AEs  
All AEs, serious and non-serious and regardless of causality to study drug (including the 
exacerbation of a pre-existing condition), will be fully recorded on the appropriate e-CRF. For each 
AE, the Investigator must provide its duration (start and end dates or ongoing), severity (intensity), 
assessment of causality and seriousness and whether corrective action or therapy was required and 
whether action was taken with regard to study drug treatment. 
Any AE that occurs after the signing of the ICF should be recorded on the AE e-CRF page regardless 
the relationship with the study procedure. All AEs occurring from the first dose of study drug 
including the 30 days after the last dose of study (30-day follow-up period) drug must be recorded 
on the AE e-CRF regardless of the relationship with the study drug. 
If an AE occurs more than once in the same subject during the study, each occurrence must be 
recorded as a separate AE. 
Any SAE occuring from the signing of the ICF should be reported as an SAE regardless of the 
relationship with the protocol procedure or with study drug.  
The investigator must notify the sponsor of this event by sending within 24 hours the "SAE Form”, 
with all the available information about the event, to the sponsor's Corporate Vigilances e-mail 
dedicated box : 
HQ.pharmacovigilance@pierre-fabre.com 
In case it is not possible to send the report by e-mail it can be sent by fax to:  
+ 33 1 49 10 80 90 
In addition, all SAEs must be recorded into the e-CRF. 
Study disease progression (including malignant disease progression with fatal outcome), if 
documented by the use of appropriate method (as per protocol) will be reported as progression of 
study disease in the e-CRF (study end-point) and should NOT be reported as an SAE unless a causal 
relationship to study treatment is suspected. 
 
 
 
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10.2.3. Follow-up of SAEs 
The Investigator will provide follow-up information regarding a reported SAE using the SAE form 
providing the results of relevant examinations, laboratory and diagnosic tests, and hospitalisation 
records as needed. 
Investigators must follow subjects with AEs/SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, subject is lost to follow-up or death OR until 30 days after the 
last dose of study drug, whichever occurs first. Ongoing treatment-related AEs/SAEs may be 
followed beyond the 30-day follow-up period if clinically indicated. 
10.2.4. SAEs occurring after the 30-day safety follow-up period 
After the 30 day follow-up period, any SAEs that are considered related to any study drug or 
protocol procedures will be captured in the e-CRF and reported to the Sponsor using the SAE form. 
10.3. REPORTING OF STUDY TREATMENT OVERDOSE TO THE 
SPONSOR 
An overdose of study drug (whether symptomatic or asymptomatic) is to be reported as an AE in 
the e-CRF. 
For the purpose of this trial, an overdose will be defined as any study drug dose administration 
exceeding the subject’s assigned dose of study drug (s) as per protocol recommendations. 
In the absence of associated AE seriousness criteria, the overdose and associated non-serious AE, 
are reported only on the AE page of the e-CRF. If the definition of seriousness criteria is met for 
any associated AE, the SAE form must be also completed and transmitted to the Sponsor. 
 
 
 
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10.4. REPORTING OF PREGNANCY TO THE SPONSOR 
Pregnancy occurring during the period between signing of the ICF but before any study treatment 
exposure is not to be reported to the Sponsor unless associated to an AE.  
If pregnancy is suspected while the female subject is receiving study treatment, the study 
treatment(s) should be discontinued immediately until the result of the pregnancy testing is known. 
If pregnancy is confirmed, administration of study drug is to be discontinued immediately and the 
subject must be withdrawn from the study.  
The Investigators must report to the Sponsor any on-treatment pregnancy of a female subject or a 
female partner of a male subject which occurs during study treatment and within the 30 days after 
the last dose administration of binimetinib or encorafenib and within the 6 months after the last dose 
administration of cetuximab.  
On-treatment pregnancy (of female subject and female partner of male subject) must be reported to 
the Sponsor within 24 hours of the Investigator’s knowledge using the investigational product 
pregnancy form.  
Any pregnancy will be followed through to outcome, and the outcome must be reported to the 
Sponsor, including the infant’s health status, using the pregnancy outcome report form. 
10.5. SPONSOR'S RESPONSIBILITIES FOR SAFETY REGULATORY 
REPORTING PURPOSES 
The Sponsor and/or designee will submit expedited and periodic reports to both Competent 
Authorities and Ethics Committees as regards to the Directive 2001/20/EC EU regulations or as per 
local specific regulatory requirements in participating countries. 
 
 
 
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11. DATA COLLECTION AND STUDY MONITORING 
11.1. DATA COLLECTION 
11.1.1. Case Report Forms   
An e-CRF will be provided by the CRO. It will contain fields for all the data required to be obtained 
based on the protocol, except any computerized data which will be directly transferred to the 
database. 
The Investigator is responsible for ensuring that all required data are properly recorded in each 
subject’s e-CRF and related documents. Prior to the start of the study, the Investigator will complete 
a delegation form. The signature and initials of all persons in charge of e-CRF completion should 
be recorded on this form. 
The e-CRFs are to be completed in a timely manner and preferably within 3 days of the study visit, 
allowing extraction of appropriate e-CRF data available for Sponsor review. All the information 
will be recorded from source documents into the e-CRF by an authorized person. 
All answer fields in the e-CRF pages must be filled in for all visits, otherwise an explanation should 
be given.  
The completed e-CRF, including any paper SAE/pregnancy/pregnancy outcome forms, must be 
promptly reviewed, signed and dated by a qualified person, who is an Investigator.  
Each subject who will have received the study treatment must be entered into the e-CRF.  
For all other subjects having signed an ICF, the subject's summary page of the e-CRF, along with 
all applicable information documenting the screen failure/discontinuation reason must be 
completed. 
The Investigator is responsible for the management, completeness and accuracy of the information 
in the e-CRF. The CRAs will be trained about the e-CRF and have access to the e-CRF module for 
monitoring purposes. 
A copy of the e-CRF with all related documentation will be stored by the Sponsor at the end of the 
study. Another copy of the e-CRF data will be stored by the Investigator for at least 25 years or 
according to the local requirements. 
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11.1.2. Source Documents 
A source document is an original record or certified copy of an original record of clinical findings, 
observations or any other medical or paramedical activities performed during the clinical trial, 
necessary for the transcription and the verification of the collected data. 
Source documents along with all other trial-related documents (copies of all ICFs, e-CRFs, 
treatment inventories and any correspondence related to the study) must be kept in the Investigator's 
file throughout the study, and then must be stored in the study center's archives for a period of at 
least 25 years or as per local legal requirements.  
For further details see Section 15.2 
11.2. STUDY MONITORING 
11.2.1. Monitoring visits 
On-site visits will be carried out by a representative of the Sponsor's staff (Study Manager or CRA) 
prior to study initiation and at regular intervals to closely monitor the study throughout its duration. 
Additional visits and communication by telephone, mail, email, fax or meeting may be performed 
if necessary. Any site visit performed by the Sponsor's representatives will be recorded in the 
Investigator's site file. 
11.2.1.1. Site Preselection Visit 
Before selecting a center for the study, a visit will be carried out by the CRA and/or the Study 
Manager to ensure that the Investigator has the necessary capacities (availability subject, 
recruitment, environment), technical means and staff to carry out the study. 
 
 
 
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11.2.1.2. Initiation Visit 
Before the start of the study at all investigational sites, an initiation visit will be carried out by the 
CRA to check at a minimum that: 
• The Investigator: 
− has received the technical protocol, administrative and financial agreement signed by all 
parties 
− has received the written statement of the IEC/IRB approval and the list of its members and 
their functions 
− has received the written statement of Competent Authority approval 
• The original dated and signed curriculum vitae of the Investigator(s) has been collected 
• Laboratory normal ranges have been collected  
• All study materials are available on the study site 
• All participants agree with the monitoring procedures and know the study procedures 
• All participants are aware of a possible audit or inspection 
The CRA also has to provide training on the study protocol requirements and study specific 
procedures. 
11.2.1.3. Follow-up Visits 
Throughout the study, regular follow-up visits will be carried out by the CRA to check compliance 
with GCP, strict application of the protocol, subject’s informed consents, proper retention, storage 
and management of the study treatment, as well as the source and other trial-related documents. It 
is the CRA’s responsibility to inspect e-CRFs at regular intervals throughout the study to verify the 
completeness, accuracy and consistency of the data, to verify the conformity of the data entered into 
the e-CRF with the source documents and to ensure its correct completion, and AE reporting. 
 
 
 
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11.2.1.4. Closing Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
• Verify that the copies of e-CRFs are correctly stored 
• Control the accountability of intact and used treatment units before destruction 
• Obtain the last data clarifications and/or solutions if any 
• Make an on-site review of all study documentation and complete it if necessary 
• Remind the Investigator of his/her regulatory obligations, study document archiving process 
and duration. 
 
11.2.2. Direct Access to Source Documents 
In accordance to the requirements of GCP, all Sponsor representatives (Study Manager, CRA and 
Auditors) must be given direct access to all source and study data to perform quality 
monitoring/audit, thus ensuring accuracy and completeness of data.  
Investigators are reminded that all Sponsor representatives maintain professional confidentiality 
with regards to the subject data. 
11.3. PERIODIC SAFETY DATA REVIEW 
All safety data collected from the study (SAEs, AEs, clinical laboratory data, vital signs, physical 
examinations, ophthalmic examinations, dermatologic examinations, tumor assessments, ECG, 
ECHO/MUGA scans, etc.) are periodically reviewed by the medical monitor or designee to detect 
any potential safety signals during the study and to review safety critical data. The modalities of 
this safety signal detection review is described in a separate document. 
 
 
 
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11.4. STEERING COMMITTEE 
A steering committee (SC) will be established comprising Investigators participating in the trial and 
Sponsors’ representatives from the Clinical Study Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will be responsible 
for reviewing the safety data of the subjects treated in the study as well as reviewing efficacy results 
for ORR from the interim and final analyses. 
The SC will review protocol amendments as appropriate. The details of the role of the Steering 
Committee will be defined in a SC charter.   
 
11.5. IDSMC 
An Independent Data Safety Monitoring Committee (iDSMC) will be established to perform 
additional review of available safety data at regular intervals to ensure that the overall safety of the 
trial remains acceptable. The iDSMC will also have the opportunity to review toxicities observed 
over time, in cycles of treatment beyond the first cycle. Following each meeting, the iDSMC will 
provide in writing, recommendations to the Sponsor whether to continue, modify, or stop the study 
in compliance with the iDSMC Charter. 
The iDSMC membership, data to be reviewed, timing of the planned reviews as well as the 
operating procedures will be described in the iDSMC charter.  
12. DATA MANAGEMENT  
Data management will be subcontracted to a CRO brafunder the supervision of the Sponsor’s Data 
Manager of the IRPF Biometry Department. 
All clinical data related to the study will be collected and saved in a computerized database 
according to the following procedures. 
 
 
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12.1. DATA COLLECTION 
12.1.1. Electronic Case Report Form (e-CRF)  
An e-CRF will be developed for this study. The electronic Case Report Form (e-CRF) will be used 
to record all subject data required by the protocol. 
The e-CRF should be compliant with FDA regulations (Guidance for industry: Computerized 
systems used in clinical investigations 2007), European regulations (GCP guidelines – ICH E6 R2), 
compliant with 21CFR part 11 (electronic records and electronic signatures) and Japanese 
regulations,  fully validated, and should include an access control and a traceability system for data 
corrections (audit trail). 
Prior to the start of the study, the Investigator will complete a delegation form. The signature and 
initials of all persons in charge of e-CRF completion should be recorded on this form. Each person 
involved in e-CRF completion, review, correction and/or validation will be trained and will then 
have an individual login and access code to the e-CRF. An e-CRF user guide will be available for 
Investigators/on-site personnel involved in e-CRF completion and for CRAs. 
All information entered into the e-CRF will be recorded from source documents by authorized 
personnel. The Investigator is responsible for the management and accuracy of the information 
entered into the e-CRF. 
Each local assessment or examination (ECG, Laboratory samples, Questionnaires, …) will be 
entered into the appropriate e-CRF forms by the designated investigational site staff at each site. 
An e-CRF must be completed for each subject enrolled in the study (i.e. signed ICF).  
12.1.2. Pharmacokinetics data 
Actual dates and times of blood collections for study treatments dosing will be entered in both the 
e-CRF and the requisition form. Appropriate dates and times of study treatment intake will be 
entered in the e-CRF. The samples will be sent to a designated CRO for analysis. 
Validated results from bioanalysis of treatments concentrations in plasma or serum will be 
transmitted by the bioanalytical center to the sponsor or designated CRO. The study treatment 
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concentrations will be uploaded in the final database from an electronic data file provided by the 
bioanalytical laboratory. 
12.1.3. Biomarkers 
Dates and actual times of biomarker samples will be entered in both the e-CRF and the requisition 
form. 
BRAFV600E mutation status: is assessed by local laboratory and/or by central laboratory. Results 
from central laboratory will be sent to each site for validation of local result. The result from local 
laboratory will be entered by the designated investigational site staff at each site into the e-CRF as 
well as the confirmation provided by the central laboratory. The result from the central laboratory 
will be provided with an electronic data file. 
Other biomarkers: The samples will be sent to sponsor or a designated CRO for analysis. If any of 
the biomarker analyses are intended to form part of the CSR, they will be transferred to the data 
management CRO for validation and integration into the study database. 
CEA, CA 19-9: are assessed by local laboratory, and data will be entered into the appropriate e-
CRF forms by the designated investigational site staff at each site. 
12.1.4. Imaging 
Local assessment (Main study and Study extension periods): scans will be assessed by local 
radiologists at the sites and RECIST measurements will be entered into the appropriate e-CRF forms 
by the designated investigational site staff at each site. 
Central assessment (Main study period only): scans will then be submitted for a centralized review. 
The central imaging reader will review the scans and results will be provided with an electronic 
data file to the CRO. 
 
 
 
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12.2. DATA CLEANING 
The Data Manager will define descriptions of manual and electronic edit checks in the study Data 
Validation Plan for reviewing and querying data. Upon approval, the edit checks and listings will 
be programmed. 
The Data Manager will follow the cleaning of the data over the course of the study. The Investigator 
will be asked to resolve queries by making changes directly into the e-CRF. The system’s automatic 
audit trail will record the date, time and author of the changes. 
12.3. DATA CODING 
AEs, concomitant diseases, medical/surgical histories will be coded using MedDRA dictionary 
(latest version in use). 
Prior and concomitant medications will be coded using WHO-DRUG dictionary (latest version in 
use).  
The coding will be validated by a physician. 
12.4. DATABASE LOCK 
The validated database will be locked upon request of the Sponsor’s Data Manager following the 
completion of all required steps, i.e.: entry, reception and check of all data, resolution of all queries, 
validation of the coding, Clinical and Pharmacovigilance database reconciliation, and data review / 
validation committee meeting performed. 
 
 
 
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12.5. DATA STORAGE 
Data and any modifications will be saved and kept available upon request of the Sponsor. The 
Sponsor’s Data Manager will assume storage of the locked clinical database in SAS format on a 
secured server. 
Electronic capture of all e-CRFs will be sent in PDF format to the Sponsor, and then stored on a 
dedicated secured server by the Sponsor.  
A CD-ROM containing the PDF version of all e-CRFs of the site (including audit-trail) will be 
archived by the investigational site. 
 
13. STATISTICAL ANALYSIS 
13.1. GENERAL CONSIDERATIONS 
A detailed statistical analysis plan (SAP) will be prepared by the Sponsor. This plan may modify 
the statistical methods outlined in the protocol; however, any major modifications related to the 
primary outcome measure definition or analysis will also be described in a protocol amendment.  
The statistical analysis will be done under the supervision of the study statistician at the Biometry 
Department, IRPF. Analyses will be programmed in accordance with the SAP. 
The CSR is planned to be written at the time of the primary outcome measure analysis (after Stage 
1 if the study is stopped for futility, otherwise after Stage 2).  
The cut-off date for futility analysis and Stage 2 analysis is estimated to occur approximately when 
all treated subjects with a centrally confirmed BRAFV600E mutation of the concerned stage have 
either discontinued or have four post-baseline tumor assessments. And in case the last subject 
required for the concerned stage has an objective response, it should be confirmed in the following 
tumor assessment before the analysis is being performed. However, it will be possible to proceed 
to Stage 2 as soon as 40 subjects with a centrally confirmed BRAFV600E mutation are treated and 12 
confirmed responses are observed.  
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All available data will be included at the time of the cut-off date for secondary time-to-event 
endpoints and safety assessments. Unless the study is stopped at an earlier point in time, any further 
CSR update (or addendum) will be written at the end of study. 
After the primary outcome measure analysis (after Stage 1 if the study is stopped for futility, 
otherwise after Stage 2), an analysis will be performed at the end of the Main study period, and at 
the end of the Study extension period). 
Descriptive methods will be used to present all relevant data: 
- 
Continuous data will be summarized with: frequency, median, range, mean, standard deviation 
and standard error if relevant. 
- 
Categorical data will be presented in contingency tables with frequencies and percentages of 
each modality. 
13.2. OUTCOME MEASURES 
13.2.1. Primary outcome measure 
The best overall confirmed response assessed per RECIST v1.1 will be used to evaluate the tumor 
response in terms of cORR for the combination of encorafenib, binimetinib and cetuximab. This 
will be based on local radiologist/investigator-assessed tumor evaluations.  
The cORR is defined as the number of subjects achieving an overall best confirmed response of CR 
or PR divided by the total number of subjects. This may also refer to as confirmed ‘objective 
response rate’ in some protocols or publications. 
13.2.2. Secondary outcome measures 
The following secondary outcome measures will be determined: 
- 
The cORR assessed by central radiologist review. 
- 
The ORR (for confirmed + unconfirmed responses) based on local radiologist/investigator-
assessed tumor evaluations, and ORR assessed by central radiologist review. 
- 
Overall survival defined as the time from first dose to death due to any cause. If a subject is not 
known to have died, survival will be censored at the date of last known date the subject was 
alive or at the cutoff date, whatever is earlier. OS will be calculated for FAS (see Section 13.5). 
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- 
Progression-free survival, defined as the time from first dose to the earliest documented date of 
disease progression or death due to any cause, per RECIST v1.1 and as determined by local 
radiologist/investigator assessments. Tumor assessment assessed by central review will be also 
used in a supportive analysis of PFS. 
- 
Duration of response is defined as the time from first radiographic evidence of response to the 
earliest documented PD or death due to underlying disease and is calculated for responders only. 
Responders who do not have a PD or death date by the data cutoff date will be censored for 
DOR at their last adequate tumor assessment of CR, PR or SD prior to the cutoff date. It will be 
assessed based on local radiologist/investigator review and central radiologist review. 
- 
Time to response (CR or PR) is defined as the time from first dose until first documented 
radiographic evidence of response of CR or PR. Subjects who do not have a CR or PR by the 
cutoff date will be censored for TTR at their last adequate tumor assessment date. It will be 
assessed based on local radiologist/investigator review and central radiologist review. 
Endpoints for Study extension period will be based on local radiologist/investigator review only  
13.3. SAMPLE SIZE 
The sample size is based on a two-stage design with nominal alpha=2.5% and beta=20%. The null 
hypothesis that the true response rate is 30% will be tested against a one-sided alternative. In the 
first stage, 40 subjects will be treated. In case of discordance in the results between the local assay 
and the central laboratory (potential false-positive local result), or lack of BRAFV600E confirmation, 
subject will be replaced. If there are 11 or fewer confirmed responses in the 40 treated subjects with 
a centrally confirmed BRAF BRAFV600E mutation, inactivity will be declared and the study will be 
stopped for futility. 
If the study continues to the second stage, 50 additional subjects will be treated to achieve a total of 
90 subjects. In case of discordance in the results between the local assay and the central laboratory 
(potential false-positive local result), or lack of BRAFV600E confirmation, subject will be replaced. 
The null hypothesis will be rejected if 37 or more confirmed responses are observed in 90 treated 
subjects with a centrally confirmed BRAFV600E mutation. This design yields a 1-sided type I error 
rate equal to 1.6% and power of 80% when the true response rate is 45%. 
The sample size calculation was based on binomial probabilities calculated in R (version 3.2.3). 
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This binomial design matches the O’Brien-Fleming design (O'Brien, 1979) for one sample 
obtained using East software (version 6.4) with a 1-sided type I error rate equal to 2.5% and a power 
of 81%. 
If 37 confirmed responders are observed in 90 subjects, the Clopper-Pearson (exact) binomial 95% 
confidence interval would be [30.8%, 52.0%] with the lower limit exceeding the clinically relevant 
response rate of 30%. 
 
13.4.  PROTOCOL DEVIATIONS 
A protocol deviation will be considered major when it is likely to significantly bias the estimate of 
the primary outcome measure.  
Major protocol deviations will be identified using the list of pre-defined reasons for exclusion from 
analysis sets for the study described in a specific document separately from the statistical analysis 
plan. 
All deviations will be reviewed and classified as major or minor before analysis. 
 
All protocol deviations linked to COVID-19 pandemic will be identified in the list of protocol 
deviations with a dedicated code and will be reviewed on a regular basis by the Study Sponsor, and 
by iDSMC. 
 
Subjects with major deviations will be excluded from the Per Protocol set (see Section 13.5) 
13.5.  ANALYSIS SETS  
For inclusion in any analysis set, it is required that a subject has signed his/her informed consent. 
The analysis sets are defined as follows:  
• The Full Analysis Set (FAS) is composed of all included subjects having received at least 
one dose of study treatment (partial or full). Unless otherwise specified, the FAS will be the 
default analysis set used for all analyses.  
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• The Efficacy Set (ES) is composed of all FAS subjects with a centrally confirmed 
BRAFV600E mutation. The ES will be the analysis set used for the primary analysis of the 
main criterion and all other efficacy analyses. 
• The Per Protocol Set (PPS) will consist of all subjects from the FAS without any major 
protocol deviations. The PPS will be the analysis set used for the supportive analysis of the 
main criterion. 
• The PK Set will consist of all subjects who receive at least 1 dose of encorafenib, 
binimetinib or cetuximab and who have at least 1 post-dose PK blood collection with 
associated bioanalytical results. 
 
 
13.6.  HANDLING OF DROPOUTS AND MISSING DATA 
As of the date of data-cutoff for the primary CSR for the purposes of reporting:  
Subjects continuing to receive study drugs at the time of analysis will have time-to-event data (e.g., 
PFS, DOR) censored at the time of last tumor assessment prior to the data cut-off point used. 
Ongoing events (e.g., AEs, concomitant medication, etc.) will be summarized using the data cut-
off date as the date of completion, with an indication that the event is ongoing. 
For subjects who drop out from the study with ongoing events, the discontinuation date will be used 
as the completion date of the event with the appropriate censoring. 
The reason for discontinuation from study will be summarized, along with the dates of first and last 
study drugs, duration of exposure to study drugs and date of discontinuation for each subject.  
Specific details regarding the handing of missing data will be included in the statistical analysis 
plan. 
13.7.  DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Baseline subject characteristics including demographics and other baseline data, ECOG PS, 
histology, primary site of disease and medical history will be summarized using the ES and FAS. 
Demographic and disease characteristics will be also summarized for the subgroup of Japanese 
subjects. 
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13.8.  ANALYSIS OF OUTCOME MEASURES  
Efficacy analyses will be conducted using the ES and FAS. A supportive analysis of the primary 
outcome will be conducted using the PPS. 
13.8.1. Analysis of Primary Outcome Measure  
13.8.1.1. Primary Analysis 
The cORR will be provided with a corresponding Clopper-Pearson (exact) binomial 95% CI 
(Clopper CJ et al, 1934) for the ES. As detailed (in Section 13.3), the two-stage method will be 
used to test the null hypothesis with the possibility of stopping accrual earlier for futility. If the 
observed cORR at the end of the first stage is less than 28% (i.e., ≤ 11 confirmed CRs and/or PRs 
among 40 treated subjects with a centrally confirmed BRAFV600E mutation), then insufficient 
efficacy will be concluded. Otherwise, at the end of stage 2, if the observed ORR is ≥41% (i.e., ≥37 
confirmed responses among 90 treated subjects with a centrally confirmed BRAFV600E mutation), 
the null hypothesis will be rejected. 
 
13.8.1.2. Supportive Analysis 
The cORR will be provided with a corresponding Clopper-Pearson (exact) binomial 95% CI for the 
PPS and FAS (see Section 13.5). 
13.8.1.3. Exploratory Analysis 
Exploratory analyses may be performed on various subgroups such as by age (< 65 vs. ≥ 65 years 
old), gender, CRP levels (>ULN and <ULN), MSI status (high and low), location of primary disease 
and possibly others. The primary endpoint and the corresponding 95% CI will be displayed using a 
forest plot by subgroups. Further details including the precise subgroups used will be detailed in the 
SAP. 
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cORR based on investigator-assessed tumor evaluation for the subgroup of Japanese subjects will 
also be examined separately. 
 
13.8.2. Analysis of Secondary Outcome Measures 
The cORR based on central review, and ORR (for confirmed + unconfirmed responses) based on 
local radiologist/investigator-assessed tumor evaluations and central radiologist review will be 
provided with a corresponding Clopper-Pearson (exact) binomial 95% CI for the ES and FAS. 
The Kaplan-Meier (KM) method used to describe OS will present median time with 95% CI and 
estimates at several time points (including 2, 4, 6, 8, 10 and 12 months). Subjects without a death 
date by the data cut-off date will be censored for OS at their last contact date. 
PFS will be calculated for the FAS and summarized using the KM method. The corresponding 
median PFS as well as PFS rates at selected time points (e.g. 3 and 6 months) will be provided with 
a 95% CI. 
Progressive disease and death from any cause will be considered as events. If death or PD is not 
observed, the PFS will be censored at the date of last adequate tumor assessment prior to the cutoff 
date. However, if a PFS event is observed after more than 1 missing or inadequate tumor 
assessment, it will be censored at the last adequate tumor assessment. If a PFS event is observed 
after a single missing or non-adequate tumor assessment, the actual date of event will be used. 
Subjects who received a new anti-tumoral treatment (chemotherapy, hormonotherapy, radiotherapy, 
surgery or other anti tumoral treatment), whatever the type of treatment before their disease 
progression will be censored at the last adequate assessment prior to the start date of the new 
antitumoral treatment. 
Additional sensitivity analyses examining alternative censoring rules could be applied and will be 
described in the SAP. 
Analysis of DOR and TTR will be summarized using KM method in a similar way. 
Secondary outcomes measures in the subgroup of Japanse subjects will be examined separately. 
 
 
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13.9. SAFETY ANALYSIS  
The FAS will be used to perform all analyses of the safety criteria. 
13.9.1. Treatment exposure 
Duration of study drug exposure, actual and relative dose intensity will be summarized. The number 
of subjects with dose changes/interruptions will be presented, along with reasons for the dose 
change. The actual daily doses and reasons for dose change will be listed. These analyses will be 
applied for each study drug individually on the FAS. 
Separate summaries will be generated for the subgroup of Japanese subjects. 
13.9.2. Adverse Events 
Any AE reported during the study for a given subject will be classified by preferred term and 
corresponding system organ class using the MedDRA terminology. 
The occurrence of an AE will be defined by the appearance of a new single event, the reappearance 
of a previously recovered event or the worsening of a continuous event (relative to its previous 
status).  
A treatment emergent adverse event (TEAE) is defined as any event that first occurred during the 
treatment period (i.e. from first treatment administration date up to last administration date + 30 
days) or that worsened during that study period.  
Summary tables will display the number and percentage of subjects with TEAEs overall and by 
maximum grade, system organ class (SOC) and preferred term (PT). A subject with multiple 
occurrences of an AE will only be counted under the maximum NCI-CTCAE grade for this AE.  
Similar analyses will also be performed for TEAEs assessed as related to study treatment by the 
investigator. 
 
 
 
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SAEs will also be described on an individual basis: subject’s code, sex and age, Investigator's 
reported term, preferred term, date of the first study treatment administration, duration of each study 
drug, action taken regarding the study treatments administration, use of a corrective treatment, 
outcome and relationship to the study treatments in the Investigator’s opinion. 
Categories of adverse events of special interest (AESIs) will be considered. Such categories consist 
of one or more well-defined safety events which are similar in nature and for which there is a 
specific clinical interest in connection with the study drugs. These analyses will be specified in the 
SAP.  
The number and percentage of subjects with at least one AE occurring before the first administration 
will be tabulated by MedDRA SOC and PT.  
As per the EudraCT requirement: The number and percentage of subjects with at least one TEAE, 
and the number of occurrences of TEAEs, will be tabulated by MedDRA SOC, PT and seriousness 
(by descending order of frequency). 
The same analysis will be performed for TEAEs assessed as related to study treatment by the 
investigator. 
AE analyses will be generated for the subgroup of Japanese subjects. 
All Adverse Events related to COVID-19 pandemic will be flagged in listings to assess any potential 
impact of the pandemic on the study integrity and subjects’ safety. These Adverse Events will be 
reviewed by iDSMC. 
 
13.9.3. Clinical Safety Laboratory Evaluation 
For each hematology and chemistry laboratory parameter, data will be tabulated over time and plots 
of measurements over time will be generated for selected parameters. 
The absolute changes in post-trial treatment administration versus baseline (the baseline value being 
the value measured on the last blood sample collected before the first study treatments 
administration) will be calculated and tabulated by parameter and post-trial treatment administration 
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assessment time. Results of retests performed post-trial treatment administration will not be 
analyzed and tabulated and will only be displayed in individual data listings. 
For laboratory tests covered by the NCI-CTCAE v4.03, laboratory data will be graded accordingly. 
For laboratory tests covered by the NCI-CTCAE, Grade 0 will be assigned for all non-missing 
values not graded as 1 or higher. Grade 5 will not be used. Shift tables of baseline grade vs. 
maximum grade on study will be presented. 
For laboratory parameters that are not gradable by NCI-CTCAE, shift tables of normal-abnormal 
will be provided. 
Analyses of laboratory data will be generated for the subgroup of Japanese subjects. 
13.9.4. Other Safety Data 
Vital signs, body weight, ECOG PS, ECG, dermatologic and ophthalmic examination data will be 
summarized descriptively over time for values and changes from baseline and/or with shift tables 
if applicable. Summaries of clinically notable measurements will also be provided. Definitions will 
be detailed in the SAP. 
13.10. QUALITY OF LIFE ANALYSIS  
Quality of Life will be evaluated through the EORTC QLQ-C30, EQ-5D-5L QoL and PGIC 
questionnaires. 
Descriptive statistics will be used to summarize the scores over time on the FAS. Additionally, 
changes from baseline for EORTC QLQ-C30 and EQ-5D-5L scores will be described over time. 
Further analysis will be detailed in the SAP. 
13.11. EXPLORATORY ANALYSIS 
The relationship between protein levels, mutations and/or gene expression and clinical outcomes 
may be explored. Details of all exploratory analyses will be provided in the SAP. 
 
 
 
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13.12. CONCOMITANT THERAPIES AND THERAPEUTIC/ DIAGNOSTIC 
PROCEDURE 
Concomitant therapies prior to and after the start of the study treatments will be tabulated from a 
descriptive perspective. They will be classified by therapeutic area according to the WHO-DRUG 
dictionary using the "anatomical therapeutic chemical (ATC) classification for the FAS.  
These summaries will include medications starting on or after the start of study drugs or medications 
starting prior to the start of study drugs and continuing after the start of study drugs. 
Any other medications starting and ending prior to the start of study drugs will be listed. 
Numbers and percentages of subjects with at least one concomitant therapeutic / diagnostic 
procedure will be tabulated by treatment group, SOC and PT using the MedDRA terminology. 
13.13. HEALTHCARE RESOURCE UTILIZATION 
Type of hospital facility, reason and length of hospitalization and hospital discharge will be 
summarized descriptively on the FAS. 
13.14. PHARMACOKINETICS ANALYSIS 
Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) and related descriptive statistics will be summarized. Serum concentrations of 
cetuximab and related descriptive statistics will be reported in tables. 
Given the sparse PK sample collection, PK parameters for encorafenib, binimetinib and the active 
metabolite of binimetinib (AR00426032) and cetuximab may be generated by a compartmental 
approach such as a population approach, as appropriate. Details of these analyses and of the 
incorporation of prior information to support the model building will be provided in a specific 
standalone modeling plan. Analyses will be provided in a separate report. 
Relationships between PK and biomarkers, clinical response and/or safety will be explored if 
appropriate and if data quality is adequate. Details of analyses will be included in a specific 
standalone modeling plan and results will be reported separately. 
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13.15. INTERIM ANALYSIS 
The two-stage design involves an interim analysis to allow for the possibility of stopping the study 
early for futility.  
The interim analysis of the cORR is planned and based on the 40 treated subjects from stage 1 of 
the study. 
The time point for the futility analysis will be after all 40 treated subjects of stage1 with centrally 
confirmed BRAFV600E mutation had the opportunity to complete four post baseline tumor 
assessment. And in case last subject required for the futility analysis has an objective response, it 
should be confirmed in the following tumor assessment before the futility analysis is performed. 
However, it will be possible to proceed to Stage 2 as soon as 40 subjects with a centrally confirmed 
BRAFV600E mutation are treated and 12 confirmed responses are observed. 
Subjects data that will be analyzed during the futility analysis will be reviewed on an ongoing basis 
in order to determine as soon as possible (even before the inclusion of the 40th subject) whether the 
criteria for continuing to stage 2 (12 confirmed responses) have been met. 
As it may take several treatment cycles for subjects to achieve a confirmed response, if 12 confirmed 
responses are not observed at the time the 40th subject is treated in Stage 1, a limited number of 
subjects (maximum 12) subjects from stage 2 may be treated while waiting for all subjects in the 
initial cohort of 40 subjects in Stage 1 to be evaluable for a confirmed response providing no safety 
concern was raised by the iDSMC. They will not count towards responses in Stage 1 but will be 
included as part of the Stage 2 cohort, should the study move forward into Stage 2. 
If at any time it becomes evident that the threshold of 12 responses is unlikely to be met, then 
additional subjects may not be recruited (eg: 6 or fewer responses among 35 subjects with sufficient 
follow up [potential for at least 2 assessments]). 
If 11 or fewer confirmed responses are observed in subjects with centrally confirmed BRAFV600E 
mutation in stage 1, the treatment will be deemed not efficacious. Inactivity will be declared and 
the study will be stopped for futility. 
 
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If 12 or more confirmed responses are observed in stage 1, 50 additional subjects with a centrally 
confirmed BRAFV600E mutation have to be treated. The cut-off for stage 2 analysis will be after all 
90 treated subjects of stage 1 and 2 with centrally confirmed BRAFV600E mutation had the 
opportunity to complete four post-baseline tumor assessments, and after subjects with an initial 
objective response have had an opportunity to have a confirmation scan. 
An SC will review the primary outcome and safety data for the interim and final analyses (see 
Section 11.4).  
An iDSMC will review the available safety information at regular interval (see Section 11.5). 
Analyses for iDSMC will be based on safety, thus this will not affect the statistical operating 
characteristics of the Stage 1 and Stage 2 analyses. 
14. GENERAL ETHICAL CONSIDERATIONS 
14.1. ETHICAL CONDITIONS 
This study is performed in accordance with the principles stated in the Declaration of Helsinki and 
subsequent amendments and in accordance with the Good Clinical Practice Guideline 
(EMA/CHMP/ICH/135/1995). 
14.2. INDEPENDENT ETHICS COMMITTEE AND LEGAL 
REQUIREMENTS 
All documents required by National Regulations and any other informative documents that may be 
requested are submitted for review to the appropriate IEC/IRB whose procedures and operations 
meet national legal requirements. 
Depending on national regulations, the application is submitted to the IEC/IRB by the Sponsor or 
by the Investigator. 
 
 
 
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A copy of the formal written approval from the IEC/IRB is provided to the Sponsor (directly by the 
IEC/IRB or via the Investigator) with a list of names and qualifications of its members. The request 
for authorization by the Competent Authority or notification (depending on national regulations) is 
carried out by the Sponsor. 
Screening of subjects will not start before the approval of the IEC/IRB has been obtained and the 
study was authorized by the Competent Authority (or notified to the Competent Authority, 
depending on the national regulations). 
14.3. SUBJECT’S INFORMATION LEAFLET AND INFORMED 
CONSENT FORM 
Information must be given to each subject before his/her decision to participate or abstain from 
participation. This information is based on the elements set out in the Declaration of Helsinki and 
the ICH GCP guideline. It must also describe the measures taken to safeguard subject’s privacy and 
protection of personal data, according to EU General Data Protection Regulation (2016/679). 
Restraints and risks must be explained, as well as the right to discontinue participation in the study 
at any stage, without affecting their further relationship with the Investigator and/or their future 
care. 
The written information and consent form must be submitted to the subject with an oral explanation. 
It must be agreed and signed by the subject before any study-related procedure starts. 
This information and consent procedure is under the Investigator’s responsibility. 
The information and consent documents are prepared in duplicate: the original copy is kept by the 
Investigator, and the other copy is given to the subject. 
If any information becomes available during the trial that may be relevant to the subject’s 
willingness to continue participating in the trial, an updated written informed consent must be 
submitted to the subject to confirm his/her agreement to continue participating. 
 
 
 
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14.4. PERSONAL DATA PROTECTION 
All information from this study (excluding data from the informed consent) are captured in an 
electronic database into a computer under the Sponsor’s responsibility in accordance with the 
French law, "Loi Informatique et Libertés" (January 6, 1978 and subsequent amendments) and with 
the EU General Data Protection Regulation (2016/679). 
14.5. INSURANCE POLICY 
In accordance with the provisions of the law and GCP, the Sponsor Pierre Fabre Medicament has 
an insurance policy intended to guarantee against possible damage resulting from the research. 
The studies and/or experiments performed on behalf of the Sponsor Pierre Fabre Medicament are 
specifically and expressly guaranteed. 
It is advisable to underline that non-compliance with the Research Legal Conditions is a cause for 
guarantee exclusion.  
Unintentional infringements and vicarious liability are covered by our insurance.  
14.6.  FINANCIAL CONSIDERATIONS 
The funding of research is provided by the Sponsor (Investigator fees, study costs, subject 
compensation for travel expenses, etc.). 
By signing the protocol, the Investigator declares no conflicts of interest. 
 
 
 
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15. ADMINISTRATIVE PROCEDURES 
15.1. PROTOCOL AMENDMENTS 
Neither the Investigator nor the Sponsor may alter the protocol without the authorization of the 
other party. All changes to the protocol will be subject to an amendment which must be dated and 
signed by both parties and must appear as an amendment to the protocol.  
Substantial amendments are submitted for approval/authorization to the IEC/IRB and Competent 
Authorities. Urgent amendments are submitted for approval/authorization to the IEC/IRB and 
Competent Authorities but may be implemented immediately under specific conditions defined with 
the Sponsor. 
15.2. SOURCE DOCUMENTS, INVESTIGATOR'S FILE STORAGE 
The Investigator: 
- keeps all trial-related documents in appropriate file folders. Records of subjects, original ICFs, 
source documents, e-CRFs, treatment inventory, IEC/IRB and Sponsor correspondence pertaining 
to the study must be kept on file, 
- retains all documents relating to the screening (consent and investigation results) of all subjects 
screened in the trial or not,  
- retains a list of the subjects’ names, addresses (and/or number of medical file), code numbers, 
dates of entry into and completion of the trial period, to allow checking of data reported on e-CRFs 
with those from source documents,  
- authorizes direct access to source documents for monitoring, audits and inspections. 
The trial-related documents must be retained as strictly confidential at the Investigator's site for a 
duration of 25 years or according to local requirements, after the completion or discontinuation of 
the trial. 
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15.3. END OF STUDY  
15.3.1. Definition of the end of study 
The end of the study is defined as the time point when all treated subjects will have either progressed 
or discontinued study treatments (including 30-day Safety Follow-Up visit) for any other reason 
(unacceptable toxicity, subject’s decision, withdrawal of consent, initiation of subsequent 
anticancer therapy or death). 
15.3.2. Supply of product after Main study period 
After  the Main study period (from first subject screened to 1 year after the start of study treatment 
of the last subject enrolled – 27 Dec 2020),  access to study treatment will be provided through a 
Study extension period (from 28 Dec 2020) to all subjects whom the investigator considers are 
continuing to benefit from study treatment.  
These subjects will receive treatment with encorafenib/binimetinib/cetuximab as long as they 
continue to demonstrate benefit and do not experience unacceptable toxicities and as long as none 
of the treatment discontinuation criteria are met or until binimetinib/encorafenib are commercially 
available in the first line setting of BRAF V600E mutated mCRC or until the binimetinib/encorafenib 
development program is stopped (whichever comes first). 
15.4. AUDIT 
The purpose of a sponsor’s audit, independent of and separate from monitoring or quality control 
activities, is to evaluate trial conduct and compliance with the protocol, sponsor’s standard 
operating procedures, Good Clinical Practice, and the applicable regulatory requirements. 
Audits may be conducted by the sponsor’s Clinical Quality Assurance Department or delegate at 
each relevant location where activities dedicated to clinical trial are performed: for example at 
sponsor’s site(s), at the investigational site(s), at CRO(s) site(s) and laboratory(ies) if applicable. 
All study related documentation must be directly accessible to auditors. 
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The practical conditions for the audit are discussed between the auditees and the sponsor’s Clinical 
Quality Assurance Department or their delegate. 
 
15.5. INSPECTION 
The relevant Health Authorities may inspect any investigational site or the Sponsor during the 
course of the study or after its completion, to verify the conduct of the study and quality of the data. 
The Investigator must provide direct access to the respective source documents. 
15.6. CONFIDENTIALITY 
The study materials (protocol, e-CRF, Investigator's brochures) contain confidential information. 
Except if agreed to in writing with the Sponsor, the Investigators must hold such information 
confidential, and must not disclose it to others (except where required by applicable law). 
15.7. CLINICAL STUDY REPORT 
Data analysis and CSR writing are the Sponsor’s responsibility. Upon completion of the data 
analysis, a final report including a review of the objectives and methods, a presentation and 
discussion of the results are drawn up according to ICH Guidelines (Structure and Content of 
Clinical Study Reports, ICH-E3, CPMP/ICH/137/95. 
The report is a clinical, (and) statistical, and pharmacokinetic integrated report. It must be signed 
by the sponsor's representative(s) and the coordinating Investigators. 
15.8. STUDY RESULTS COMMUNICATION 
Within a maximum period of 12 months after study completion global results of the research will 
be communicated to the Investigator.  
According to the local regulations, subjects can ask the Investigator for the results.  
If this study is part of a marketing authorisation application, its results will be published on the 
European Medicines Agency (EMA) website and on Pharmaceuticals and Medical Devices Agency 
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(PMDA) website (Japan). In that case, the documents will be anonymised to ensure data protection 
of individuals. 
 
15.9. STUDY RESULTS PUBLICATION 
The results of this study including data, reports, discoveries and inventions are the property of the 
Sponsor and are considered as confidential. Subject to any applicable laws in force, the Sponsor 
retains the right to be the first to publish or communicate the results of the study. In any case, no 
publication or communication relating to results of the study, in written or oral form, shall be made 
without Sponsor’s prior written consent and shall comply with the following provisions: 
- any communication or publication project must be provided to the Sponsor for review at least 
60 days prior to the expected date of submission to the intended publisher or of planned 
presentation. 
If requested by the Sponsor, the communication or publication project shall be withheld for an 
additional 60 days, to allow the filing of a patent application, or to allow the Sponsor to take any 
measures deemed appropriate to establish and preserve proprietary rights. 
In case of a multicentric study, the Sponsor, in consultation with the SC, shall determine the author’s 
list and order within the publication project according to their participation in the design of the 
protocol as well as their recruitment of eligible and analyzable subjects. 
 
 
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Eur J Cancer 2008, 44(6):781-90 
Vermorken JB, Mesia R, Rivera F, et al.  
Platinum-based chemotherapy plus cetuximab in head and neck cancer.  
N Engl J Med. 2008;359:1116-27. 
Yang H, Higgins B, Kolinsky K et al.  
Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant 
colorectal cancer. 
Cancer Res 2012; 72: 779–789. 
Zhao B, Wang L, Qiu H, Zhang M, Sun L, Peng P et al. 
Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. 
Oncotarget 2017;8: 14012. 
Zheng Z, Hanna N, Onukwugha E, Reese ES, Seal B, Mullins CD.  
Does the type of first-line regimens influence the receipt of second-line chemotherapy 
treatment? An analysis of 3211 metastatic colon cancer patients.  
Cancer Med.2014;3(1):124–133. 
 
 
 
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17. APPENDICES 
 
17.1. RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
CETUXIMAB-INDUCED, ENCORAFENIB-INDUCED AND/OR 
BINIMETINIB-INDUCED SKIN TOXICITY 
Clinical judgment and experience of the treating physician should guide the management plan of 
each subject. In general, the following interventions are in addition to the cetuximab-induced rash 
and the encorafenib-induced and/or binimetinib-induced rash dosing guidelines provided (in 
Section 1.2). 
The Initial Rash Treatment Regimen may be initiated as prophylactic treatment 24 hours prior to 
the first treatment, or later as needed to treat mild rash (NCI-CTCAE Grade 1). 
Initial Rash Treatment Regimen: 
• Application of topical agents to the most commonly affected skin areas such as face, scalp, 
neck, upper chest and upper back. Topical agents include the following: 
− Non-oily sunscreen (PABA-free, SPF ≥ 30, UVA/UVB protection); 
− Topical steroids, preferably mometasone cream (e.g., Elocon®); 
− Topical erythromycin (e.g., Eryaknen®); 
− Topical pimocrolimus. 
Note: Topical agents should be applied on a daily basis starting on Day 1 of study treatment or 
24 hours prior to first treatment, and more often as needed. 
• Possibly oral doxycycline (100 mg daily) for the first 2 to 3 weeks of study drug 
administration. 
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids. 
 
 
 
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The treatment algorithm based on NCI-CTCAE grade is as follows: 
Mild Rash (CTCAE Grade 1) Treatment Regimen: 
• Initiate Initial Rash Treatment Regimen, if not already started. 
• Use of topical corticosteroid (e.g., mometasone cream) and/or topical antibiotic (e.g., 
erythromycin 2%) is recommended. 
• The subject should be reassessed within a maximum of 2 weeks, or as per Investigator 
opinion. 
Moderate Rash (CTCAE Grade 2) Treatment Regimen: 
• Use of topical erythromycin or clindamycin (1%) plus topical mometasone or topical 
pimecrolimus (1% cream) plus oral antibiotics, such as lymecycline (408 mg QD), 
doxycycline (100 mg BID) or minocycline (50 to 100 mg BID). 
• Although there has been no evidence of phototoxicity or photosensitivity in subjects treated 
with binimetinib, doxycycline (or minocycline as second-line) should be used with thorough 
UV protection (i.e., avoidance of direct exposure to sunlight, use of sunscreen and 
sunglasses, etc.). 
• Use of acitretin is not recommended. 
Severe Rash (CTCAE Grade 3-4) Treatment Regimen: 
CTCAE Grade 3: 
• In addition to the interventions recommended for moderate rash, consider oral prednisolone 
at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise manner (25 mg for 
7 days, subsequently decreasing the dose by 5 mg/day every day). 
• Alternatively, in addition to the interventions recommended for moderate rash, consider oral 
isotretinoin (low dose, i.e., 0.3 to 0.5 mg/kg) (Kopetz S el al, 2017; Lacouture ME et al, 
2011) 
• Use of acitretin is not recommended. 
 
 
 
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CTCAE Grade 4 Treatment Regimen: 
• Immediately discontinue the subject from study drug and treat the subject with oral or 
topical medications (see recommendation CTCAE Grade 3). 
Symptomatic Treatment Regimen: 
It is strongly recommended that subjects who develop rash/skin toxicities receive symptomatic 
treatment: 
• For pruritic lesions: use cool compresses and oral antihistamine agents. 
• For fissuring: use Monsel’s solution, silver nitrate or zinc oxide cream. If not sufficient, use 
mild corticosteroid ointments or ointments containing a combination of corticosteroid and 
antibiotic such as Fucicort®. 
• For desquamation: use emollients that are mild pH 5/neutral (recommended to contain 10% 
urea). 
• For paronychia: use antiseptic bath and local potent corticosteroids, use oral antibiotics, and, 
if no improvement is seen, refer to a dermatologist or surgeon. 
• For infected lesions: obtain bacterial and fungal cultures and treat with topical or systemic 
antibiotics, if indicated, based on sensitivity of culture. 
 
 
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17.2. RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
ENCORAFENIB-INDUCED HAND-FOOT SKIN REACTIONS (HFSR) 
Clinical judgment and experience of the treating physician should guide the management plan of 
each subject. In addition to the HFSR dosing guidelines in the protocol, the following algorithm is 
recommended for the management of HFSR based on the severity (CTCAE grading,) of HFSR 
(adapted from Nardone B et al, 2012). HFSR (adapted from Nardone B et al, 2012). 
Algorithm for the Management of HFSR Based on the Severity of HFSR 
HFSR severity 
Intervention 
No HFSR 
Maintain Frequent Contact with physician to ensure early diagnosis of HFSR 
Therapy initiation 
Full body-skin examination, pedicure, evaluation by podiatrist or orthotist; wear thick cotton 
gloves and/or socks; avoid hot water, constrictive footwear and excessive friction 
If symptoms develop, proceed to next step 
 
Grade 1 
Maintain current dose of BRAF inhibitor; monitor subject for change in severity 
Minimal skin changes or 
dermatitis without pain e.g.: 
• 
Numbness 
• 
Tingling 
• 
Dysesthesia 
• 
Paresthesia 
• 
Erythema 
• 
Edema 
• 
Hyperkeratosis 
No interference with ADL 
Avoid hot water; use moisturizing cream for relief; wear thick cotton gloves and/or socks; 
use a 20-40% urea , salicylic acid 3-6%; ammonium lactate 12 % or lactic acid 12 % based 
creams to aid exfoliation. 
If symptoms worsen, proceed to next steps 
 
 
 
 
 
Grade 2 
Maintain current dose of BRAF inhibitor; monitor subject for change in severity 
Skin changes with pain e.g. 
Peeling 
• 
Blisters 
• 
Bleeding 
• 
Edema 
• 
Hyperkeratosis 
Limited instrumental ADL 
 
 
 
Treat as with Grade 1 toxicity, with the following additions: clobetasol 0.05% ointment, 2-
4% lidocaine, opiates, NSAIDS, or GABA agonists for pain; follow dose modifications 
listed in Table 14  
If no improvement within 15 days, proceed to next steps. 
 
 
 
 
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The following supportive care measures for the prevention, and/or management of HFSR 
summarized in the table below should be instituted along with proper subject education. 
Supportive Care for the Prevention and Management of HFSR 
 
Stage 
Recommendations 
Prior to initiation of study treatment 
Educate the subject about the early signs and symptoms of HFSR and 
discuss the importance of early reporting. HFSR could start as early as 2-5 
days after study drug initiation, and mostly expected to occur during the 
first 2 months of treatment. 
Prevention of HFSR for the first 2 months of 
treatment with encorafenib 
Monitor the subject for signs and symptoms of HFSR. Instruct the subject 
to: 
- Apply emollient cream regularly to hands and feet: use 20-40% urea , 
salicylic acid 3-6%; ammonium lactate 12% or lactic acid 12 % based 
creams 
- Wear cotton socks or gloves to bed to enhance the absorption of creams 
- Avoid tight, irritating or ill-fitting clothing and shoes 
- Avoid repetitive activity or staying in one position for long periods of 
time 
- Pat (do not rub) skin dry with towels 
- Avoid extremes of temperature, pressure and friction 
- Avoid performing mechanically stressful manual work 
- Cushioning of callused areas 
- Use of moisturizing and keratolytic creams to control existing palmar 
and plantar hyperkeratosis 
Treatment of HFSR 
1) Ensure that subject follows treatment interruption or dosage reduction 
guidelines 
2) Monitor the subject for worsening/resolution of HFSR (Normal 
frequency monthly, except if subject has Grade 2 or 3 HFSR, where bi 
weekly- visits are recommended) 
3) Prescribe analgesics if necessary 
4) Instruct the subject to: 
- Continue the use of prevention strategies 
- Cushion sore skin 
- For control or relief of pain symptoms, subject may submerge hands and 
feet in cool water baths or apply cold compresses for relief 
a Wear loose-fitting clothing made of soft, natural fabrics and shoes that are wide and comfortable. Avoid tight belts, panties 
and bras. 
This table is adapted from (VonMoos et al, 2008). 
 
 
 
Grade 3 
Interrupt dose until improvement to Grade 0-1 
Severe skin changes with pain 
e.g. 
Peeling 
• 
Blisters 
• 
Bleeding 
• 
Edema 
• 
Hyperkeratosis 
Limiting self-care ADL 
Treat as for Grades 1 and 2 
 
Follow dose modifications listed in Table 14 
 
 
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17.3. RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB-INDUCED DIARRHEA 
 
Proactively Investigate for Occurrence of Diarrhea and Educate Subject: 
1. 
Remind subjects at each visit to contact the Investigator immediately upon the first sign of 
loose stool or symptoms of abdominal pain. Additionally, at each study visit, each subject 
should be asked regarding occurrence of diarrhea or diarrhea-related symptoms. If the 
subject has had symptoms, the subject should be asked regarding the actions taken for these 
symptoms and re-instruct if indicated. 
2. 
Subjects should be instructed on dietary modification and early warning signs of diarrhea 
and potentially life-threatening illnesses (e.g., severe cramping might be a sign of severe 
diarrhea; fever with diarrhea might be a sign of infection; fever and dizziness on standing 
might be a sign of shock).  
3. 
Subjects should be educated about what to report to the Investigator (i.e., number of stools, 
stool composition, stool volume). 
Anti-Diarrhea Therapy: 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, subject education as outlined above, as well as proper management of diarrhea is 
important.  
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose stools 
or overt diarrhea. All concomitant therapies /used for treatment of diarrhea must be recorded on the 
e-CRF. It is recommended that subjects be provided loperamide tablets and be instructed on the use 
of loperamide on the first day of binimetinib dosing. In addition to the binimetinib-induced diarrhea 
dosing guidelines provided in Table 14 of the protocol, these instructions should be provided at 
each visit and the site should ensure that the subject understood the instructions.  
See Section 7 in the protocol to explain the frequency of diarrhea and its relationship to NCI-
CTCAE, v.4.03 grading and to determine if diarrhea is complicated or uncomplicated. 
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Rule out Other or Concomitant Causes: 
These may include: 
• Infection with Candida, Salmonella, Clostridium difficile, Campylobacter. Giardia, 
Entamoeba or Cryptosporidium species, which can lead to severe infections in 
immunosuppressed subjects. 
• Medication-induced diarrhea. 
• Malabsorption/lactose intolerance. 
• Fecal impaction, partial bowel obstruction. 
For Uncomplicated Grade 1/2 Diarrhea: 
• Stop all lactose-containing products and alcohol, and eat frequent small meals that include 
bananas, rice, applesauce or toast. 
• Stop laxatives, bulk fiber (e.g., Metamucil®), and stool softeners (e.g., docusate sodium, 
Colace®). 
• Stop high-osmolar food supplements (e.g., Ensure® Plus, Jevity® Plus [with fiber]). 
• Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte®, Gatorade®, 
broth). 
• Consider administration of a standard dose of loperamide: initial administration 4 mg, then 
2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool. 
• Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval. 
• Consider temporary interruption of binimetinib until resolved to Grade ≤ 1. Re-treatment 
may then be resumed at current dose level. 
• If uncomplicated Grade 1 to Grade 2 diarrhea persists for more than 24 hours, escalate to 
high-dose loperamide: 2 mg every 2 hours (maximum of 16 mg/day) or after each unformed 
stool. 
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of the 
physician. 
• If uncomplicated Grade 1 to Grade 2 diarrhea persists after 48 hours of treatment with 
loperamide, discontinue loperamide and begin a second-line agent which can be an opiate 
(opium tincture or paregoric), octreotide acetate or steroid (budesonide). 
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For Complicated Grade 1/2 Diarrhea or Any Grade 3/4 Diarrhea: 
• The subject must call the Investigator immediately. 
• Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. Restart binimetinib 
at a reduced dose level. 
• If loperamide has not been initiated, initiate loperamide immediately. Initial administration 
4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool. 
• Administer IV fluids and electrolytes as needed. In case of severe hydration, replace 
loperamide with octreotide acetate. 
• Monitor/continue IV fluids and antibiotics as needed. Intervention should be continued until 
the subject is diarrhea-free for at least 24 hours. 
• Hospitalization may need to be considered. 
 
 
 
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17.4. SNELLEN EQUIVALENCE (VISUAL ACUITY CONVERSION 
CHART) 
 
 
 
 
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17.5. LIST OF CONCOMITANT MEDICATIONS 
The following lists are not necessarily exhaustive lists of every possible 
substrate/inhibitor/inducer. 
Table A: List of CYP450 Substrates to be Used With Caution* 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
Amodiaquine 
Acenocoumarol 
Clopidogrel 
Alfentanil 1,2 
Ergotamine 2 
Cerivastatin 
Celecoxib 
Diazepam 
Alpha-
dihydroergocryptine 1 
Everolimus 1 
Repaglinide 
Diclofenac 
Esoprazole 
Alprazolam 
Felodipine 1 
Rosiglitazone 
Glipizide 
Lansoprazole 
Amlodipine 
Fentanyl 2 
Torasemide 
Irbesartan 
Moclobemide 
Aplaviroc 
Fluticasone 1 
 
Losartan 
Omeprazole 
Aprepitant 1 
Indinavir 1 
Phenytoin 2 
Pantoprazole 
Aripiprazole 
Lopinavir 1 
Piroxicam 
Phenobarbitone 
Atorvastatin 
Lovastatin 1 
S-ibuprofen 
Phenytoin 2 
Boceprevir 
Maraviroc 1 
Sulfamethoxazole 
Proguanil 
Brecanavir 
Midazolam 1 
Tolbutamide 
Rabeprazole 
Brotizolam 1 
Nifedipine 
Torasemide 
S-mephenytoin 
Budesonide 1 
Nisoldipine 
 
 
Buspirone 1 
Nitrendipine 
capravirine 
Perospirone 1 
casopitant 
Quinine 
Conivaptan 1 
Saquinavir 1 
Cyclosporine 2 
Sildenafil 1 
Darifenacin 1 
Simvastatin 1 
Darunavir 1 
Sirolimus 1,2 
Diazepam 
Telaprevir 
Diergotamine 2 
Tipranavir 1 
Diltiazem 
Tolvaptan 
Ebastine 1 
Triazolam 1 
Eletriptan 1 
Verapamil 
Eplerenone 1 
 
*Table was compiled from the Indiana University School of Medicine’s “Clinically Relevant” table, a list by the United States Food and Drug 
Administration (FDA) fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm, and 
the University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs whose plasma area under concentration-time curve (AUC) values have been shown to increase 5-fold or higher 
when co-administered with a potent inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure levels by the 
concomitant use of potent inhibitors may lead to serious safety concerns (e.g., TdP). 
 
 
 
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Table  B: List of CYP450 Substrates to be used with Caution – CYP2B6 
CYP2B6* 
bupropion 1 
Cyclophosphamide 
Efavirenz 1 
Ifosfamide 
Methadone 
Thiotepa 
*Table was compiled from the Indiana University School of Medicine’s “Clinically Relevant” table, a list by the FDA 
(http://.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm) and the University of 
Washington’s Drug Interaction Database. 
1 Sensitive substrates: The area under the concentration-time curves (AUCs) of these substrates were not increased by 5-fold or more with a 
CYP2B6 inhibitor, but they represent the most sensitive substrates studied with available inhibitors evaluated to date. 
 
 
Table  C: Strong/moderate CYP3A4 Inhibitors and CYP3A4 Inducers to be Prohibited or 
Administered with Caution when Co-administered with Encorafenib 
Strong Inhibitors (prohibited) 
boceprevir  
nefazodone  
Clarithromycin 
Nelfinavir 
Conivaptan 
Posaconazole 
Indinavir 
Ritonavir 
Itraconazole 
Saquinavir 
Ketoconazole 
Telithromycin 
Lopinavir 
Troleandomycin 
Telaprevir 
Grapefruit juice (citrus paradisi fruit juice) 
Mibefradil 
Voriconazole 
Moderate inhibitors (use with caution)  
Ciprofloxacin 
Erythromycin 
Fluconazole 
Amprenavir 
Verapamil 
Imatinib 
Atazanavir 
Schisandra sphenanthera 
Aprepitant 
Casopitant 
Cyclosporine 
Cimetidine 
Tofisopam 
Dronedarone 
Fosamprenavir 
Darunavir 
Diltiazem 
 
Strong Inducers (prohibited) 
Avasimibe 
Rifampin 
Carbamazepine 
St. John’s wort 
Phenytoin 
 
Moderate Inducers (prohibited) 
 
Bosentan 
Efavirenz 
Etravirine 
Modafinil 
Reproduced from fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
 
 
 
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Table  D: Substrates of BCRP, OCTs, OATs and OATPs to be administered with Caution 
 
Substrates 
BCRP 
Imatinib, irrinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan  
P-gp 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, 
imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, 
sitagliptin, talinolol, tolvaptan, topotecan  
OCT2 
Amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, 
procainamide, ranitidine, varenicline, oxaliplatin 
OAT1 
Adefovir, captopril, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, zalcitabine, 
zidovudine 
OAT3 
Acyclovir, bumetanide, ciprofloxacin, famotidine, furosemide, methotrexate, zidovudine, 
oseltamivir acid, (the active metabolite of oseltamivir), penicillin G, pravastatin, rosuvastatin, 
sitagliptin 
OATP1B1 
Atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 (active metabolite of 
irinotecan), rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, 
valsartan, olmesartan 
OATP1B3 
Atorvastatin, rosuvastatin, pitavastatin, telmisartan, valsartan, olmesartan 
Reproduced from fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
 
 
Table  E: Pg-P and BCRP Inhibitors/Inducers to be used with Caution 
Transporter 
Gene 
Inhibitor 1 
Inducer 2 
P-gp 
ABCB1 
Amiodarone, azithromycin,captopril, 
carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, dronedarone, 
erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir and ritonavir, quercetin, 
quinidine, ranolazine, verapamil 
Avasimibe,carbamazepine,phenytoin, 
rifampin, St John’s wort, 
tipranavir/ritonavir 
BCRP 
ABCG2 
Cyclosporine, elacridar (GF120918), 
eltrombopag, gefitinib 
Not known 
Reproduced from fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
 
1. Inhibitors listed for P-gp are those that showed > 25% increase in digoxin area under the concentration-time curve (AUC) or otherwise 
indicated if substrate is other than digoxin. 
2. Inducers listed for P-gp are those that showed > 20% decrease in digoxin AUC or otherwise indicated if substrate is other than digoxin. 
 
 
Table F: List of Inhibitors of UGT1A1 to be used with Caution 
Inhibitors of UGT1A1 
atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, ketoconazole, nilotinib, 
pazopanib, propofol, regorafenib, sorafenib 
 
 
 
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Table G: List of Potential QT Prolonging Drugs of Potential QT Prolonging Drugs1 
Drug 
QT risk2 
Comment 
Alfuzosin 
possible risk 
  
Amantadine 
possible risk 
  
Amiodarone 
known risk  
Females > Males, TdP risk regarded as low 
Amitriptyline 
conditional risk 
Risk of TdP with overdosage. Substrate of CYP2C19 
Arsenic trioxide 
known risk  
  
Astemizole 
known risk  
No Longer available in U.S. Substrate for 3A4 
Atazanavir 
possible risk 
  
Azithromycin 
possible risk 
Rare reports 
Bepridil 
known risk  
Females > Males 
Chloral hydrate 
possible risk 
  
Chloroquine 
known risk  
  
Chlorpromazine 
known risk  
  
Ciprofloxacin 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Cisapride 
known risk  
No longer available in the U.S.; available in Mexico. Substrate for 3A4 
Citalopram 
known risk  
  
Clarithromycin 
known risk  
Substrate for 3A4 
Clomipramine 
conditional risk 
  
Clozapine 
possible risk 
  
Desipramine 
conditional risk 
Risk of TdP with overdosage 
Diphenhydramine 
conditional risk 
Risk of QT increase/TdP in overdosages 
Disopyramide 
known risk  
Females > Males 
Dofetilide 
known risk  
  
Dolasetron 
possible risk 
  
Domperidone 
known risk  
Not available in the U.S. 
Doxepin 
conditional risk 
  
Dronedarone 
possible risk 
Substrate for 3A4 
Droperidol 
known risk  
  
Eribulin 
possible risk 
  
Erythromycin 
known risk  
Females>Males. Substrate for 3A4 
Escitalopram 
possible risk 
  
Famotidine 
possible risk 
  
Felbamate 
possible risk 
  
Fingolimod 
possible risk 
  
Flecainide 
known risk  
  
Fluconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Fluoxetine 
conditional risk 
  
Foscarnet 
possible risk 
  
Fosphenytoin 
possible risk 
  
Galantamine 
conditional risk 
  
Gatifloxacin 
possible risk 
  
Gemifloxacin 
possible risk 
  
Granisetron 
possible risk 
  
Halofantrine 
known risk  
Females>Males 
Haloperidol 
known risk  
When given intravenously or at higher-than- recommended doses, risk 
of sudden death, QT prolongation and torsades increases. Substrate for 
3A4 
Ibutilide 
known risk  
Females>Males 
Imipramine 
conditional risk 
Risk of TdP in overdosage 
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Drug 
QT risk2 
Comment 
Indapamide 
possible risk 
  
Isradipine 
possible risk 
  
Itraconazole 
conditional risk 
Drug metabolism inhibitor- Risk for drug interactions 
Ketoconazole 
conditional risk 
Drug metabolism inhibitor 
Levofloxacin 
possible risk 
  
Levomethadyl 
known risk  
Not available in the U.S. 
Lithium 
possible risk 
  
Mesoridazine 
known risk  
  
Methadone 
known risk  
Females>Males. Substrate for 3A4 
Moexipril/HCTZ 
possible risk 
  
Moxifloxacin 
known risk  
  
Nicardipine 
possible risk 
  
Nortriptyline 
conditional risk 
  
Octreotide 
possible risk 
  
Ofloxacin 
possible risk 
  
Ondansetron 
possible risk 
  
Oxytocin 
possible risk 
  
Paliperidone 
possible risk 
  
Paroxetine 
conditional risk 
  
Pentamidine 
known risk  
Females > Males 
Perflutren lipid microspheres 
possible risk 
  
Pimozide 
known risk  
Females > Males. Substrate for 3A4 
Probucol 
known risk  
No longer available in U.S. 
Procainamide 
known risk  
  
Protriptyline 
conditional risk 
  
Quetiapine 
possible risk 
Substrate for 3A4 
Quinidine 
known risk  
Females > Males. Substrate for 3A4 
Ranolazine 
possible risk 
  
Risperidone 
possible risk 
  
Ritonavir 
conditional risk 
Substrate for 3A4 
Roxithromycin* 
possible risk 
*not available in the United States 
Sertindole 
possible risk 
  
Sertraline 
conditional risk 
  
Solifenacin 
conditional risk 
  
Sotalol 
known risk  
Females > Males 
Sparfloxacin 
known risk  
  
Tacrolimus 
possible risk 
Substrate for 3A4 
Telithromycin 
possible risk 
Substrate for 3A4 
Terfenadine 
known risk  
No longer available in U.S.Substrate for 3A4 
Thioridazine 
known risk  
  
Tizanidine 
possible risk 
  
Trazodone 
conditional risk 
Substrate for 3A4 
Trimethoprim-Sulfa 
conditional risk 
  
Trimipramine 
conditional risk 
  
Vandetanib 
known risk  
  
Vardenafil 
possible risk 
Substrate for 3A4 
Venlafaxine 
possible risk 
  
Voriconazole 
possible risk 
  
Ziprasidone 
possible risk 
  
1 Additional agents can be found at https://www.crediblemeds.org  
2 Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
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17.6. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS RECIST 
VERSION 1.1 
 
17.6.1. Measurability of Tumor at baseline 
• Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
• Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
− 10 mm by CT scan (CT scan slice thickness no greater than 5 mm); 
− 10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable); 
− 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
• Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, and 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses 
/abdominal organomegaly identified by physical examination that is not measurable by reproducible 
imaging techniques. 
 
 
 
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• Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
− Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
− Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
− Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
− Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
− ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
− Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
 
17.6.2. Specifications by methods of measurements 
• Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
 
 
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• Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g., for body scans).  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there 
is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials were recurrence following complete response or surgical 
resection is an endpoint. 
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Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a subject to be 
considered in complete response. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain).When effusions are known to be a potential adverse 
effect of treatment (e.g., with certain taxane compounds of angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can 
be considered if the measurable tumor has met criteria for response or stable disease in order to 
differentiate between response (or stable disease) and progressive disease. 
17.6.3. Tumor Response Evaluation 
• Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable disease 
is defined by the presence of at least one measurable lesion (as detailed above).  
• Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in instances 
where subjects have only one or two organ sites involved, a maximum of two and four lesions 
respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which can 
be measured reproducibly should be selected.  
 
 
 
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Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As previously noted, pathological nodes which 
are defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, saggital, or coronal). The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm X 30 mm has a short axis of 20 
mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as 
the node measurement. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as previously noted, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ (more 
details to follow). In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
• Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response for 
target lesions. 
 
 
 
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• Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
• Special notes on the assessment of target lesions 
 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm. Case report forms (e-CRFs) or 
other data collection methods may therefore be designed to have target nodal lesions recorded in a 
separate section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. 
For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesion. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes which 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small to measure’. 
When this occurs, it is important that a value be recorded on the e-CRF. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If 
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the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small 
to measure, a default value of 5 mm should be assigned in this circumstance as well). This default 
value is derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness). The measurement of these lesions is potentially non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon measurement error. If the 
radiologist is able to provide an actual measurement, that should be recorded, even if below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’. 
 
17.6.4. Evaluation of non-target lesion 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in the 
protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. The appearance 
of one or more new lesions is also considered progression. 
 
 
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• Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanations as follows: 
When the subject also has measurable disease. In this setting, to achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare.  
When the subject has only non-measurable disease. This circumstance arises in some phase III trials 
when it is not a criterion of study entry to have measurable disease. The same general concepts 
apply here as previously noted, however, in this instance there is no measurable disease assessment 
to factor into the interpretation of an increase in non-measurable disease burden. Because worsening 
in non-target disease cannot be easily quantified, a useful test that can be applied when assessing 
subjects for unequivocal progression is to consider if the increase in overall disease burden based 
on the change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase in diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols as 
‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the subject should 
be considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so, 
therefore the increase must be substantial. 
• New lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific criteria 
for the identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging modality 
or findings thought to represent something other than tumor. This is particularly important when 
the subject’s baseline lesions show partial or complete response. 
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A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the subject 
who has visceral disease at baseline and while on study has a CT or MRI brain scan ordered which 
reveals metastases. The subject’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan.  
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imagine can be 
identified according to the following algorithm: 
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. A ‘positive’ FDG-PET scan lesion is one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that time (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
• Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response. Protocols must specify 
how any new therapy introduced before progression will affect best response designation. The 
subject’s best overall response assignment will depend on the findings of both target and non-target 
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• Best overall response: all time points 
The best overall response is determined once all the data for the subject is known.  
Best response is defined as the best response across all time points (for example, a subject who has 
SD at first assessment, PR at second assessment, and PD on last assessment has a best overall 
response of PR). When SD is believed to be the best response, it must also meet the protocol 
specified minimum time from baseline. If the minimum time is not met when SD is otherwise the 
best time point response, the subject’s best response depends on the subsequent assessments. For 
example, a subject who has SD at first assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD. The same subject lost to follow-up after the first 
SD assessment would be considered not evaluable.  
• Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ size 
(< 10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based 
on the increase in size of the nodes. As noted earlier, this means that subjects with CR may not have 
total sum of ‘zero’ on the e-CRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response: 
it is a reason for stopping study therapy. The objective response status of such subjects is to be 
determined by evaluation of target and non-target disease. 
Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of complete response depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of complete 
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response. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication. However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes or 
necrosis in existing lesion), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45 (2):2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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17.7. RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB AND CETUXIMAB -ASSOCIATED INTERSTITIAL 
LUNG DISEASE/PNEUMONITIS 
Clinical judgment and experience of the treating physician should guide the management plan of 
each subject. In general, the following interventions are in addition to the binimetinib-associated 
interstitial lung disease (ILD) dosing guidelines provided in Table 14 of the protocol and, moreover 
if ILD is diagnosed, cetuximab must be discontinued.  
Drug-associated ILD or pneumonitis is a clinical diagnosis based on clinical signs and symptoms, 
radiological changes, pulmonary function tests (PFT) and exclusion of other possible etiologies of 
parenchymal lung disease. The most common symptoms of ILD are nonspecific and include 
dyspnea, dry cough, fever, fatigue, hypoxia, and occasional hemoptysis. The CTCAE v.4.03 criteria 
for ILD (pneumonitis) are provided below. 
 
 
CTCAE v. 4.03 Criteria for Pneumonitis 
 
Grade 
Adverse 
Event 
1 
2 
3 
4 
5 
Pneumonitis 
Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated 
Symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL 
Severe 
symptoms; 
limiting self 
care ADL; 
oxygen 
indicated 
Life-threatening 
respiratory 
compromise; urgent 
intervention indicated 
(e.g., tracheotomy or 
intubation) 
Death 
Definition: A disorder characterized by inflammation or diffusely affecting the lung parenchyma. 
 
All subjects should be instructed to immediately report new or worsening respiratory symptoms. 
Diagnostic procedures include PFT and high-resolution CT scans. In case of ILD the subject should 
be treated according to the best available local practices and procedures. 
The principal management of ILD consists of drug interruption and/or dose reduction and treatment 
with steroids (eg. as specified below). Empirical antibiotics directed at likely pathogens should also 
be considered while the results of diagnostic procedures and cultures are pending.  
• Prednisolone 40 mg oral, daily 
− Reduce dose by 10 mg every 2 weeks × 2 (until dose reduced to 20 mg oral, daily) 
− Reduce dose by 5 mg weekly × 4 weeks 
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• Combine with empirical antimicrobial therapy while awaiting results of diagnostic 
procedures 
Willemsen A, Gutters J, Gerritsen W, et al. mTOR inhibitor-induced interstitial lung disease in 
cancer patients: Comprehensive review and practical management algorithm. In J Cancer 
(2016):138:2312-2321. 
 
 
 
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17.8. PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
Subjects will be asked the following:  
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 
(7) Very much worse 
(Mesa AM et al, 2013). 
 
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4. TABLE OF CONTENTS 
 
1. 
TITLE PAGE ................................................................................................................... 1 
2. 
SIGNATURES ................................................................................................................. 1 
3. 
VERSIONING ................................................................................................................. 1 
4. 
TABLE OF CONTENTS .............................................................................................. 21 
5. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 25 
6. 
INTRODUCTION ......................................................................................................... 27 
6.1. 
STUDY DESIGN ......................................................................................................... 27 
6.2. 
STUDY OBJECTIVES ................................................................................................ 29 
6.3. 
STUDY ENDPOINTS ................................................................................................. 30 
6.3.1. 
Primary endpoint ....................................................................................................... 30 
6.3.2. 
Secondary endpoints .................................................................................................. 30 
6.3.3. 
Exploratory endpoints ............................................................................................... 32 
6.4. 
STUDY TIMEPOINTS ................................................................................................ 32 
6.5. 
SAMPLE SIZE ............................................................................................................. 33 
6.6. 
CUT-OFF DATES ....................................................................................................... 34 
6.7. 
STEERING COMMITTEE (SC) ................................................................................. 35 
6.8. 
INDEPENDENT DATA SAFETY MONITORING COMMITEE (IDSMC) ............. 35 
6.9. 
STUDY FLOW-CHART ............................................................................................. 37 
6.10. STUDY SCHEME ....................................................................................................... 46 
7. 
ANALYSIS SETS .......................................................................................................... 47 
8. 
INFERENTIAL PRINCIPLES .................................................................................... 49 
9. 
REPORTING CONVENTIONS AND DEFINITIONS ............................................. 49 
9.1. 
DEFINITIONS ............................................................................................................. 49 
9.1.1. 
General ...................................................................................................................... 49 
9.1.2. 
Dates and period ........................................................................................................ 49 
9.1.3. 
Durations and times ................................................................................................... 51 
9.2. 
REPORTING CONVENTIONS .................................................................................. 52 
9.3. 
ANALYSIS VISITS ..................................................................................................... 53 
9.4. 
BASELINE ................................................................................................................... 61 
9.5. 
CUT-OFF CONVENTIONS ........................................................................................ 62 
10. DEVIATIONS AND ADDITIONAL REASONS OF EXCLUSION FROM 
ANALYSIS SETS .......................................................................................................... 63 
11. HANDLING OF MISSING DATA AND ANALYSIS OF DROP-OUTS ................ 64 
11.1. DROP-OUTS ................................................................................................................ 64 
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11.2. MISSING DATA (OTHER THAN DROP-OUT) ....................................................... 64 
11.2.1. Missing efficacy data ................................................................................................. 64 
11.2.2. Missing Safety data ................................................................................................... 64 
11.2.3. Missing QoL data ...................................................................................................... 65 
11.2.4. Missing or incomplete dates ...................................................................................... 65 
12. DISPOSITION OF SUBJECTS ................................................................................... 71 
13. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................... 71 
14. ANALYSIS OF EFFICACY ......................................................................................... 76 
14.1. PRIMARY ENDPOINT: CONFIRMED ORR BASED ON INVESTIGATOR-
ASSESSED TUMOR EVALUATION ........................................................................ 76 
14.1.1. Primary Analysis ....................................................................................................... 80 
14.1.2. Supportive Analyses .................................................................................................. 81 
14.1.3. Exploratory Analyses ................................................................................................ 81 
14.2. SECONDARY EFFICACY ENDPOINTS .................................................................. 82 
14.2.1. cORR assessed by central radiologist review ............................................................ 82 
14.2.2. ORR (for confirmed+unconfirmed responses) based on investigator-assessed tumor 
evaluation .................................................................................................................. 84 
14.2.3. ORR (for confirmed+unconfirmed responses) assessed by central radiologist review
 ................................................................................................................................... 86 
14.2.4. PFS based on investigator assessment ....................................................................... 86 
14.2.5. PFS assessed by central radiologist review ............................................................... 91 
14.2.6. Overall survival (OS) ................................................................................................ 91 
14.2.7. DOR based on investigator-assessed tumor evaluation ............................................ 91 
14.2.8. DOR assessed by central radiologist review ............................................................. 93 
14.2.9. TTR based on investigator-assessed tumor evaluation ............................................. 93 
14.2.10. TTR assessed by central radiologist review .............................................................. 95 
14.2.11. Percentage change in tumor measurement from baseline ......................................... 95 
14.2.12. Duration of Follow-Up .............................................................................................. 96 
15. SAFETY ANALYSIS .................................................................................................... 97 
15.1. TREATMENT EXPOSURE ........................................................................................ 97 
15.2. ADVERSE EVENTS ................................................................................................. 101 
15.3. LABORATORY DATA ............................................................................................. 109 
15.4. VITAL SIGNS ........................................................................................................... 111 
15.5. ECG ............................................................................................................................ 112 
15.6. MUGA/ECHOCARDIOGRAM ................................................................................ 113 
15.7. ECOG PS .................................................................................................................... 114 
15.8. PHYSICAL EXAMINATION ................................................................................... 114 
15.9. DERMATOLOGIC EXAMINATION ....................................................................... 114 
15.10. OPHTHALMIC EXAMINATION ............................................................................ 114 
15.11. CONCOMITANT THERAPIES AND THERAPEUTIC / DIAGNOSTIC 
PROCEDURES .......................................................................................................... 117 
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16. QUALITY OF LIFE ANALYSIS .............................................................................. 120 
16.1. EORTC QLQ-C30 SCORING ................................................................................... 121 
16.2. EQ-5D-5L ................................................................................................................... 123 
16.3. PGIC ........................................................................................................................... 123 
17. BIOMARKERS ANALYSIS ...................................................................................... 124 
18. HEALTHCARE RESOURCE UTILIZATION ....................................................... 124 
19. PHARMACOKINETICS ANALYSIS ...................................................................... 125 
19.1. DESCRIPTIVE STATISTICS ................................................................................... 125 
19.2. POPULATION PK AND EXPOSURE RESPONSE ANALYSES ........................... 126 
20. CHANGES TO THE STATISTICAL ANALYSIS PLAN SINCE PROTOCOL 
WRITING .................................................................................................................... 127 
21. DATA PROCESSING ................................................................................................. 129 
22. REFERENCE .............................................................................................................. 130 
23. APPENDIX .................................................................................................................. 131 
APPENDIX 1 ......................................................................................................................... 132 
APPENDIX 2 ......................................................................................................................... 133 
APPENDIX 3 ......................................................................................................................... 134 
APPENDIX 4 ......................................................................................................................... 135 
APPENDIX 5 ......................................................................................................................... 136 
APPENDIX 6 ......................................................................................................................... 138 
 
 
 
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List of Tables 
Table 1: Study Timepoints .............................................................................................................. 32 
Table 2: Time windows for weight, ECOG PS, ophthalmic and dermatological examination, 
ECHO/MUGA, coagulation, urinalysis, EORTC QLQ-C30; EQ-5D-5L, PGIC .................... 54 
Table 3: Time windows for vital signs ............................................................................................ 55 
Table 4: Time windows for ECG .................................................................................................... 56 
Table 5: Time windows for hematology ......................................................................................... 57 
Table 6: Time windows for chemistry ............................................................................................ 58 
Table 7: Time windows for CEA, CA19-9 ..................................................................................... 59 
Table 8: Illustration of D1 and D2 Criteria ..................................................................................... 61 
Table 9: Demographics and Baseline Characteristics ..................................................................... 72 
Table 10: Best Overall Confirmed Response .................................................................................. 77 
Table 11: Best Overall Response (confirmed+unconfirmed) .......................................................... 85 
Table 12: Censoring rules for PFS .................................................................................................. 89 
Table 13: Censoring rules for PFS (sensitivity analysis) ................................................................ 90 
Table 14: Censoring rules for DOR ................................................................................................ 92 
Table 15: Censoring rules for TTR ................................................................................................. 95 
Table 16: Summary of Clinical Laboratory Tests ......................................................................... 109 
Table 17: Censoring rules for TST ................................................................................................ 119 
Table 18: Censoring rules for PFS2 .............................................................................................. 119 
Table 19: Patient Reported Outcomes Compliance....................................................................... 120 
Table 20: EORTC QLQ-C30 questionnaire scoring ..................................................................... 122 
 
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5. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification 
BID 
Bis in Die 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BOCR 
Best Overall Confirmed Response 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CK 
Creatine Kinase 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete Response 
CtDNA 
Circulating tumor DNA 
CT scan 
Computed Tomography scan 
DBP 
Diastolic Blood Pressure 
DI 
Dose Intensity 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EQ VAS 
EuroQol Visual Analog Scale 
ES 
Efficacy Set 
FA 
Fluorescein Angiography 
FAS 
Full Analysis Set 
FPFV 
First Patient First Visit 
HR 
Heart Rate 
ICH 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
KM 
Kaplan-Meier 
LLT 
Lowest Level Term 
LPLV 
Last Patient Last Visit 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI 
MicroSatellite Instability 
NGS 
Next Generation Sequencing 
OCT 
Optical Coherence Tomography 
ORR 
Overall/Objective Response Rate  
PD 
Progressive Disease 
PDI 
Planned Dose Intensity 
PFS 
Progression-Free Survival 
PGIC 
Patient Global Impression Change 
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PK 
Phamacokinetic 
PP 
Per Protocol Set 
PCR 
Polymerase Chain Reaction 
PR 
Partial Response 
PT 
Preferred Term 
QD 
Quaque Die (once daily) 
QoL 
Quality of Life 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
QW 
Quaque Week (once a week)  
Q2W 
Quaque 2 Weeks (once every 2 weeks) 
RBC 
Red blood cells 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria In Solid Tumours 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
SD 
Stable Disease 
StD 
Standard Deviation 
SEM 
Standard Error of Mean 
SOC 
System Organ Class 
SPC 
Summary Of Product Characteristics 
TA 
Tumor Assessment 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
ULN 
Upper Limit Normal 
USM 
Urgent Safety Measure 
VAS 
Visual Analysis Scale 
WBC 
White Blood Cells 
WHODrug 
World Health Organisation Drug 
 
 
 
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6. INTRODUCTION 
This document describes the interim and final statistical analyses of the study, including 
pharmacokinetic analysis, that will be performed after the Stage 1 and Stage 2 snapshots, and final 
lock of the clinical database.  
This statistical analysis plan will be approved, finalised and signed before the first subject is 
screened in the study. 
6.1. 
STUDY DESIGN 
This Phase II study is conducted as an open-label, single arm, multinational, multicenter study of 
encorafenib, binimetinib plus cetuximab in subjects with previously untreated BRAFV600E -mutant 
Metastatic Colorectal Cancer.  
The study will include two stages according to a two-stage design.  
Stage 1: In the first stage, 40 subjects will be treated. In case of discordance in the results between 
the local assay and the central laboratory (potential false-positive local result), or lack of BRAFV600E 
confirmation, subject will be replaced for the interim primary analysis (futility analysis). If there 
are 11 or fewer confirmed responses (CR or PR) in the 40 treated subjects with a centrally confirmed 
BRAFV600E mutation, the study will be stopped. Otherwise, additional subjects will enter stage 2. 
Stage 2 may be initiated as soon as 40 subjects with a centrally confirmed BRAFV600E mutation are 
treated and confirmed responses are observed in at least 12 subjects. 
Stage 2: 50 additional subjects will be treated, for a total of 90 subjects with a centrally confirmed 
BRAFV600E mutation. In case of discordance in the results between the local assay and the central 
laboratory (potential false-positive local result), or lack of BRAFV600E confirmation, subject enrolled 
in the stage two of the trial will be replaced for the primary analysis.  
If at any time there is lack of confirmation of the BRAFV600E mutation in a total of 6 subjects (≥ 6% 
of the total planned enrollment) or discordance between the local assay and the central laboratory 
in 3 subjects (≥ 3% of the total planned enrollment), all subsequent subjects will be required to have 
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BRAFV600E determined by the central laboratory prior to study treatment assignment  (i.e., local 
BRAF testing will no longer be accepted for trial eligibility).   
Subjects will be eligible for the study based on identification of a BRAFV600E mutation in the tumor 
tissue as determined by local laboratory result obtained at any time prior to Screening. Only 
polymerase chain reaction (PCR) and next generation sequencing (NGS)-based results will be 
acceptable. The BRAF mutation status must be confirmed by central laboratory no later than 30 
days after the first dose of study treatment. In cases where there is a discordance between local 
assay and central laboratory results (i.e. either no BRAF mutation identified or not a BRAFV600E 
mutation), or if the central laboratory is not able to confirm presence of a BRAFV600E mutation due 
to inadequate or poor sample condition or absence of available material within 30 days of initiating 
study therapy, subjects may only continue treatment if there is no clinical indication of deterioration 
or disease progression and the Investigator determines that the subject is deriving benefit. In such 
instances, subjects must be informed that the BRAFV600E mutation status is unconfirmed and must 
sign a separate informed consent form (ICF) that includes this information and describes alternative 
treatment options. Subjects with an unconfirmed BRAFV600E mutation status will be included in the 
Full Analysis Set (when they have received at least one dose of study treatment (partial or full), cf. 
section 7). 
Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, 
subject’s decision, withdrawal of consent, initiation of subsequent anticancer therapy or death.  
After discontinuation of study treatment, there will be a 30-day safety follow-up period. Subjects 
will then enter a survival follow-up period after the completed 30 days safety follow up and will be 
followed for at least 1 year after the start of study treatment of the last subject enrolled. If a subject 
discontinues the treatment for a reason other than progressive disease, tumor assessment must be 
performed (as per local and central review) until the start of new anti-cancer therapy, disease 
progression, death, lost to follow-up, subject decision or withdrawal consent. 
 
 
 
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The investigational products in this study are encorafenib and binimetinib in combination with 
cetuximab. Dose schedule is the following: 
• Encorafenib: 300 mg PO (oral capsule 4X 75 mg) QD. 
• Binimetinib: 45 mg PO (oral tablet 3X 15 mg) BID. 
• Cetuximab: 400 mg/m2 intravenous (IV) at Cycle 1 day 1 then 250 mg/m2 IV every week 
(QW) for the first 28 weeks. Then, 500mg/m2 IV every two weeks (Q2W) from week 29 
(Cycle 8 day 1).  
If there is a dose modification prior to switching to the biweekly schedule, the total dose per cycle 
should be maintained (i.e. 200mg/m2 QW may be changed to a 400mg/m2 Q2W). 
The end of the study is defined as the time point when all subjects have been followed for at least 1 
year after the start of study treatment of the last subject enrolled (including survival status). 
6.2. 
STUDY OBJECTIVES 
The primary objective of the study is to evaluate the antitumor activity of the combination of 
encorafenib, binimetinib and cetuximab by assessing the confirmed overall response rate (cORR) 
by local radiologist/investigator assessment in adult subjects with previously untreated centrally 
confirmed BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC). 
The secondary objectives of the study are: 
• To evaluate the cORR by central radiologist assessment. 
• To 
evaluate 
ORR 
(for 
confirmed 
and 
unconfirmed 
responses) 
by 
local 
radiologist/investigator and central assessment. 
• To assess the effect of the combination of encorafenib, binimetinib and cetuximab on the 
duration of response (DOR).  
• To assess the effect of the combination of encorafenib, binimetinib and cetuximab on other 
time-related efficacy parameters: time to response (TTR), progression-free survival (PFS) 
and overall survival (OS). 
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• To characterize the safety and tolerability of the combination of encorafenib, binimetinib 
and cetuximab.  
• To assess the effect on quality of life (QoL). 
• To explore health care resource utilization. 
• To describe the pharmacokinetics (PK) of encorafenib, binimetinib, a metabolite of 
binimetinib (AR00426032) and cetuximab. 
 
Exploratory objectives: 
• To assess the relationship between changes in tumor markers (carcinoembryonic antigen 
[CEA] and carbohydrate antigen 19-9 [CA19-9]) and radiographic response to treatment. 
• To assess BRAFV600E status in blood circulating tumor DNA (ctDNA) at baseline. 
• To assess the   potential predictive significance of the microsatellite instability (MSI) status 
in subjects with BRAFV600E mutant mCRC.  
• To assess blood- and tissue-based predictive biomarkers of activity 
6.3. 
STUDY ENDPOINTS 
6.3.1. Primary endpoint  
The primary endpoint is the confirmed Objective Response Rate (cORR) as assessed by local 
radiologist/investigator review as per Response Evaluation Criteria in Solid Tumours (RECIST 
1.1[1]).  
The cORR is defined as the number of subjects achieving a best overall confirmed response of CR 
or PR divided by the total number of analysed subjects. 
6.3.2. Secondary endpoints 
The following secondary efficacy endpoints will be determined: 
• cORR as assessed by central radiologist review as per RECIST 1.1. 
• ORR (for confirmed and unconfirmed responses) as per local radiologist/investigator-
assessment. 
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• ORR (for confirmed and unconfirmed responses) as per central assessment. 
• Overall survival (OS) defined as the time from first dose to death due to any cause. If a 
subject is not known to have died, survival will be censored at the date of last known date 
the subject was alive or at the cutoff date, whatever is earlier.  
• Progression-free survival (PFS), defined as the time from first dose to the earliest 
documented date of disease progression or death due to any cause, assessed based on local 
radiologist/investigator review.  
• PFS defined with tumor assessment assessed based on central review will be also used in a 
supportive analysis of PFS. 
• Duration of response (DOR) defined as the time from first radiographic evidence of response 
assessed based on local radiologist/investigator review to the earliest documented PD or 
death due to underlying disease and is calculated for responders only. Responders who do 
not have a PD or death date by the data cutoff date will be censored for DOR at their last 
adequate tumor assessment of CR, PR or SD prior to the cutoff date.  
• Duration of response assessed based on central radiologist review. 
• Time to response (TTR) defined as the time from first dose until first documented 
radiographic evidence of response of CR or PR assessed based on local 
radiologist/investigator review. Subjects who do not have a CR or PR by the cutoff date will 
be censored for TTR at their last adequate tumor assessment date if they didn’t have a PFS 
event, and at maximum follow-up (i.e. FPFV to LPLV used for the analysis) if they had a 
PFS event.  
• Time to response assessed based on central review. 
• Type and severity of adverse events (AEs) and serious adverse events (SAEs), changes in 
hematology and chemistry values, physical examinations, vital signs, electrocardiogram 
(ECGs) and echocardiogram (ECHO)/ multi-gated acquisition (MUGA) scans and 
ophthalmological examinations graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events v4.03 (NCI-CTCAE v4.03). 
• Change from baseline in the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire for Cancer subjects (QLQ-C30), EuroQol-5D-5L 
(EQ-5D-5L), and Patient Global Impression of Change (PGIC). 
• Resource utilization focused on hospitalizations occurring during the study treatment phase. 
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• Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) and serum concentration of cetuximab. 
6.3.3. Exploratory endpoints 
The following exploratory efficacy endpoints will be determined: 
• Changes from baseline in blood tumor markers (carcinoembryonic antigen [CEA] and 
carbohydrate antigen 19-9 [CA19-9]) at the beginning of each cycle and at the end of 
treatment. 
• BRAF V600E mutation status in blood circulating tumor DNA (ct-DNA) at baseline. 
• MSI status in formalin-fixed paraffin-embedded (FFPE) samples via established PCR assays 
in tumor sample versus germline control at screening. 
 
6.4. 
STUDY TIMEPOINTS 
 
Table 1: Study Timepoints 
Analysis Visit 
Number 
Study Phase Number 
Study Phase  
Visit Label for Statistical 
Output 
1 
1 
Screening 
Screening 
x.1 
2 
Treatment 
CxD1 
x.2 
CxD8 
x.3 
CxD15 
x.4 
CxD22 
901 
End of treatment 
902 
Safety follow-up 
91y 
3 
Long-term follow-up 
Survival y 
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6.5. 
SAMPLE SIZE 
The sample size is based on a two-stage design with nominal risks alpha=2.5% and beta=20%.  
The null hypothesis that the true response rate is 30% will be tested against a one-sided alternative. 
In the first stage, 40 subjects will be treated. Subjects in whom the presence of BRAFV600E is not 
confirmed (discordance or lack confirmation) by central laboratory will be replaced. If there are 11 
or fewer confirmed responses in these 40 treated subjects, inactivity will be declared, and the study 
will be stopped for futility. 
The time point for the futility analysis will be after all 40 treated patients of stage 1 with centrally 
confirmed BRAFV600E mutation had the opportunity to complete four post baseline tumor 
assessment1. And in case the last subject required for the concerned stage has an objective response, 
it should be confirmed in the following tumor assessment before the analysis is being performed. 
However, it will be possible to proceed to Stage 2 as soon as 40 subjects with a centrally confirmed 
BRAFV600E mutation are treated and 12 confirmed responses are observed.  
Subjects data that will be analyzed during the futility analysis will be reviewed on an ongoing basis 
in order to determine as soon as possible (even before the inclusion of the 40th patient) whether the 
criteria for continuing to stage 2 (12 confirmed responses) are satisfied or not. 
As it may take several treatment cycles for subjects to achieve a confirmed response, then a limited 
number of subjects (maximum 12) from stage 2 may be treated while waiting for all subjects in the 
initial cohort of 40 subjects in Stage 1 to be evaluable for a confirmed response. These additional 
subjects will not count towards responses in Stage 1 but will be included as part of the Stage 2 
cohort, should the study move forward into Stage 2. 
If at any time it becomes evident that the threshold of 12 responses is unlikely to be met, then 
additional patients may not be recruited (e.g.: 6 or fewer responses among 35 patients with sufficient 
follow-up [potential for at least 2 post-baseline assessments]).   
 
1 NB: This means that patients who discontinued are to be taken into account  
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If the study continues to the second stage, 50 additional subjects will be treated for a total of 90 
subjects with a centrally confirmed BRAFV600E mutation. 
The null hypothesis will be rejected if 37 or more confirmed responses are observed in 90 treated 
subjects. This design yields a 1-sided type I error rate equal to 1.6% and power of 80% when the 
true response rate is 45%. 
NB: Due to the time needed to get the central confirmation of the BRAFV600E mutation, more than 
90 subjects with centrally confirmed BRAFV600E mutation may be treated. If so, the nominal alpha 
and power will be computed. The Clopper-Pearson (exact) binomial 95% confidence interval will 
be computed with 37 confirmed responders observed among the N patients and the lower limit will 
be compared to the clinically relevant response rate of 30%.  
Moreover, the primary analysis at Stage 2 will be repeated when excluding the overrunning patients 
(i.e. on the 90 first treated subjects with a centrally confirmed BRAFV600E mutation, see section 
14.1.1) and differences between the two analyses will be discussed. 
The cut-off for stage 2 analysis will be after all 90 treated patients of stage 1 and 2 with centrally 
confirmed BRAFV600E mutation had the opportunity to complete four post-baseline tumor 
assessments1, and after subjects with an initial objective response have had an opportunity to have 
a confirmation scan. The sample size calculation was based on binomial probabilities calculated in 
R (version 3.2.3). 
This binomial design matches the O’Brien-Fleming design (O’Brien, 1979[2]) for one sample 
obtained using East software (version 6.4) [3] with a 1-sided type I error rate equal to 2.5% and a 
power of 81%. 
6.6. 
CUT-OFF DATES 
3 statistical analyses are planned: Stage 1 analysis (futility analysis), Stage 2 analysis and analysis 
at the end of the study. 
The cut-off date for Stage 1 and Stage 2 analyses is estimated to occur approximately when all 
treated subjects with a centrally confirmed BRAFV600E mutation of the concerned stage (i.e. 40 
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patients for Stage 1 and 90 patients for Stage 2) had the opportunity to complete four post baseline 
tumor assessment). And in case the last subject required for the concerned stage has an objective 
response, it should be confirmed in the following tumor assessment before the analysis is being 
performed.  
The end of the study is defined as the time point when all subjects have been followed for at least 
1 year after the start of study treatment of the last subject enrolled (including survival status). 
Scope of each cut-off analysis is described in Appendix 5 (List of statistical Tables, figures and 
Listings). 
6.7. 
STEERING COMMITTEE (SC) 
A steering committee (SC) will be established comprising Investigators participating in the trial and 
Sponsors’ representatives from the Clinical Study Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will be responsible 
for reviewing the safety data of the subjects treated in the study as well as reviewing efficacy results 
for cORR from the interim and final analyses. 
The SC will review protocol amendments as appropriate. The details of the role of the Steering 
Committee will be defined in an SC charter.  
6.8. 
INDEPENDENT DATA SAFETY MONITORING COMMITEE (IDSMC) 
An Independent Data Safety Monitoring Committee (iDSMC) will be established to perform 
additional review of available safety data at regular intervals to ensure whether the overall safety of 
the trial remains acceptable. The iDSMC will also have the opportunity to review toxicities 
observed over time, in cycles of treatment beyond the first cycle. Following each meeting, the 
iDSMC will provide in writing recommendation to the Sponsor whether to continue, modify, or 
stop the study in compliance with the iDSMC Charter.  
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The iDSMC membership, data to be reviewed, timing of the planned reviews as well as the 
operating procedures will be described in the iDSMC charter. 
Analyses for iDSMC will be based on safety, thus this will not affect the statistical operating 
characteristics of the Stage 1 and Stage 2 analyses. 
 
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a 
Except C1D1, if visit is missed. 
Theoretical cycles dates (7 days ± 3) are kept constant irrespectively of whether the visit is done and/or the product is administered or not. 
If patient doesn´t come for CnD1 visit, the CnD1 assessments will still need to be performed (and shall be recorded on the unscheduled visit in the eCRF). 
b 
Local urine pregnancy test for women of childbearing potential except serum pregnancy test at EOT.  
c 
Hematology - list of analytes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils/absolute neutrophil count (ANC), platelets, red blood cells (RBC), white blood cells (WBC) 
d 
Clinical Chemistry – list of analytes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (total and direct),albumin, alkaline phosphatase, bicarbonate (HCO3), blood urea nitrogen (BUN)/ 
urea, calcium, chloride, creatine kinase (CK), creatinine, glucose, lactate dehydrogenase (LDH), magnesium, potassium, sodium, total protein, troponin I or T, uric acid, amylase, lipase.  
Calculated creatinine clearance (Cockroft-Gault formula) will be measured at screening  
Bicarbonates (HCO3): not mandatory in Japan  
e 
Coagulation – list of analytes: prothrombin time (PT) or International Normalized Ratio (INR);activated partial thromboplastin time (aPTT)  
f 
Urinalysis – list of analytes: blood, glucose, ketones, leukocytes, hydrogen ion concentration (pH), protein 
g 
Procedure does not have to be repeated if performed within 72 hours prior to Cycle 1 Day 1 (i.e., first day of dosing). 
h 
Electrocardiograms are to be performed in triplicate predose on Cycle 1 Day 1 (conducted within approximately 5 to 10 minutes total time), followed by a single ECG at 2.0 (± 0.5) hours after administration of 
encorafenib and binimetinib and before the start of the cetuximab infusion. Single ECGs are to be performed on Cycle 2 Day 1 predose and at 2.0 (+ 0.5) hours after administration of encorafenib and binimetinib  
and before the start of the cetuximab infusion. Single ECGs are to be performed predose at remaining time points. Electrocardiograms should be performed prior to PK and PD blood collection at equivalent 
nominal timepoints. 
i 
Visual assessment (General inspection of the eyes, examination of motility and alignment, visual disturbance including diminished central vision, blurred vision or loss of vision) to be performed on site by the 
investigator. 
Full ophthalmic examination by ophthalmologist to be performed at EOT and, if clinically indicated during treatment,, including best corrected visual acuity for distance testing, OCT and/or fluorescein 
angiography, slit lamp examination, intraocular pressure and dilated fundoscopy with attention to retinal abnormalities. 
An ophthalmic examination at the 30-day follow up is only required if there was a clinically significant abnormality noted at EOT.  
j 
Dermatologic examinations are to be performed every 8 weeks from Cycle 1 Day 1 (i.e., on Day 1 of Cycles 3, 5, 7…).  
k 
ECHO/MUGA scans are to be performed on Cycle 2 Day 1 and Cycle 5 Day 1, then every 12 weeks and EOT 
l 
Tumor evaluations are to be performed every 6 weeks (±7 days) from first dose for the first 12 weeks, then every 8 weeks (±7 days) until disease progression. The time window allowed for the first tumor  
assessment (i.e. day 42 from first dose) is +7 days. 
m 
If a subject discontinue study treatment for reasons other than disease progression, then tumor assessments must be performed (as per local and central review) every 6 weeks (first 12 weeks) 
 then every 8 weeks  until the start of new anti-cancer therapy, disease progression, death, lost to follow-up, subject’s decision or consent withdrawn. 
n 
PK samples will be collected during Cycle 1 and Cycle 2 only. On Cycle 1 Day 1 postdose at 2 h (± 10 min) and 6 h (± 30 min). PK samples will be collected on Cycle 2 Day 1 predose (just prior to dosing) and 
postdoseat 2 h (± 10 min). PK blood samples for encorafenib/binimetinib and potentially relevant metabolites will be processed to plasma. PK blood samples for cetuximab will be processed to serum. 
o 
Optional tumour sample will be requested only for subjects that discontinue study  drug treatment due to disease progression. 
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p 
For subjects who discontinue study treatment due to disease progression  the survival follow up phase will start after the 30-days safety follow up is complete The subject will be contacted by phone for 
collection of information This may be conducted more frequently as needed. 
For subjects who discontinue study treatment due to reasons other than disease progression,  tumor assessment  must be performed until start of new anti cancer therapy,disease progression, death, lost to 
follow-up, subject’s decision or consent withdrawn. 
q 
To be performed 30-day after end of treatment (EOT) , when clinically appropriate, it is recommended subjects be monitored with physical examinations, dermatological examinations and chest CT scans for  
cutaneous and non-cutaneous secondary malignancies for up to 6 months after the last encorafenib dose or until initiation of another antineoplastic therapy.  
r 
To be performed prior to study treatment administration. Only for vital signs: not to be performed at D8 and D22 starting week 29. 
s 
The questionnaires should be completed by the subjects at the beginning of the study visit prior to receiving any study treatment, prior to any other study assessment or consultation with the Investigator, 
and prior to being informed of their current disease status.  
t 
Cetuximab wil be administered as a weekly schedule for the first 28 weeks. Subjects on study will switch to a biweekly schedule starting on week 29 (Cycle 8 day 1). If there was a dose modification prior 
to switching to the biweekly schedule, the total dose per cycle should be maintained (i.e. 200mg/m2 QW, may be changed to a 400mg/m2 Q2W)  
u 
Information related to the length of stay, hospital facilities used, reasons for hospitalization, and hospital discharge information will be collected 
v 
From Week 29 (cycle 8), D8 and D22 visits will not be performed (biweekly infusions of cetuximab: no cetuximab infusion on D8 and D22) 
Abbreviations:  BSA = body surface area; CA19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative  
Oncology Group Performance Status; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D-5L = EuroQol-5D-5L; HIV= Human immuno deficiency virus; IV = 
intravenous(ly); MRI = magnetic resonance imaging; MSI = microsatellite instability; MUGA = multi-gated acquisition; PD = progressive disease; PGIC = Patient's Global Impression of Change; PK = pharmacokinetic(s). 
 
 
 
 
 
 
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7. ANALYSIS SETS 
The following analysis sets are defined:  
• The Screened subjects set (SCR) consists of all subjects who have signed any informed consent. 
• The Full Analysis Set (FAS) is composed of all subjects having received at least one dose of 
study treatment (partial or full). The analysis of efficacy, safety, quality of life, biomarkers and 
healthcare resource utilization will be done on the FAS. 
Note: Partial dose is defined as at least one dose of encorafenib, binimetinib or cetuximab. 
• The Efficacy Set (ES) is composed of all FAS subjects with a centrally confirmed BRAFV600E 
mutation. The analysis of efficacy, including the primary analysis of the primary endpoint, will be 
done on the ES. 
• The Per Protocol set (PP set) is composed of all FAS subjects without any major protocol 
deviations. The PP set will be defined prior to the database lock supporting the primary analysis, 
and will be used for the supportive analyses of primary efficacy endpoint. Note: In this SAP, the 
term “major protocol deviations” describes all deviations likely to significantly bias the 
interpretation of the primary efficacy endpoint results leading to exclusion of PP set. There may be 
protocol deviations identified as major by the clinical team (in CTMS) that will not lead to exclusion 
of PP set. All deviations recorded in CTMS will be reviewed prior to database snapshot/lock to 
identify any potential deviations leading to exclusion of PP set.  
Continuation of the study despite BRAFV600E -mutant status not centrally confirmed is allowed by 
the protocol (i.e. not a protocol deviation), provided the subject had signed the appropriate ICF. As 
the study investigates “encorafenib, binimetinib plus cetuximab in subjects with previously 
untreated BRAFV600E -mutant Metastatic Colorectal Cancer”, subjects with no central confirmation 
of the BRAFV600E -mutant status (i.e. unconfirmed or negative) will be excluded from the PP set. 
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• The Pharmacokinetics Set (PK Set) will consist of all subjects who receive at least 1 dose of 
encorafenib, binimetinib or cetuximab and who have at least 1 post-dose PK blood collection with 
associated bioanalytical results. 
 
 
 
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8. INFERENTIAL PRINCIPLES 
Only the test on the primary efficacy endpoint, on which is based the sample size justification, may 
lead to a causal interpretation. All other statistical results are to be regarded within an exploratory 
perspective.  
 
9. REPORTING CONVENTIONS AND DEFINITIONS 
9.1. DEFINITIONS 
9.1.1. General 
Study treatment will refer to the combination of encorafenib (LGX818 or W0090), binimetinib 
(MEK162 or W0074) and cetuximab.  
The treatment label for all Tables, Listings and Figures will be: “Encorafenib + Binimetinib + 
Cetuximab”. 
Study drug will refer to encorafenib, binimetinib or cetuximab. 
When displaying summaries for each study drug, drug labels to be used are: Encorafenib, 
Binimetinib and Cetuximab, respectively. 
9.1.2. Dates and period 
Date of first administration of study treatment is derived as the first date when a non-zero dose of 
any study drug was administered and recorded on the eCRF.  
Date of last administration of study treatment is defined as the last date when a non-zero dose of 
any study drug was administered and recorded on the eCRF. Note: if at a given analysis time point, 
the patient has a start date but with no end date and no EOT page is filled-in, the patient will be 
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considered as ongoing and the end date will be imputed to the cut-off date for the calculation of 
treatment duration. 
Last contact date will be derived for patients (known to have died or not) at the analysis cut-off. 
Imputed date (e.g. analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be considered for the determination of last contact date. 
Only dates associated with patient visits or actual examinations of the patient will be used in the 
derivation. If after derivation, the last contact date is posterior to the cut-off date, then the last 
contact date will be taken to be the cut-off date. Last contact date will only be derived using the 
latest complete date among the following: 
• Start/end date of study medication with non-missing dose (doses of 0 are allowed); 
• RECIST assessment date with evaluation marked as “done”; 
• Laboratory/PK collection date with sample collection marked as “done”; 
• Vital sign date with non-missing parameter value; 
• Cardiac evaluation date with non-missing parameter value; 
• ECG evaluation date with non-missing parameter value; 
• Ophthalmologic evaluation date with non-missing parameter value; 
• Physical examination date with non-missing parameter value; 
• Questionnaire evaluation date with non-missing parameter value; 
• Performance status date with non-missing performance status; 
• Start/end date of adverse events with non-missing/non-“None” verbatim term and outcome 
different from “Fatal” and grade less than 5 
• Start date of fatal AE (i.e. outcome “Fatal” and grade 5) when the Start date is strictly before 
the end date 
• Start/end date of antineoplastic therapies administered after study treatment discontinuation 
with non-missing medication/procedure term; 
• Date of contact in survival status when the patient is marked as alive; 
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• Treatment assigned date. 
 
FPFV used for analysis will be defined as the earliest date of first study treatment administration. 
 
LPLV used for analysis will be defined as the greatest Last Contact Date. 
  
Unless otherwise stated, reference dates are defined as: 
• For the Reference Start Date/Time: the date/time of first study treatment administration for 
treated subjects and the date/time of first visit in other case  
• For the Reference End Date/Time: the date/time of last administration to study treatment. 
 
Study treatment period will refer to the period from first study treatment administration date up to 
last study treatment administration date + 30 days (included). 
 
9.1.3. Durations and times 
Some analysis may require the computation of a duration from a reference day to a post-reference 
day. 
Duration will be defined in days (or in seconds, if applicable) as following: 
• Duration (in days) = Date - Reference date + 1 day 
• Duration (in seconds) = (DateTime) – (Reference DateTime) + 1 sec 
Unless specified otherwise, durations of events (e.g., duration of treatment) will be calculated in 
days. Conversions to weeks, months, years will be days/7, days/30.4375, days/365.25, respectively. 
The onset day of AE is calculated from the date of first study treatment administration up to the start 
date of the AE notification, as follows: 
• If start date ≥ Date of first administration: onset day = Date AE notification – Date of first 
study treatment administration + 1  
• If start date < Date of first administration: onset day = Date AE notification – Date of first 
study treatment administration  
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Study day is defined in the following manner:  
• On or after the start date of study treatment: the study day will be calculated as (date of 
safety assessment) – (start date of study treatment) + 1. Study day 1 will therefore be the 
first day of study treatment. 
• Before the start date of study treatment: the study day will be calculated as (date of safety 
assessment) – (start date of study treatment).  
Time to event is defined in the following manner:  
• The time from event i to an event j (in days) will be calculated as (date of event j – date of 
event i) + 1 
 
9.2. REPORTING CONVENTIONS 
Summary statistics will be summarized by visit when appropriate and will consist of values for: 
• number of subjects, mean, standard deviation, median, lower and upper quartiles, minimum 
and maximum for quantitative parameters (95% confidence interval around the mean will 
be presented when relevant)  
• number and percentage of subjects for qualitative parameters  
 
Summary statistics will be presented in tabular and/or graphics format when appropriate.  
Mean and standard error of mean (SEM) will be represented graphically by time windows for 
relevant criteria.  
Qualitative variables must be displayed by increasing order of modalities if ordinal, and by 
alphabetical order otherwise.  
All tables describing events by MedDRA System Organ Class (SOC) and/or Preferred Term (PT), 
or by WHODrug "Anatomical Therapeutic Chemical" (ATC) classification, should be displayed by 
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decreasing order of frequency (%) of SOC and PT, or ATC, and by alphabetical order when similar 
frequencies.  
For quantitative variables:  
- 
Calculated statistics (mean, std, median, lower and upper quartiles and 95% confidence 
interval) will be displayed with one more significant figure than the observed data. 
- 
For description of changes over time, baselines and values for present changes will be also 
described at a given visit.  
- 
For description of values over time, baselines for present values will be also described at a 
given visit.  
For percentages,  
- 
One decimal digit should be given, 
- 
No percentage should be given for cells with 0 subjects. 
- 
They will be computed on the analysis population.  
 
Individual data listings will be provided for all analyzed criteria, sorted by treatment group, subject 
identifier, parameter and corresponding date of assessment. 
When results are graphically represented, time units (Days, Weeks, Months...) must be used for 
horizontal axis and scale of axis must be proportional to time interval duration. Number of subjects 
(N=xx) per timepoint should be displayed on the horizontal axis. 
 
9.3. ANALYSIS VISITS 
Time windows 
Except for ECG baseline, if two or more assessments are performed within a time window then the 
assessment closest to the planned visit is used in analyses by time window. For worst post-baseline 
assessment all on-treatment values are considered regardless of time windows. 
Time windows for criteria are defined in Table 2 to Table 7.  
 
 
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Table 2: Time windows for weight, ECOG PS, ophthalmic and dermatological examination, 
ECHO/MUGA, coagulation, urinalysis, EORTC QLQ-C30; EQ-5D-5L, PGIC 
 
Time Window 
Planned Visit Timing 
Time Window Definition 
Baseline 
Study day 1 pre-dose 
Before first study treatment 
administration 
Cycle 2 Day 1 
Study day 29 
Study day 1 post-dose to 43 
Cycle x Day 1 
 
Study day (x-1)*28+1 = k 
Study days k-13 to k+14 
Safety follow-up 
 
Post treatment study day 30* 
Last administration of study 
treatment day+1 to Post 
treatment study day 37 
* Study day i = First day of study treatment administration + (i-1) day(s) 
   Post treatment study day i = Last administration of study treatment day + i day 
 
 
 
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Table 3: Time windows for vital signs 
 
Time Window 
Planned Visit Timing 
Time Window Definition 
Baseline 
Study day 1 pre-dose 
Before first study treatment 
administration 
Up to week 28 
Cycle 1 Day 8 
Study day 8 
Study days 1 post dose to 11 
Cycle 1 Day 15 
Study day 15 
Study days 12 to 18 
Cycle 1 Day 22 
Study day 22 
Study days 19 to 25 
Cycle 2 Day 1 
Study day 29 
Study days 26 to 32 
Cycle x Day y 
(except C1D8) 
Study day (x-1)*28+y = k 
Study days k-3 to k+3 
From week 29 (Cycle 8 Day 1) 
Cycle 8 Day 1  
 
Study day 197 
Study days 194 to 204 
Cycle 8 Day 15  
 
Study day 211 
Study days 205 to 218 
Cycle 9 Day 1  
 
Study day 225 
Study days 219 to 233 
Cycle x Day y 
from cycle 8 Day 15 
Study day Study day (x-
1)*28+y = k 
Study days k-6 to k+7 
Safety follow-up 
 
Post treatment study day 30 
Last administration of study 
treatment day+1 to Post 
treatment study day 37 
* Study day i = First day of study treatment administration + (i-1) day(s) 
   Post treatment study day i = Last administration of study treatment day + i day 
 
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Table 4: Time windows for ECG 
 
Time Window 
Planned Visit Timing 
Time Window Definition 
Baseline 
Study day 1 pre-dose 
Before first study treatment 
administration 
Cycle 1 Day 1 post-dose 
Study day 1 post-dose 
Study days 1 post dose to 8 
Cycle 1 Day 15  
Study day 15 
Study days 9 to 22 
Cycle 2 Day 1 pre-dose 
Study day 29 pre-dose 
Study days 23 to before C2D1 
study treatment administration 
Cycle 2 Day 1 post-dose 
Study day 29 post-dose 
Study days 29 C2D1 post dose 
to 43 
Cycle x Day 1 from cycle 3 
 
Study day (x-1)*28+1 = k 
Study days k-13 to k+14 
Safety follow-up 
 
Post treatment study day 30* 
Last administration of study 
treatment day+1 to Post 
treatment study day 37 
* Study day i = First day of study treatment administration + (i-1) day(s) 
   Post treatment study day i = Last administration of study treatment day + i day 
 
 
 
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Table 5: Time windows for hematology 
 
Time Window 
Planned Visit Timing 
Time Window Definition 
Baseline 
Study day 1 pre-dose 
Before 1rst administration 
Cycle 1 Day 15  
Study day 15 
Study day 1 post-dose to 18 
Cycle 1 Day 22  
Study day 22 
Study days 19 to 25 
Cycle 2 Day 1 
Study day 29 
Study days 26 to 43 
Cycle x Day 1 from cycle 3 
 
Study day (x-1)*28+1 = k 
Study days k-13 to k+14 
Safety follow-up 
 
Post treatment study day 30* 
Last administration of study 
treatment day+1 to Post 
treatment study day 37 
* Study day i = First day of study treatment administration + (i-1) day(s) 
   Post treatment study day i = Last administration of study treatment day + i day 
 
 
 
 
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Table 6: Time windows for chemistry 
 
Time Window 
Planned Visit Timing 
Time Window Definition 
Baseline 
Study day 1 pre-dose 
Before 1rst administration 
Cycle 1 Day 1  
Study day 1 post-dose 
Study days 1 post dose to 8 
Cycle 1 Day 15  
Study day 15 
Study days 9 to 22 
Cycle 2 Day 1 
Study day 29 
Study days 23 to 43 
Cycle x Day 1 from cycle 3 
 
Study day (x-1)*28+1 = k 
Study days k-13 to k+14 
Safety follow-up 
 
Post treatment study day 30* 
Last administration of study 
treatment day+1 to Post 
treatment study day 37 
* Study day i = First day of study treatment administration + (i-1) day(s) 
   Post treatment study day i = Last administration of study treatment day + i day 
        
 
 
 
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Table 7: Time windows for CEA, CA19-9 
 
Time Window 
Planned Visit Timing 
Time Window Definition 
Baseline 
Study day 1 pre-dose 
Before 1rst administration 
Cycle 2 Day 1  
Study day 29 
Study days 1 post dose to 43 
Cycle x Day 1 from cycle 3 
 
Study day (x-1)*28+1 = k 
Study days k-13to k+14 
Safety follow-up 
 
Post treatment study day 30* 
Last administration of study 
treatment day+1 to Post 
treatment study day 37 
* Study day i = First day of study treatment administration + (i-1) day(s) 
   Post treatment study day i = Last administration of study treatment day + i day 
Determination of Missing Adequate Tumor Assessments  
The term ‘adequate Tumor Assessments (TA)’ is defined as TA with overall lesion response 
different from missing and ‘Unknown’. The term ‘missing adequate TA’ is defined as TA not done 
or TA with overall lesion response equal to ‘Not Evaluable’. For the sake of simplicity, the ‘missing 
adequate TA’ will also be referred as ‘missing TA’. An exact rule to determine whether there is one 
or two missing TAs is therefore needed.  
This rule will be based on the distance between the last adequate TA date and the event date. 
Let D1 be the largest distance (relative to the last adequate TA date) that a patient can have a tumor 
assessment and not be classified as having missed an assessment. Let D2 be the largest distance 
(relative to the last adequate TA date) that a patient can have a tumor assessment and not be 
classified as having missed two assessments. If the distance exceeds threshold D1 or D2 then the 
analysis will assume one or two missing TAs, respectively.  
The threshold D1 will be defined as the protocol specified interval between the TAs plus the 
protocol allowed window around the assessments. Similarly, the threshold D2 is defined as two 
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times the protocol specified interval between the TAs plus the protocol allowed window around the 
assessments. 
As per protocol, post-screening assessments are expected to be performed every A=6 weeks (±B=7 
days)  from the first dose for the first 12 weeks of treatment (I=84 days); except for first tumor 
evaluation for which the time-window allowed is day 42 +7 days from first dose, then every X=8 
weeks (±Y=7 days) thereafter until disease progression, subject decision, withdrawal of consent, 
initiation of subsequent anticancer therapy, subject is lost to follow-up, death or defined end of 
study. 
Therefore: 
• if the last adequate tumor assessment before the event date is performed on or before study 
day 21 (=7*A/2) then D1=49 (=A*7+B) days and D2=91 (=2*A*7+B) days; 
­ This accounts for the scenario where the last adequate tumor assessment is the 
baseline assessment. This also allows for the rare instance where an additional 
assessment occurred early in the study. 
• if the last adequate tumor assessment before the event date is performed between study 
day M+1 (where M= I- (1.5*A)*7) to study day N then D1=A*7+2*B days and 
D2=(A+X)*7+B+Y days; 
­ Day N is calculated as N = I– (0.5*A)*7. 
­ This accounts for the scenario where only the first scheduled assessments after the 
last adequate tumor assessment occur prior to month I. 
• if the last adequate tumor assessment before the event date is performed between study 
day N+1 and study day P then D1=X*7+B+Y days and D2=2*X*7+B+Y days; 
­ Day P is calculated as P = I+ (0.5*X)*7. 
­ This accounts for the scenario where only the last adequate tumor assessment occurs 
prior to month I/7. 
• otherwise, when the last adequate tumor assessment before the event date is performed 
after study day P+1, then D1=X*7+2*Y days and D2=2*X*7+2*Y days. 
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Using the D2 definition above, an event is censored as occurring after ≥2 missing tumor assessments 
if the distance between the last adequate tumor assessment date and the event date is larger than D2.  
Table 8: Illustration of D1 and D2 Criteria  
 
If the last tumor assessment before the event 
date occurs between Study Days 
D1 
D2 
1 – 21 
49 
91 
22 – 63 
56 
112 
>=64 
70 
126 
 
Example: For a patient with a tumor assessment SD at Day 21(last tumor assessment before PFS 
event), and PD at the next tumor assessment on 
- 
Scenario 1: Day 46 (i.e. 25 days after SD). Patient is classified as not having missed tumor 
assessment between both scans. PFS is not censored. 
- 
Scenario 2: Day 76 (i.e. 55 days after SD). Patient is classified as having missed 1 tumor 
assessment between both scans. PFS event is not observed after more than 1 missing or 
inadequate tumor assessment. PFS is not censored. 
- 
Scenario 3: Day 113 (i.e. 92 days after SD). Patient is classified as having 2 missing tumor 
assessments between both scans. PFS event is observed after more than 1 missing or 
inadequate tumor assessment. Using the D2 definition, PFS is censored at the last adequate 
tumor assessment (at SD scan). 
 
9.4. BASELINE 
Baseline is defined as the last available assessment before the first study treatment administration, 
unless otherwise specified.  
If an assessment is planned to be performed prior to the first dose of study treatment in the protocol 
and the assessment is performed on the same day as the first administration of study drug, it will be 
assumed that it was performed prior to study treatment administration (if time is not available).  
Unscheduled assessments will be used in the determination of baseline.  
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ECG Baseline will be the mean of the triplicate measurements at Cycle 1 Day 1 before the first 
study treatment administration. 
Change from baseline will be defined as the difference between the value of the endpoint at the time 
point of interest and the baseline value. 
9.5. 
CUT-OFF CONVENTIONS 
All available data will be included at the time of the cut-off date. 
Subjects continuing to receive study treatment at the time of analysis will have time-to-event data 
(e.g., PFS, DOR) censored at the time of last tumor assessment prior to the data cut-off point used, 
if the event has not been observed before. Ongoing events (e.g., AEs, concomitant medication, etc.) 
will be summarized for analysis using the data cut-off date as the date of completion, with an 
indication that the event is ongoing. 
For subjects who drop out from the study with ongoing events, the discontinuation date will be used 
as the completion date of the event with the appropriate censoring. 
Data obtained after the cut-off will not be displayed in any listings or used for summary statistics 
(e.g. laboratory values of samples taken after data cut-off, AE with onset date after data cut-off, 
etc.). 
For exposure data, if the treatment was started before the cut-off date and ended after the cut-off 
date, the end date will be imputed by the cut-off date. This imputed date will be used for duration 
and cumulative dose derivations. 
 
 
 
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10. DEVIATIONS AND ADDITIONAL REASONS OF EXCLUSION 
FROM ANALYSIS SETS  
The protocol deviations will be reviewed prior to database lock. These will be classified as major or 
minor.  
A deviation will be considered as major if it is likely to significantly bias the interpretation of the 
primary efficacy endpoint results. 
Note: In this SAP, major protocol deviations described all deviations leading to exclusion of PP set. 
There may have protocol deviations identified as major by clinical team (in CTMS) that will not 
lead to exclusion of PP set. All deviations recorded in CTMS will be reviewed prior to database 
snapshot/lock to identify any potential deviations leading to exclusion of PP set. 
Major protocol deviations and additional reasons of exclusion from analysis sets will be qualified 
in accordance with the list of pre-defined reasons for exclusion from analysis sets for the study. 
This list, as large as possible, will be described in a specific document, separately from the statistical 
analysis plan.   
The number and percentage of subjects with at least one major deviation will be tabulated by type 
of major deviations on the Full Analysis Set. 
The number and percentage of subjects with at least one minor deviation will be also tabulated by 
type of minor deviations on the Full Analysis Set. 
The number and percentage of subjects with at least one reason of exclusion from analysis sets will 
be tabulated by type of reason of exclusion on the Full Analysis Set. 
In order to describe the impact of the COVID-19 pandemic on the study, the number and 
percentages of subjects with at least one deviation related to COVID-19 will be tabulated on the 
Full Analysis Set, for minor deviations, major deviations and both combined. Type of minor and 
major deviations will also be described on the Full Analysis Set.  
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Same description will be performed for the number of deviations reported. Deviations related to 
COVID-19 pandemic are reported with a prefix “COVID19”. Prefix will not be displayed in the 
outputs.  
11. HANDLING OF MISSING DATA AND ANALYSIS OF DROP-
OUTS 
11.1. DROP-OUTS 
No missing data due to drop out will be imputed.  
11.2. MISSING DATA (OTHER THAN DROP-OUT) 
 
11.2.1. Missing efficacy data 
Missing values will not be substituted by estimated values but considered as missing in statistical 
analysis. 
Note: For tumor assessment, when no imaging/measurement is done at all at a particular time point, 
the patient is not evaluable (NE) at that time point and will be analysed as such. 
11.2.2. Missing Safety data 
For laboratory data, in the case that an upper limit is mentioned in the associated character variable, 
missing numerical value will be replaced by the limit mentioned in the character variable. (For 
lower limit, missing numeric value will be replaced by the lower limit).  
Example: for a measure of ALAT with a character variable “<4”, missing numeric value will be 
replaced by 4.  
Missing numeric values with an associated character variable “>50” will be replaced by 50. In 
listings, character variable will be displayed. 
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In case of missing BSA at an assessment time, the measurement at the previous assessment time 
will be used for the Cetuximab exposure analysis.   
11.2.3. Missing QoL data 
EORTC QLQ-C30 
For each of the 15 scores: 
• if at least half of the items from the score have been answered, the score will be calculated 
based on the mean of the present items.  
• If more than half of the items are missing, the score will be missing. 
• None single-item scores can be imputed 
 
EQ-5D-5L and PGIC 
Missing item scores will not be substituted by estimated values but considered as missing for 
statistical analysis. 
11.2.4. Missing or incomplete dates 
Replacement of missing or incomplete dates presented hereafter is defined in a conservative 
approach. 
 
 Missing dates of first study treatment administration 
Missing dates of the first study treatment administration will be considered equal to the Cycle1 Day 
1 visit date for subjects assigned to treatment and with confirmation that this subject actually 
received treatment. 
 
 Missing dates of start of adverse event 
In case of completely missing date, it will be estimated by the date of first study treatment 
administration. 
 
 
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If the day and the month are missing, 
- 
If the year is the same as the year of first study treatment administration, it will be estimated 
by the date of first study treatment administration. 
- 
If the year is prior to the year of first study treatment administration, it will be estimated by 
the 31 December. 
- 
If the year is after the year of first study treatment administration, it will be estimated by the 
1st January. 
 
If only the day is missing, 
- 
If the month/year are the same as the month/year of first study treatment administration, it 
will be estimated by the date of first study treatment administration. 
- 
If the month/year are prior to the month/year of first study treatment administration, it will 
be estimated by the 15th day of the month. 
- 
If the month/year are after to the month/year of first study treatment administration, it will 
be estimated by the first day of the month. 
 
If after imputation, the estimated start date is after the end date of the adverse event, it will be 
replaced by the end date of the adverse event 
 
 Missing dates of end of adverse event 
For adverse events that are not “ongoing” at the end of the study (i.e. with an outcome other than 
“Not recovered/not resolved” or “Recovering/resolving”), completely missing AE end dates will be 
estimated by the last contact date.  
For adverse event with a start date and which are “ongoing”, completely missing AE end date will 
be imputed to the cut-off date. 
If the day and the month are missing, 
- 
If the year is the same as the year of last contact date, it will be estimated by the last contact 
date 
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- 
If the year is prior to the year of last contact date, it will be estimated by the 31 December 
 
If only the day is missing, 
- 
If the month/year are the same as the month/year of last contact date, it will be estimated by 
the last contact date 
- 
If the month/year are prior to the month/year of last contact date, it will be estimated by the 
last day of the month 
If after imputation, the estimated end date is before the start date of the adverse event, it will be 
replaced by the start date of the adverse event. 
 
 Missing or incomplete time of onset of adverse event 
In case of completely missing time: 
- 
If the onset date is the same as the date of the first study treatment administration, time will be 
estimated by the time of the first study treatment administration. 
 
 Prior and Concomitant medications and Procedures (except antineoplastic) 
Start date: 
Missing or incomplete start dates will be imputed using the same rules as for start date of adverse 
event, except if “taken Prior to the study entry” was ticked “Yes”, where the following rules apply: 
If the start date is completely missing, it will be estimated by the date of ICF signed - 1 (i.e. the day 
before) 
If the day and the month are missing,  
- 
If the year is the same as the year of ICF signed, it will be estimated by the date of ICF 
signed - 1 
- 
If the year is prior to the year of ICF signed, it will be estimated by the 31st December 
If only the day is missing, 
- 
If the month/year are the same as the month/year of the ICF signed, it will be estimated by 
the date of ICF signed – 1 
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- 
If the month/year are prior to the month/year of the ICF signed, it will be estimated by the 
15th day of the month 
 
End date: 
 
Missing or incomplete end dates will be imputed using the same rules as for end date of adverse 
event. 
 
 Prior and subsequent antineoplastic therapies (Medications/Surgeries/Radiotherapies) 
• 
Prior antineoplastic therapies: 
 
These rules apply to all prior antineoplastic therapies collected, i.e. medications, surgeries and 
radiotherapies. 
Start date: 
Missing or incomplete start dates will be imputed using the following rules: 
If the start date is completely missing, it will be estimated by the first study treatment administration 
- 1 (i.e. the day before) 
If the day and the month are missing,  
- 
If the year is the same as the first study treatment administration, it will be estimated by the 
date of first study treatment administration - 1 
- 
If the year is prior to the year of first study treatment administration, it will be estimated by 
the 31st December 
If only the day is missing, 
- 
If the month/year are the same as the month/year of the first study treatment administration, 
it will be estimated by the date of first study treatment administration – 1 
- 
If the month/year are prior to the month/year of the first study treatment administration, it 
will be estimated by the 15th day of the month 
 
 
 
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End date: 
 
Missing or incomplete end dates will be imputed using the same rules as for end date of adverse 
event. 
 
• 
Subsequent antineoplastic therapies: 
 
 These rules apply to all subsequent antineoplastic therapies collected, i.e. medications (both start 
and end dates), surgeries (start date only) and radiotherapies (start and end dates). 
 
Start date: 
 
Missing or incomplete start dates of subsequent antineoplastic therapies will be imputed using the 
following rules: 
If the start date is completely missing, it will be estimated by the EOT decision date + 1 (i.e. the 
day after) 
If the day and the month are missing,  
- 
If the year is the same as the EOT decision date, it will be estimated by the EOT decision 
date + 1 
- 
If the year is posterior to the year of the EOT decision date, it will be estimated by the 1st 
January 
If only the day is missing, 
- 
If the month/year are the same as the month/year of the EOT decision date, it will be 
estimated by the EOT decision date + 1 
- 
If the month/year are posterior to the month/year of the EOT decision date, it will be 
estimated by the first day of the month 
NB: “EOT decision date” refers to the date collected on the “End-of-treatment” disposition form of 
the e-CRF.  
 
End date: 
Missing or incomplete end dates will be imputed using the same rules as for end date of adverse 
event.  
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As radiotherapies cannot be reported as “ongoing”, completely missing end date of radiotherapy 
will be imputed to the cut-off date. 
 
 Date of death 
 
Missing or partial dates of death will be imputed as follows: 
- 
If only the day is missing: 1st day of the month and year of death 
- 
If the day and the month are missing: January 1st of the year of death  
- 
If the date is completely missing: it will be estimated by the last contact date 
 
If after imputation: death date < last contact date, then it will be estimated by the last contact date. 
 
 Date of initial diagnosis of primary site 
 
Completely missing dates will not be imputed. 
Partial dates of initial diagnosis of primary site will be imputed as follows: 
- 
If only the day is missing: 
o If the month/year are the same as the month/year of the first study treatment 
administration: it will be estimated by the first study treatment administration – 1 
(i.e. the day before) 
o If the month/year are before the month/year of the first study treatment 
administration: it will be estimated by the 15th day of the month 
- 
If the day and the month are missing:  
o If the year is the same as the year of the first study treatment administration: it will 
be estimated by the first study treatment administration – 1 (i.e. the day before) 
o If the year is before the year of the first study treatment administration: it will be 
estimated by the 1st of July 
 
 Date of first metastasis 
 
Missing or partial dates of first metastasis will be imputed as described for date of initial diagnosis 
of primary site. If after imputation: date of first metastasis < date of initial diagnosis of primary site, 
then the date of first metastasis will be considered same as the date of initial diagnosis of primary 
site. 
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12. DISPOSITION OF SUBJECTS 
The number of screened, assigned to treatment and treated subjects, and main reason for 
discontinuation or no assignment will be provided on the Screened subjects set. 
The number of subjects in each analysis set detailed in section 7 (except the Screened subjects set) 
will be provided overall, and by country and centre on the Full Analysis Set. The number of subjects 
in the PK Set will be provided only when Pharmacokinetics parameters described in section 19 are 
analysed (i.e. End-Of-Study analysis). 
The number of subjects by time windows will be also tabulated for the FAS. 
The number and percentage of subjects who discontinued the study treatment will be provided by 
reasons for discontinuation for the FAS.  
The number and percentage of patients who discontinued from the 30 days safety follow-up will be 
provided by reasons for discontinuation for the FAS. The same analysis will be performed for long-
term follow-up discontinuation. 
 
13. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Before the first study treatment administration, subject’s background, medical and surgical history, 
prior therapies, demographic data, disease characteristics, BRAF mutation data and ECOG PS will 
be described on the ES and FAS. 
If more than 10.0% subjects of the FAS are excluded from the Per Protocol Set, demographic data, 
disease characteristics and BRAF mutation data will be repeated on the PP Set. 
 
The table below presents the variables that will be described:  
 
 
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The number of patients with at least one combination identified in Appendix 1 with start dates 
within the same month or treatments taken in parallel despite being started within the same one 
month interval will be tabulated. 
 
 Other Prior Medications 
Number and percentage of subjects with at least one prior medication used before signature of any 
informed consent (as described in PRIOR AND CONCOMITANT THERAPY eCRF page) will be 
tabulated descriptively. They will be classified by therapeutic area according to the WHO-DRUG 
dictionary using the "anatomical therapeutic chemical" (ATC) classification, by WHO-DRUG 
ATC2, ATC4 and Preferred Term. 
 
 
 
Prior procedures 
Number and percentage of subjects with at least one prior therapeutic / diagnostic procedure (as 
described in MEDICAL AND SURGICAL PROCEDURES eCRF page) will be tabulated by SOC 
and PT using the MedDRA terminology. 
Number and percentage of subjects with at least one prior antineoplastic surgery received prior to 
study entry (as described in PRIOR ANTI-NEOPLASTIC THERAPY - SURGERY eCRF page) 
will be tabulated by site, location and treatment intent. Location will be classified as done for 
primary tumor location (cf. Table 9). 
Result of surgery will be described by location (primary site, metastatic site). 
Number and percentage of subjects with at least one prior antineoplastic surgery will be also 
tabulated by SOC and PT using the MedDRA terminology. 
The following number and percentage of subjects will be provided: 
• with at least one prior antineoplastic surgery associated with an ileostomy or colostomy, 
• with at least one prior antineoplastic surgery associated with an ileostomy,  
• with at least one prior antineoplastic surgery associated with a colostomy  
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• with no resection of the primary tumor and with an ileostomy or a colostomy 
• with an ileostomy or colostomy ongoing at study entry 
• with a permanent ileostomy or colostomy 
The time since the creation of the ileostomy or colostomy will be described for stomies that are 
ongoing at study entry, and the duration of the stomy will be described for stomies that were 
removed before study entry. The time since the creation of the ileostomy or colostomy will be 
derived as (reference start date - date of stomy creation). 
The number and percentage of subjects with at least one prior antineoplastic therapy (Radiotherapy) 
used prior to study entry (as described in PRIOR ANTI-NEOPLASTIC THERAPY – 
RADIOTHERAPY eCRF page) will be tabulated by location, treatment intent (palliative, curative, 
unknown), treatment setting (adjuvant, neo-adjuvant, metastatic, locally advanced, unknown), 
procedure linked to Chemotherapy (No/Yes) and Best Overall Response. 
 
 
 
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14. ANALYSIS OF EFFICACY 
Efficacy analyses will be conducted using the ES and FAS. A supportive analysis of the primary 
outcome will be conducted using the PPS. 
14.1. PRIMARY ENDPOINT: CONFIRMED ORR BASED ON INVESTIGATOR-
ASSESSED TUMOR EVALUATION 
BOCR 
The best overall confirmed response (BOCR) will be derived as per RECIST guideline version 
1.1[1]. 
Only tumor assessments performed before the start of any further antineoplastic therapies (i.e. any 
additional secondary antineoplastic medication or anti-cancer surgery or radiotherapy) and not later 
than 30 days after last study treatment administration will be considered in the assessment of BOCR. 
Clinical deterioration or clinical progression noted on the end-of-treatment eCRF will not be 
considered as documented disease progression. 
The BOCR for each subject is determined from the sequence of overall (lesion) responses according 
to the following rules: 
 CR: at least two determinations of CR at least 4 weeks apart before progression  
 PR: at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR)  
 SD: at least one SD assessment (or better) ≥ 6 weeks after start of treatment (and not 
qualifying for CR or PR). 
 PD: early progression ≤ 9 weeks after first study treatment administration (and not 
qualifying for CR, PR or SD). 
 NE = all other cases (i.e. not qualifying for confirmed CR or PR and without SD ≥6 weeks 
or early progression ≤ 9 weeks after first study treatment administration) 
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Best overall confirmed response will be summarized, with reasons for having unknown status in 
Non-Evaluable patients, including: 
• No baseline assessment, no measurable disease at baseline 
• No post-baseline assessment 
• All post-baseline assessments have overall response of “NE” 
• New antineoplastic therapy (i.e. any additional secondary antineoplastic medication or 
anti-cancer surgery or radiotherapy) started before first post-baseline assessment 
• Unconfirmed CR, PR or SD with first adequate assessment < 6 weeks Progression >9 
weeks after first study treatment administration 
The following table, based on Table 3 from the RECIST 1.1[1] guidelines, summarizes the algorithm 
describing how Best Overall Confirmed Response (BOCR) is determined from the overall tumor 
assessments. The order used to determine the BOCR is CR>PR>SD>PD, ignoring visits with 
missing tumor assessments.  
All assessments following an assessment of PD will be excluded from the derivation of BOCR.  
Table 10: Best Overall Confirmed Response 
 
 
Case 
Best Overall response 
BOCR 
First 
timepoint 
Subsequent 
timepoint  
1 
CR 
CR 
CR (if assessments at least 4 weeks (28 days) apart). 
(note: sequence of CR – NE – CR would be considered 
as confirmed CR) 
2 
CR 
PR 
SD, PD or PR 
• If a CR truly met at first timepoint, any subsequent 
assessment of PR should make the disease PD at that 
point. That is, neither a PR nor SD may follow CR 
• Therefore, SD, if CR assessment ≥ 6 weeks, i.e. 42 
days after date of first administration of study 
treatment,  
• otherwise PD. 
However BOCR may be PR if subsequent scans suggests 
small lesions were still present at first time point (in 
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Case 
Best Overall response 
BOCR 
First 
timepoint 
Subsequent 
timepoint  
which case first assessment of CR should be changed to 
PR)* 
3 
CR 
SD 
SD or PD 
• SD, if CR or SD assessment ≥ 6 weeks, i.e. 42 days 
after date of first administration of study treatment,  
• otherwise PD 
 
4 
CR 
PD 
SD or PD 
• SD, if CR assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise PD 
5 
CR 
NE 
SD or NE 
• SD, if CR assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment, 
• otherwise NE  
6 
PR 
CR 
PR (if assessments at least 4 weeks (28 days) apart). 
7 
PR 
PR 
PR (if assessments at least 4 weeks (28 days) apart). 
(note: sequence of PR – NE – PR would be considered as 
confirmed PR) 
8 
PR 
SD 
SD or PD 
• SD, if PR or SD assessment ≥ 6 weeks, i.e. 42 days 
after date of first administration of study treatment,  
• otherwise PD 
9 
PR 
PD 
SD or PD or NE 
• SD, if PR assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise PD if PD assessment ≤ 9 weeks, i.e. 63 
days after date of first administration of study 
treatment,  
• otherwise NE 
10 
PR 
NE 
SD or NE 
• SD, if PR assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise NE 
11 
SD 
SD 
SD 
12 
SD 
PD 
SD or PD or NE 
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Case 
Best Overall response 
BOCR 
First 
timepoint 
Subsequent 
timepoint  
• SD, if SD assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise PD if PD assessment ≤ 9 weeks, i.e. 63 
days after date of first administration of study 
treatment,  
• otherwise NE 
13 
SD 
NE 
SD or NE 
• SD, if SD assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise NE 
14 
NE, - 
SD 
SD or NE 
• SD, if SD assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise NE 
15 
CR, PR, 
SD 
- 
SD or NE 
• SD, if assessment ≥ 6 weeks, i.e. 42 days after date 
of first administration of study treatment 
• otherwise NE. 
16 
PD 
 
PD or NE 
 
• PD if PD assessment ≤ 9 weeks, i.e. 63 days after 
date of first administration of study treatment,  
• otherwise NE 
 Ignore all assessments after initial overall response of 
PD.  
17 
NE 
NE 
NE 
Where all assessments are Not evaluable 
* As per Table 3 from RECIST guideline (version 1.1). 
 
 
 
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Confirmed objective response rate 
The confirmed objective response rate will be defined as the sum of confirmed CR and PR rate: 
N
PR
CR
∑
+
=
)
#
(#
cORR
 
with: 
- # CR = number of subjects with a best confirmed complete response  
- # PR = number of subjects with a best confirmed partial response. 
- N = number of subjects in the analysis set. 
14.1.1. Primary Analysis 
The cORR will be provided with a corresponding Clopper-Pearson (exact) binomial 95% CI 
(Clopper CJ et al, 1934)[4] for the ES. The two-stage method will be used to test the null hypothesis 
with the possibility of stopping accrual earlier for futility. If the observed cORR at the end of the 
first stage is less than 28% (i.e., ≤ 11 confirmed CRs + PRs among 40 treated subjects with a 
centrally confirmed BRAFV600E mutation), then insufficient efficacy will be concluded. Otherwise, 
at the end of stage 2, if the observed cORR is ≥ 41% (i.e., ≥ 37 confirmed responses among 90 
treated subjects with a centrally confirmed BRAFV600E mutation), the null hypothesis will be 
rejected. 
In case of N > 90 subjects treated with a centrally confirmed BRAFV600E mutation, this analysis will 
be repeated for the Stage 2 analysis, when excluding the overrunning subjects (i.e. on the 90 first 
treated subjects with a centrally confirmed BRAFV600E mutation).  
 
In addition to the Stage 1 and Stage 2 analyses, the analyses for cORR will also be conducted at the 
time of the end of study. 
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14.1.2. Supportive Analyses  
The cORR will be provided with a corresponding Clopper-Pearson (exact) binomial 95% CI for the 
PPS and FAS (see section 7). 
In order to assess the impact of the Urgent Safety Measure (USM) implemented during the COVID-
19 pandemic (see section 15.1), the cORR will be provided with a corresponding Clopper-Pearson 
(exact) binomial 95% CI, on the subset of the ES composed of subjects who benefited from the 
USM. 
14.1.3. Exploratory Analyses 
Primary analysis of the main criterion will be conducted for ES on the subgroups of subjects defined 
as: 
• Age < 65 and ≥ 65 years old 
• Males and Females 
• Baseline CRP level (≤ local ULN and >local ULN) 
• Baseline CEA (≤ local ULN and >local ULN) 
• Baseline CA19-9 (≤ local ULN and >local ULN) 
• MSI status at screening (MSI-High and Non MSI-High)2 
• Primary tumor location (right-sided and left-sided) 
Note: Primary tumor location reported as “COLON, TRANSVERSE” will be 
considered as right-sided. Primary tumor location “Rectum” (reported as “Other”) 
will be considered as left-sided. 
Patients with primary tumor location reported as “OTHER” (except “Rectum”, 
cf. above, and modalities considered as right-sided or left-sided cf. section 13) 
will not be included in this subgroup analysis. 
• Number of metastatic organs (1, 2 and >2)  
Note: “1”, “2-3” and “>3” could be used if relevant (i.e.  over-represented category) 
• Baseline ECOG PS (0 and 1) 
 
2 Blood sample for MSI testing (control sample) will not be processed on an ongoing basis during the study, but once 
for all subjects enrolled. MSI Status will thus remain undetermined during the study and will be described when 
available (cf. Appendix 5).   
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The primary endpoint and the corresponding 95% CI will be displayed using a forest plot by 
subgroups. 
At the time of the primary analysis (i.e. Stage 2 or at Stage 1 if study stops for futility), analysis of 
cORR based on investigator-assessed tumor evaluation will be repeated on the ES, when excluding 
the patients with no confirmed metastatic disease at inclusion (i.e. Inclusion criterion #3 not filled). 
cORR based on investigator-assessed tumor evaluation for the subgroup of subjects in Japan will 
also be examined separately at the time of the primary analysis (i.e. Stage 2 or at Stage 1 if study 
stops for futility) on the ES and FAS, and according to MSI status at screening on the ES. 
 
14.2. SECONDARY EFFICACY ENDPOINTS 
The statistical analyses for the secondary criteria will be described on the FAS unless otherwise 
stated. 
14.2.1. cORR assessed by central radiologist review 
For each tumor assessment performed, central radiologist review is performed by two independent 
readers (“reader 01” and “reader 02”). When there is a discrepancy between both reviews, a third 
independent reader (named the “adjudicator”) will adjudicate and select one of the two readers. 
The data sent by the external vendor include: 
• Review of reader 01 and reader 02 
• Adjudication, if any (“Agree with reader xx”).  
o NB: The adjudicator’s choice applies to all tumor assessments performed prior to the 
adjudication. 
o NB2: At any tumor assessment where an adjudication is performed for a given subject 
(until the last tumor assessment for this subject), the adjudicator’s choice may change, 
and this will apply to all tumor assessments performed prior to the last adjudication. This 
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means that for a given subject, the results as per central review may change, until the 
last tumor assessment reviewed, for this subject.  
1) For each subject and each tumor assessment, only one reader will be used for statistical 
analysis. For a given analysis and a given subject: If no adjudication performed: 
a. For tumor assessments where both readers are in agreement => Reader 01’s 
assessment will be taken into account for analysis 
b. For tumor assessments where both readers disagree => Tumor assessments will not 
be taken into account for analysis. 
2) If at least one adjudication performed: 
a. For all tumor assessments done until the last adjudication performed => Reader xx’s 
assessment (according to the last adjudicator’s choice) will be taken into account for 
analysis. 
b. For tumor assessments done after the last adjudication performed: 
i. For tumor assessments where both readers are in agreement => Reader xx’s 
assessment (according to the last adjudicator’s choice) will be taken into 
account for analysis. 
ii. For tumor assessments where both readers disagree => Tumor assessments 
will not be taken into account for analysis. 
 
The BOCR assessed by central imaging review will be derived as done for BOCR assessed by local 
review (see section 14.1).  
The cORR assessed by central radiologist review will be provided with a corresponding Clopper-
Pearson (exact) binomial 95% CI for the ES and FAS. 
The cORR assessed by central radiologist review for the subgroup of subjects in Japan will also be 
examined separately at the time of the primary analysis (i.e. Stage 2 or at Stage 1 if study stops for 
futility). 
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14.2.2. ORR (for confirmed+unconfirmed responses) based on investigator-assessed 
tumor evaluation  
Objective Response Rate, considered for confirmed + unconfirmed responses as per local 
radiologist/investigator assessment, will be analyzed in the same manner as the primary analysis for 
the ES and FAS.  
The best overall response (BOR) for confirmed + unconfirmed responses will be derived as per 
RECIST guideline version 1.1[1]. 
Only tumor assessments performed before the start of any further antineoplastic therapies (i.e. any 
additional secondary antineoplastic medication or anti-cancer surgery or radiotherapy) and not later 
than 30 days after last study treatment administration will be considered in the assessment of BOR. 
Clinical deterioration or clinical progression noted on the end-of-treatment eCRF will not be 
considered as documented disease progression. 
The BOR for each subject is determined from the sequence of overall (lesion) responses according 
to the rules displayed in section 14.1. 
 CR: at least one determination of CR before progression 
 PR: at least one determination of PR before progression  
 SD: at least one SD assessment (or better) ≥ 6 weeks after start of treatment (and not 
qualifying for CR or PR). 
 PD: early progression ≤ 9 weeks after first study treatment administration (and not 
qualifying for CR, PR or SD). 
 NE = all other cases (i.e. not qualifying for confirmed CR or PR and without SD ≥6 weeks 
or early progression ≤ 9 weeks after first study treatment administration) 
Best overall response (confirmed+unconfirmed) will be summarized, with reasons for having 
unknown status in Non-Evaluable patients, including: 
• No baseline assessment, no measurable disease at baseline 
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• No adequate post-baseline assessment 
• All post-baseline assessments have overall response of “NE” 
• New antineoplastic therapy (i.e. any additional secondary antineoplastic medication or 
anti-cancer surgery or radiotherapy) started before first post-baseline assessment 
• SD occurred <6 weeks after first study treatment administration 
• Progression >9 weeks after first study treatment administration 
The following table, based on Table 3 from the RECIST 1.1[1] guidelines, summarizes the algorithm 
describing how Best Overall Response (BOR) for confirmed and unconfirmed response is 
determined from the overall tumor assessments. The order used to determine the BOR is 
CR>PR>SD>PD, ignoring visits with missing tumor assessments.  
All assessments following an assessment of PD will be excluded from the derivation of BOR.  
Table 11: Best Overall Response (confirmed+unconfirmed) 
Case 
Timepoint (Best 
response with 
CR>PR>SD>PD>NE) 
Best Overall Response (confirmed+unconfirmed) 
1 
CR 
CR 
2 
PR 
PR  
3 
SD 
SD or PD or NE 
• SD, if SD assessment ≥ 6 weeks, i.e. 42 days after 
date of first administration of study treatment,  
• otherwise PD if subsequent PD assessment ≤ 9 
weeks, i.e. 63 days after date of first 
administration of study treatment,  
• otherwise NE 
4 
PD 
PD or NE 
• PD if PD assessment ≤ 9 weeks, i.e. 63 days after 
date of first administration of study treatment,  
• otherwise NE 
Ignore all assessments after initial overall response of 
PD.  
5 
NE 
NE 
Where all assessments are Not evaluable. 
 
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* As per Table 3 from RECIST guideline (version 1.1). 
 
Objective Response Rate 
The Objective Response Rate will be defined as the sum of CR and PR (confirmed+unconfirmed) 
rate: 
𝑂𝑂𝑂𝑂𝑂𝑂= ∑(#𝐶𝐶𝐶𝐶+ #𝑃𝑃𝑃𝑃)
𝑁𝑁
 
with: 
- # CR = number of subjects with a best complete response (confirmed + unconfirmed)  
- # PR = number of subjects with a best partial response (confirmed + unconfirmed) 
- N = number of subjects in the analysis set. 
14.2.3. ORR (for confirmed+unconfirmed responses) assessed by central radiologist 
review 
The BOR assessed by central imaging review will be derived as done for BOR assessed by local 
review (see section 14.2.2). See section 14.2.1 for handling of central review data. 
Objective Response Rate, considered for confirmed + unconfirmed responses assessed by central 
radiologist review, will be analyzed in the same manner as the primary analysis for the ES and FAS.  
14.2.4. PFS based on investigator assessment  
PFS based on local review will be calculated and summarized using the KM method. The 
corresponding median PFS with 95% CI, 25th and 75th percentiles (Brookmeyer and Crowley 1982, 
Klein and Moeschberger 1997)[5], as well as PFS estimated probabilities at selected time points 
(every 2 months up to 14 months) will be provided with 95% CI (Kalbfleisch and Prentice 2002) 
for the FAS and ES. 
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Progressive disease and death from any cause will be considered as events. If death or PD is not 
observed, the PFS will be censored at the date of last adequate tumor assessment prior to the cutoff 
date or new anti-tumoral treatment intake. However, if a PFS event is observed after more than 1 
missing or inadequate tumor assessment, it will be censored at the last adequate tumor assessment. 
If a PFS event is observed after a single missing or non-adequate tumor assessment, the actual date 
of event will be used. 
Censoring rules to be applied to the PFS endpoint are described in detail in  
 
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Table 12. Censor status will be summarized. 
 
 
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Table 12: Censoring rules for PFS 
In the below table, “new antineoplastic therapy” refers to any additional secondary antineoplastic 
medication or anti-cancer surgery or radiotherapy. 
 
Situation 
Event Date 
Outcome 
No baseline tumor assessments 
A1 
No baseline assessment and death after the 
second scheduled post-baseline tumor 
assessment, or no death 
Date of first study treatment administration 
Censored 
A2 
No baseline assessment and death on or before 
the second scheduled post-baseline tumor 
assessment 
Date of death 
Event 
No post-baseline tumor assessments (without new antineoplastic therapy given) 
B1 Death on or before the second scheduled post-
baseline tumor assessment 
Date of death 
Event 
B2 Death after the second scheduled post-baseline 
tumor assessment or no death 
Date of first study treatment administration 
Censored 
With baseline and post-baseline tumor assessments (without new antineoplastic therapy given prior 
progression or death without progression observed) 
C1 Progression with zero or one missed/inadequate 
tumor assessment prior to progression 
Date of progression   
Event 
C2 
Death but no progression, with zero or one 
missed/inadequate tumor assessment prior to 
death 
Date of death 
Event 
D1 
Progression but two or more consecutively 
missed/inadequate tumor assessments prior to 
progression 
Date of last adequate tumor assessment* 
Censored 
D2 
Death without progression, but two or more 
consecutively missed/inadequate tumor 
assessments prior to death 
Date of last adequate tumor assessment* 
Censored 
E 
No progression, no death 
Date of last adequate tumor assessment* 
Censored 
F 
Treatment discontinuation due to ‘Disease 
progression’ without documented progression, 
i.e. clinical progression based on investigator 
claim 
N/A (not considered as an event, patient 
without documented PD should be followed 
for progression after discontinuation of 
treatment) 
Information 
ignored 
Initiation of new antineoplastic therapy given prior progression or death without progression observed 
G 
New antineoplastic therapy started before 
progression or death 
Date of last adequate tumor assessment prior 
to initiation of new antineoplastic therapy* 
Censored 
H 
No post-baseline tumor assessment and new 
antineoplastic therapy started prior to a death 
Date of first study treatment administration 
Censored 
* tumor assessment with non-missing and non-unknown overall lesion response, as defined in section 9.3. 
 
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The terms ‘adequate Tumor Assessments (TA)’ and ‘missing adequate TA’ are defined in section 
9.3, together with rules to determine whether there is one or two missing/inadequate TAs (Table 8).  
As sensitivity analyses, the analyses for PFS will be repeated with a censoring rule that includes a 
PFS event even if the event is recorded after 2 or more missing tumor assessments  
Table 13: Censoring rules for PFS (sensitivity analysis) 
In the below table, “new antineoplastic therapy” refers to any additional secondary antineoplastic 
medication or anti-cancer surgery or radiotherapy. 
 
Situation 
Event Date 
Outcome 
No baseline tumor assessments 
A1 No baseline assessment and no death 
Date of first study treatment administration 
Censored 
A2 No baseline assessment and death  
Date of death 
Event 
No post-baseline tumor assessments (without new antineoplastic therapy given) 
B1 Death  
Date of death 
Event 
B2 No death 
Date of first study treatment administration 
Censored 
With baseline and post-baseline tumor assessments (without new antineoplastic therapy given prior 
progression or death without progression observed) 
C1 Progression  
Date of progression   
Event 
C2 Death but no progression  
Date of death 
Event 
E 
No progression, no death 
Date of last adequate tumor assessment* 
Censored 
F 
Treatment discontinuation due to ‘Disease 
progression’ without documented progression, 
i.e. clinical progression based on investigator 
claim 
N/A (not considered as an event, patient 
without documented PD should be followed 
for progression after discontinuation of 
treatment) 
Information 
ignored 
Initiation of new antineoplastic therapy given prior progression or death without progression observed 
G 
New antineoplastic therapy started before 
progression or death 
Date of last adequate tumor assessment 
prior to initiation of new antineoplastic 
therapy* 
Censored 
H 
No post-baseline tumor assessment and new 
antineoplastic therapy started prior to a death 
Date of first study treatment administration 
Censored 
* tumor assessment with non-missing and non-unknown overall lesion response, as defined in section 9.3. 
In addition to the primary analysis (i.e. Stage 2 or at Stage 1 if study stops for futility), the analyses 
for PFS will also be conducted at the time of the end of study. 
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PFS based on investigator assessment in the subgroup of subjects in Japan will be examined 
separately at the time of the primary analysis (i.e. Stage 2 or at Stage 1 if study stops for futility). 
14.2.5. PFS assessed by central radiologist review 
Analysis of PFS assessed by central radiologist review will be analyzed in a similar way of PFS 
based on local review for the FAS and ES. 
PFS assessed by central radiologist review in the subgroup of subjects in Japan will be examined 
separately at the time of the primary analysis (i.e. Stage 2 or at Stage 1 if study stops for futility). 
14.2.6. Overall survival (OS) 
OS will be described using survival curves according to the Kaplan Meier method and reporting 
estimated median (in months) with 95% CI, 25th and 75th percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997)[5] and KM estimated probabilities with corresponding 95% 
CIs (Kalbfleisch and Prentice 2002) at several time points (every 2 months up to 14 months). 
In addition to the Stage 1 and Stage 2 analyses, the analyses for OS will also be conducted at the 
time of the end of study. 
OS in the subgroup of subjects in Japan will be examined separately at the time of the primary 
analysis (i.e. Stage 2 or at Stage 1 if study stops for futility). 
14.2.7. DOR based on investigator-assessed tumor evaluation 
Duration of response according to investigator will be calculated among the confirmed responders 
(i.e. CR and PR) from the time that measurement criteria are first met for complete or partial 
response (whichever status is recorded first) after first study treatment administration until the 
earliest date of progression or death due to underlying disease.  
• Patients who are lost to follow-up, or reach the time point of analysis without a known record 
of progression or death will have the duration of response censored at the date of last adequate 
tumor assessment.  
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• Patients who received a new anti-tumoral treatment (chemotherapy, hormonotherapy, 
radiotherapy, surgery or other anti-tumoral treatment), whatever the type of treatment before 
their disease progression will be censored at their last adequate radiological assessment (i.e., at 
the date of last tumor assessment of CR, PR or SD).  
• If an event is observed after a single missing or non-adequate tumor assessment, the actual date 
of progression will be used.  
• If an event is observed after two or more missing or non-adequate tumor assessment, the 
duration of response will be censored at the date of last adequate tumor assessment. 
Table 14: Censoring rules for DOR 
In the below table, “new antineoplastic therapy” refers to any additional secondary antineoplastic 
medication or anti-cancer surgery or radiotherapy. 
 
 
Situation 
Event Date 
Outcome 
With baseline and post-baseline tumor assessments (without new antineoplastic therapy given prior 
progression or death without progression observed) 
A1 Progression with zero or one missed tumor 
assessment prior to progression 
Date of progression 
Event 
A2 
Death (due to underlying disease) but no progression, 
with zero or one missed tumor assessment prior to 
death 
Date of death 
Event 
B 
Death (not due to underlying disease) but no 
progression, with zero or one missed tumor 
assessment prior to death 
Date of last adequate tumor assessment* Censored 
C1 Progression but two or more consecutively missed 
tumor assessments prior to progression 
Date of last adequate tumor assessment* Censored 
C2 
Death without progression, but two or more 
consecutively missed tumor assessments prior to 
death 
Date of last adequate tumor assessment* Censored 
D 
No progression, no death 
Date of last adequate tumor assessment* Censored 
E 
Treatment discontinuation due to ‘Disease 
progression’ without documented progression, i.e. 
clinical progression based on investigator claim 
N/A (not considered as an event, patient 
without documented PD should be 
followed for progression after 
discontinuation of treatment) 
Information 
ignored 
Initiation of new antineoplastic therapy given prior progression or death without progression observed 
F 
New antineoplastic therapy started before 
progression or death 
Date of last adequate tumor assessment 
prior to initiation of new antineoplastic 
therapy* 
Censored 
* tumor assessment with non-missing and non-unknown overall lesion response, as defined in section 9.3. 
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Analysis of DOR will be described using survival curves according to the Kaplan Meier method 
and reporting estimated median (in months) with 95% CI, 25th and 75th percentiles (Brookmeyer 
and Crowley 1982, Klein and Moeschberger 1997)[5] and KM estimated probabilities with 
corresponding 95% CIs (Kalbfleisch and Prentice 2002) at several time points (every 2 months up 
to 14 months). 
DOR in the subgroup of subjects in Japan will be examined separately at the time of the primary 
analysis (i.e. Stage 2 or at Stage 1 if study stops for futility). 
14.2.8. DOR assessed by central radiologist review 
Analysis of DOR based on central review will be analyzed in a similar way of DOR based on local 
review. 
DOR in the subgroup of subjects in Japan will be examined separately at the time of the primary 
analysis (i.e. Stage 2 or at Stage 1 if study stops for futility). 
14.2.9. TTR based on investigator-assessed tumor evaluation 
Time to first response will be calculated from the date of first study treatment administration up to 
the date of first documented CR or PR. The CR and PR does not need to be confirmed. Patients 
who do not achieve a PR or CR will be censored as follows (described in  
 
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Table 15):  
• if they do not have a PFS event, they will be censored at the last adequate tumor assessment 
date. In this case patients have not yet progressed, so they theoretically still have a chance 
of responding;  
• if they have a PFS event (i.e. progressed or died due to any cause), they will be censored at 
maximum follow-up (i.e., FPFV to LPLV used for the analysis, as defined in section 9.1.2). 
In this case, the PFS event is the worst possible outcome as it means the patient cannot 
subsequently respond. Since the statistical analysis makes use of the ranking of times to 
response it is sufficient to assign the worst possible censoring time which could be observed 
in the study which is equal to the maximum follow-up time (i.e., time from FPFV to LPLV).  
 
 
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Table 15: Censoring rules for TTR 
In the below table, “new antineoplastic therapy” refers to any additional secondary antineoplastic 
medication or anti-cancer surgery or radiotherapy. 
 
 
Situation 
Event Date 
Outcome 
A 
Documented Response (CR or PR) 
Date of first documented response  
Event 
B 
Progression or death 
Censoring time assigned to maximum follow-
up time:  
- Time to Event Origin Date = date of first 
study treatment administration 
- event date = date of first study treatment 
administration + (LPLV – FPFV) 
Censored 
C1 No adequate post-baseline tumor 
assessment* and no death 
Date of first study treatment administration 
Censored 
C2 No progression, no death 
Date of last adequate tumor assessment* 
Censored 
D1 No adequate post-baseline tumor 
assessment* and new antineoplastic 
therapy started before death  
Date of first study treatment administration 
Censored 
D2 New antineoplastic therapy started before 
progression or death 
Date of last adequate tumor assessment prior to 
initiation of new antineoplastic therapy* 
Censored 
* tumor assessment with non-missing and non-unknown overall lesion response, as defined in section 9.3. 
TTR will be described using survival curves according to the Kaplan Meier method and reporting 
estimated median (in months) with 95% CI, 25th and 75th percentiles and KM estimated probabilities 
with corresponding 95% CIs at several time points (every 2 months up to 14 months). 
TTR will be also analysed for confirmed responders only. 
14.2.10. TTR assessed by central radiologist review 
Analysis of TTR based on central review will be analyzed in a similar way of TTR based on local 
review. 
14.2.11. Percentage change in tumor measurement from baseline 
The best percentage change in tumor measurement from baseline (according to local assessments) 
will be displayed using a waterfall plot for ES. 
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The best percentage change in tumor measurement from baseline in the subgroup of subjects in 
Japan will be examined separately at the time of the primary analysis (i.e. Stage 2 or at Stage 1 if 
study stops for futility). 
14.2.12. Duration of Follow-Up 
A summary of duration between first study treatment administration and cut-off date, and follow-
up times for PFS/OS will be generated, which are defined as follows: 
• Duration between first study treatment administration and cut-off date = (Cut-off date – Date of 
first study treatment administration + 1) / 30.4375 (months). This item will be summarized in 
months overall. 
• Follow-up time = (Date of event or censoring – Date of first study treatment administration + 1) / 
30.4375 (months) regardless of censoring. This item will be summarized in months overall. 
The analysis will be performed for PFS based on local review and PFS assessed by central 
radiologist review. Date of censoring is the same as defined for main analysis of the PFS and OS. 
Separate summaries will be generated for the subgroup of subjects in Japan. 
In addition, a reverse Kaplan-Meier analysis will be performed for both PFS and OS to estimate the 
median duration of potential follow-up as described by Schemper and Smith (1996)[6]. Patients who 
were censored (e.g. lost to follow-up, withdrew consent, ongoing, etc) in the PFS (or OS) analysis 
will be considered as events for the purposes of estimating duration of potential follow-up. Patients 
who had a PFS (or OS) event for the purposes of the PFS (or OS) analysis will be censored at the 
date of the event. The same duration of time values used in the PFS (or OS) analysis will be used 
in this analysis. Kaplan-Meier estimated probabilities with corresponding 95% CIs (Kalbfleisch and 
Prentice 2002) [7] will be presented at the same time points as in the PFS (or OS) analysis. 
 
 
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15. SAFETY ANALYSIS 
All safety analyses will be presented on the FAS. 
15.1. TREATMENT EXPOSURE 
Duration of study drug exposure to any dose (in weeks), actual and relative dose intensity will be 
summarized.  
The number of subjects with at least one dose reduction will be presented, along with reasons for 
the dose reduction. The same table will be provided for dose interruptions, and for dose reductions 
or interruptions. The number of subjects with at least one definitive dose reduction (i.e. subjects 
with a dose reduction and who did not re-escalate to the protocol-planned dose) will be described. 
The actual daily doses and reasons for dose reductions/interruptions will be listed in an individual 
basis for subjects with dose reductions/interruptions.  
A dose interruption will be indicated in the eCRF by a dosing record with a total daily dose of 0 mg 
for one or more days. 
To avoid over-counting interruptions, dosing records with 0 mg entered as last dosing record will 
not be counted as interruptions (those represent the reason for permanent discontinuation and will 
therefore be presented in the reason for treatment discontinuation analysis).  
A dose reduction is defined as a decrease in dose from the protocol-planned dose and a decrease 
from the previous non-zero dose, even if this decrease has been directly preceded by an interruption. 
For example, for encorafenib, in the sequence of total daily dose 300 mg – 0 mg – 200 mg, the 200 
mg dose will be counted as a reduction. 
 
These analyses will apply for each study drug (encorafenib, binimetinib and cetuximab) 
individually on the FAS. 
 
 Duration of study drug exposure (weeks) 
This is the duration that the patient was exposed to the study drug and is defined as ([Date of last 
(non-zero) dose of study drug] – [date of first dose of study drug] + [days until next dose])/7. 
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For encorafenib/binimetinib, [days until next dose] = 1. 
For Cetuximab,  
•  before switch to a biweekly infusion: [days until next dose] = 7 
•  from switch to a biweekly infusion: [days until next dose] = 14 
NB: In the initial version of the study protocol, patients were planned to switch to cetuximab 
infusions at dosage of 500 mg/m2 administered every 2 weeks (i.e. D1 and D15) at C8D1, instead 
of weekly infusions at dosage of 250 mg/m2  (except first administration with dosage of 400 
mg/m2 ). Following the COVID-19 pandemic outbreak, an Urgent Safety Measure (USM) was 
implemented to allow the investigators to perform Cetuximab infusions at dosage of 500 
mg/m2 administered every 2 weeks (i.e. D1 and D15) instead of weekly, whatever the cycle (even 
if the subject has not reached yet C8D1), after having evaluated the benefit/risk for the subject and 
in order to reduce the number of visit at hospital. 
For subjects who benefited from this USM, records post-decision to switch to an administration 
every 2 weeks will be derived as follows: 
1) First step: Among the subjects having received at least one dose of study treatment 
(complete or partial): only the subjects who didn’t have their C8D1 before the 01MAR2020 
and who didn’t discontinue treatment before 01MAR2020 and who didn’t discontinue 
cetuximab before 01MAR2020 are to be considered 
2) Among the subjects selected from first step, subjects with an administrated dose > 400 
mg/m2 before C8D1 will be considered as having benefited from the USM.  
3) This subset of subjects will be cross-checked with reason mentioned for dose modification. 
Dose modifications for reasons not related to COVID-19 pandemic will be excluded  
The date of switch to a biweekly infusion for a given subject will be derived as the first date among 
selected records for this subject. 
NB: any infusion after this date at dosage < 500 mg/m2 will be considered as a dose reduction, even 
if occurring before C8D1. 
Duration of study drug exposure will also be described as a discrete variable, with modalities t to 
< t+4 weeks (t being the duration of exposure, in weeks), such as: < 4 weeks / 4 - < 8 weeks / 8 - < 
12 weeks / etc. 
 
 
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 Relative dose intensity (RDI) (%) 
o Cumulative actual dose (mg or mg/m2) is the total dose given during the study 
treatment exposure. The cumulative actual dose for a given patient is the sum of the 
actual dose received (mg or mg/m²). The actual dose received for Cetuximab 
(mg/m²) at cycle i is equal to the actual dose received (mg) at cycle i divided by the 
body surface area at the beginning of cycle i 
- 
NB: If needed, the BSA at a given timepoint will be derived according to 
formula displayed in section Erreur ! Source du renvoi introuvable. (with 
same rouding convention) 
 
 
For encorafenib and binimetinib (daily dosing): 
o Duration of planned exposure (this is not summarized in any exposure table) = [Date 
of EOT or data cut-off (the earliest one)] – [date of first dose of study drug] + 1 
o Dose intensity (mg/day) = [Cumulative actual dose]/[duration of planned exposure] 
o Cumulative planned dose (mg) = sum(protocol specified dose across each day of 
planned exposure) 
o Planned dose intensity (mg/day) = [Cumulative planned dose]/[duration of planned 
exposure]. 
For encorafenib, PDI = 300 mg/day. For binimetinib, PDI =90 mg/day. 
o Relative dose intensity (%) = 100 x [Dose intensity]/[Planned dose intensity]  
 
For Cetuximab (intermittent dosing): 
o Duration of planned exposure (this is not summarized in any exposure table) = [Date 
of EOT or data cut-off (the earliest one)] – [date of first dose of study drug] + 1 
o Duration of planned exposure after switch to a biweekly infusion (this is not 
summarized in any exposure table) = [Date of EOT or data cut-off (the earliest one)] 
– [date of first dose of study drug] - [number of days with weekly infusion] + 1 
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- 
planned day of the first visit when switch occurred is the theoretical day 
(based on C1D1) of the first visit where the subject was under weekly 
regimen. It represents the duration subject was under weekly regimen.  
• For instance, for subjects who did not benefit from the USM and 
switched to biweekly infusions starting from C8D1, as initially 
planned in the protocol: planned day of the first visit when switch 
occurred = 197, meaning 196 (28*7) planned days under weekly 
regimen.  
• For subjects who benefited from the USM, number of days with 
weekly infusion can be derived using the visit of switch to a biweekly 
infusion (as derived above) and the theoretical day of visits  
- 
This is calculated only if date of EOT or data cut-off (the earliest one) is after 
the switch to a biweekly infusion (28 weeks in the initial protocol (i.e. 
Duration of planned exposure > 196 (28*7) days) or USM) 
 
Let xx be the planned day of the first visit under biweekly regimen (197 in the initial protocol, where 
dosed bi-weekly from week 29/C8D1 or planned day of the first visit when switch occurred for 
subjects with USM): 
  
o Number of planned doses = number of non-zero doses plus the number of interrupted 
doses.  
- 
if date of EOT or data cut-off (the earliest one) is within the first xx-1 days 
(i.e. Duration of planned exposure ≤ xx-1 days): Number of planned doses = 
floor([duration of planned exposure – 1]/[days between doses]) + 1 
with days between doses = 7 (dosed weekly for the first xx-1 days) 
- 
if date of EOT or data cut-off (the earliest one) is after xx-1 days (i.e. 
Duration of planned exposure > xx-1 days: Number of planned doses = (xx-
1)/7 + floor([duration of planned exposure after xx-1 days – 1]/[days between 
doses]) + 1 
with days between doses=14 (dosed bi-weekly from day xx) 
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• Dose intensity (mg/m²/dose) = [Cumulative actual dose]/[number of planned doses] 
• Cumulative planned dose (mg/m²) = sum(protocol specified dose across each 
planned day of dosing) 
• Planned dose intensity(mg/m²/dose) = [Cumulative planned dose]/[number of 
planned doses]. 
For Cetuximab, PDI (mg/m2/week) = Cumulative planned dose (mg/m2)/ duration 
of planned exposure (week), taking into account the Cetuximab administration 
scheme (400 mg/m2 intravenous (IV) at Cycle 1 day 1 then 250 mg/m2 IV every week 
(QW) for the first xx days. Then, 500mg/m2 IV every two weeks (Q2W)  
• 
Relative dose intensity (%)= 100*[Dose intensity]/ [Planned dose intensity]   
 
Separate summaries will be generated for the subgroup of subjects in Japan. 
15.2. ADVERSE EVENTS 
Any adverse event having been reported during the study for a given subject will be classified by 
Preferred Term and corresponding System Organ Class using the MedDRA terminology. 
The occurrence of an adverse event is defined by the appearance of a new single event, the 
reappearance of a previously recovered event or the worsening of a continuous event in severity or 
seriousness relative to its previous status (see Appendix 2).  
 
An adverse event will be classified as: 
- 
Pre-Treatment adverse event if it occurs or worsens strictly before the first study treatment 
administration  
- 
Treatment emergent adverse event (TEAE) if it occurs during the treatment period (i.e. from 
first treatment administration date up to last administration date + 30 days included) or that 
worsens during the treatment period. Any new serious event that starts > 30 days after 
treatment discontinuation and is assessed by the Investigator as related to study treatment will 
be also considered as TEAE. 
 
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A Related TEAE (to a specific study drug) is defined as a TEAE with relationship to the study 
treatment assessed by the investigator as “Suspected” for this drug.  
A Related TEAE (to any drug) is defined as a TEAE with relationship to the study treatment 
assessed by the investigator as “Suspected” for ENCORAFENIB or BINIMETINIB or 
CETUXIMAB.  
 
An adverse event leading to study drug discontinuation (for a specific study drug) is defined as an 
adverse event with Action Taken with Study Treatment reported as “DRUG WITHDRAWN” for 
this drug. 
An adverse event leading to study treatment discontinuation is defined as an adverse event with 
Action Taken with Study Treatment reported as “DRUG WITHDRAWN” for ENCORAFENIB or 
BINIMETINIB or CETUXIMAB. 
 
An adverse Event leading to dose reduction or study drug interruption (for a specific study drug) is 
defined as an adverse event with Action Taken with Study Treatment reported as “DOSE 
REDUCED” or “DRUG INTERRUPTED” for this drug. 
An adverse Event leading to dose reduction or study treatment interruption is defined as an adverse 
event with Action Taken with Study Treatment reported as “DOSE REDUCED” or “DRUG 
INTERRUPTED” for ENCORAFENIB or BINIMETINIB or CETUXIMAB. 
 
An adverse event requiring a corrective treatment or procedure is defined as an adverse event with 
the box “yes” ticked for either Corrective Treatment or Corrective procedure. 
 
Missing severity or relationship to the study treatment will not be substituted. 
Missing or incomplete dates will be imputed for the calculation of TEAE as described in section 
11.2.4, but will be presented as reported in the CRF in the data listings. 
A summary table will be produced giving the number of: 
• Subjects with at least one AE 
• Subjects with at least one TEAE 
• Subjects with at least one related TEAE  
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• Subjects with at least one AE leading to study treatment discontinuation (at least one study 
drug) 
•  Subjects with at least one AE leading to study drug discontinuation (respectively: 
binimetinib, encorafenib, cetuximab) 
• Subjects with at least one related AE leading to study treatment discontinuation (at least one 
study drug) 
• Subjects with at least one AE leading to discontinuation of binimetinib and encorafenib 
• Subjects with at least one related AE leading to discontinuation of binimetinib and 
encorafenib 
• Subjects with at least one AE leading to discontinuation of all study drugs 
• Subjects with at least one related AE leading to discontinuation of all study drugs 
• Subjects with at least one AE leading to dose reduction or study treatment interruption (at 
least one study drug) 
• Subjects with at least one related AE leading to dose reduction or study treatment 
interruption (at least one study drug) 
• Subjects with at least one AE requiring a corrective treatment or procedure 
• Subjects with at least one related AE requiring a corrective treatment or procedure 
• Subjects with at least one Serious Adverse Event (SAE) 
• Subjects with at least one Treatment Emergent Serious Adverse Event (TESAE) 
• Subjects with at least one related TESAE 
• Subjects with at least one Adverse Event leading to death 
 
Associated number of occurrences will be provided for each case listed above. 
The number and percentage of subjects with at least one AE having occurred before first study 
treatment administration (Pre-Treatment AEs) will be tabulated by MedDRA System Organ Class 
(SOC) and Preferred Term (PT). 
 
Treatment Emergent Adverse Events 
Numbers and percentages of subjects with at least one reported TEAE will be tabulated: 
• By MedDRA System Organ Class (SOC) and Preferred Term (PT), overall and maximum 
Grade 3 or higher 
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• By MedDRA System Organ Class (SOC), Preferred Term (PT), and maximum grade (Grade 
1 to Grade 5) 
• And by MedDRA System Organ Class (SOC), Preferred Term (PT), and worst outcome 
(from “Recovered” to “Fatal” as following: Recovered/Resolved, Recovered/Resolved with 
sequelae, Recovering/Resolving, Unknown, Not Recovered/Not Resolved, Fatal) 
A subject with multiple occurrences of the same AE will only be counted under the maximum NCI-
CTCAE v4.03 grade or worst outcome for this AE, depending on the analysis.  
 
The number and percentage of subjects with at least one TEAE, and the number of occurrences of 
TEAEs, will be tabulated by MedDRA System Organ Class (SOC), Preferred Term (PT), and 
seriousness (by descending order of frequency).  
The same analyses will be performed for TEAEs assessed as related to study treatment by the 
investigator, overall and by study drug. 
Adverse Events related to COVID-19 pandemic will be listed on an individual basis: subject’s code, 
sex and age, Investigator's reported term, preferred term and LLT, NCI-CTCAE v4.03 grade, 
seriousness, onset day, date and time of the first study treatment administration, duration, 
relationship to study treatment, action taken regarding the study treatment administration, use of a 
corrective treatment, outcome, AE status with respect to treatment emergence (AE/TEAE). AEs 
related to COVID-19 are reported in the eCRF with a prefix “COVID19” and will be coded using 
appropriate MedDRA codes. Prefix will not be displayed in the listing. 
Onset day of TEAEs 
The number and percentage of subjects with at least one TEAE will be presented by MedDRA 
System Organ Class (SOC) and Preferred Term (PT), and the first onset day presented in classes 
([D1-Week4], [week4-week12], [week12-week24], [week24-EOT], Safety Follow-Up, Long term 
Follow-Up). The onset day is calculated in section 9.1.3. 
 
Serious Adverse Events (SAEs) 
The number and percentage of subjects with at least one Treatment Emergent SAE (TESAE) will 
be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT), overall and 
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maximum Grade 3 or higher. The same analysis will be performed for related TESAEs, overall and 
by study drug. 
Serious adverse events will also be listed on an individual basis: subject’s code, sex and age, 
Investigator's reported term, preferred term, NCI-CTCAE v4.03 grade, onset day, date and time of 
the first study treatment administration, duration, action taken regarding the study treatments 
administration, use of a corrective treatment, outcome and relationship to the study treatments in 
the Investigator’s opinion, SAE status with respect to treatment emergence (SAE/TESAE). 
 
Adverse events leading to study treatment discontinuation or interruption 
The number and percentage of subjects with at least one AE leading to study treatment 
discontinuation will be presented by study drug, MedDRA System Organ Class (SOC) and 
Preferred Term (PT), overall and maximum Grade 3 or higher. 
The same table will be provided for AEs having led to a study treatment interruption. 
 
AEs having led to study treatment discontinuation will be listed, on an individual basis in the same 
way as serious adverse events previously described, during the study (from the date of the first study 
treatment administration onwards). 
 
Adverse events leading to dose reduction 
The number and percentage of subjects with at least one AE leading to dose reduction will be 
presented by study drug, MedDRA System Organ Class (SOC) and Preferred Term (PT), overall 
and maximum Grade 3 or higher. 
 
Adverse events requiring corrective treatment or procedure  
The number and percentage of subjects with at least one AE requiring corrective treatment or 
procedure will be presented by MedDRA System Organ Class (SOC) and Preferred Term (PT), 
overall and maximum Grade 3 or higher. 
 
Death 
The number and percentage of subjects with adverse event leading to death will be presented by 
MedDRA System Organ Class (SOC) and Preferred Term (PT) for: 
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• on-treatment deaths (occurring during the treatment period, as defined in section 9.1.2) 
• deaths occurring > 30 days after the last study treatment administration 
 
In addition, deaths will be also listed on an individual basis for:  
• Patients who died within 30 days (included) after the last study treatment administration,  
• Patients who died > 30 days after the last study treatment administration 
 
AE analyses will be generated for the subgroup of subjects in Japan. 
 
AEs of special interest (AESI) 
AEs of special interest are described in Appendix 3.  
The MedDRA terms used to define the AESIs and the list of AESIs may be updated during the trial 
based on accumulating safety data. 
 
Treatment emergent AESIs (TEAESI) will be presented by AESI grouping and PT, overall and 
maximum Grade 3 or higher. 
The same analysis will be performed for related TEAESIs, overall and by study drug.  
 
The number and percentage of subjects with at least one Serious TEAESI (TESAESI) will be 
presented by AESI grouping and PT, overall and maximum Grade 3 or higher. The same analysis 
will be performed for related TESAESIs, overall and by study drug.  
TESAESIs will also be listed on an individual basis. 
 
The number and percentage of subjects with at least one AESI leading to study treatment 
discontinuation will be presented by study drug, AESI grouping and PT, overall and maximum 
Grade 3 or higher. 
The same table will be provided for AESIs having led to study treatment interruption. 
AESIs having led to study treatment discontinuation will be listed on an individual basis.  
 
The number and percentage of subjects with at least one AESI leading to the dose reduction will be 
presented by study drug, AESI grouping and PT, overall and maximum Grade 3 or higher. 
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The number and percentage of subjects with at least one AESI requiring corrective 
treatment/procedure will be presented by AESI grouping and PT, overall and maximum Grade 3 or 
higher. 
 
The number and percentage of subjects dead due to an AESI will be presented by AESI grouping 
and PT. 
 
Groupings of adverse events  
Such groups (see Appendix 3) consist of one or more AEs (MedDRA Preferred Terms) and for 
which there is a specific clinical interest regarding the study treatment. 
Grouping of AEs will be summarized as follows: 
• Overall summary of each grouping, including the number of subjects with at least one AESI 
of the grouping, at least one related AESI, at least one serious AESI, at least one AESI 
leading to study treatment discontinuation, at least one AESI leading to study treatment 
interruption, at least one AESI leading to dose reduction, at least one AESI requiring 
corrective treatment/procedure, and the associated numbers of occurrences. 
• Number and percentage of subjects with at least one TEAESI by grouping and PT, and by 
maximum grade (Grade 1 to Grade 5).  
• Number and percentage of subjects with at least one TEAESI by grouping and PT, and worst 
outcome  
 
The onset day of first occurrence of any TEAESI from the grouping will be described by grouping 
and Preferred Term (PT), overall and maximum Grade 3 or higher.  
 
For each grouping, the maximum duration of TEAESI occurrences for subjects with at least one 
TEAESI from the considered grouping will be also described by Preferred Term (PT), overall and 
maximum Grade 3 or higher.   For the calculation of the duration, end date of TEAESI will be 
imputed according to rules described in section 11.2.4 (AE end dates). 
 
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All AEs will be included in the listings of individual data. 
 
 
 
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15.3. LABORATORY DATA 
The following laboratory parameters will be analyzed: 
Table 16: Summary of Clinical Laboratory Tests 
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Hematology 
Chemistry 
Urinalysis 
Coagulation 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Monocytes 
Neutrophils/ANC 
Platelets 
Red blood cells (RBC,  
Erythrocytes), 
White blood cells (WBC, 
Leucocytes) 
 
ALT 
AST 
Bilirubin (total and direct) a 
Albumin 
Alkaline phosphatase 
Bicarbonate (HCO3) 
BUN 
Urea 
Calcium 
Chloride 
CK 
Serum CK isoenzymes (CK 
BB, CK MM, CK MB)  
Creatinine 
Glucose 
LDH 
Magnesium 
Potassium 
Sodium 
Total protein 
Troponin I or T 
Uric acid (Urate) 
Lipase 
Amylase  
Myoglobin  
Blood   
Glucose 
Ketones 
Leukocytes 
pH 
Protein 
Myoglobin  
PT or INR 
aPTT 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CA19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; 
CK = creatine kinase; CRP = C-reactive protein; FSH = follicle-stimulating hormone; INR = International 
Normalized Ratio; LDH = lactate dehydrogenase; LH = luteinizing hormone; pH = hydrogen ion concentration; PT 
= prothrombin time; aPPT = activated partial thromboplastin time; RBC = red blood cell(s); WBC = white blood 
cell(s); HIV = Human  Immuno deficiency Virus. 
a Direct bilirubin bilirubin (and indirect – only applicable for France)  will be measured at screening only if total bilirubin 
values are abnormal; the result will be used to calculate indirect bilirubin levels for the purposes of determining 
eligibility to participate in the study.  
For laboratory tests covered by the NCI-CTCAE v4.03, laboratory data will be graded accordingly. 
For laboratory tests covered by the NCI-CTCAE v4.03, Grade 0 will be assigned for all non-missing 
values not graded as 1 or higher. Grade 5 will not be used.  
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Sponsor specifications for lab toxicity grading will be described in a specific document, separately 
from the statistical analysis plan. Corrected Calcium will be derived for analyses purposes, as 
described in these specifications. 
Graded hematology, coagulation, urinalysis, and clinical chemistry test results will be summarized 
by worst grade on study treatment period as well as in shift tables from Baseline to worst grade on 
study treatment period. For shift tables, the number of patients with missing data at Baseline or on 
study treatment period will be displayed. 
For laboratory parameters that are not gradable by NCI-CTCAE v4.03, shift tables of normal-
abnormal will be provided for worst post-baseline value (both directions). 
Grade 3 and 4 observations will be listed on an individual basis. 
Possible Hy’s Law (subjects with any elevated ALT or AST of >3xULN, ALP <2xULN, and 
associated with an increase in total bilirubin ≥2xULN) and drug-induced liver injury (DILI) cases 
(AE preferred term) will be summarized. Drug-induced liver injuries will be flagged using the SMQ 
“Drug related hepatic disorders” (narrow terms). Hy’s Law and drug-induced liver injuries will be 
considered after the first study treatment administration. 
Values outside laboratory normal ranges and Hy’s law will be flagged in the individual data listings 
of laboratory data in appendix 16 of the ICH report. 
Laboratory data analyses will be generated for the subgroup of subjects in Japan. 
15.4. VITAL SIGNS 
The number and percentage of patients with at least one clinically notable abnormality (see 
Appendix 4) will be tabulated by type of abnormality. Clinically notable abnormality will be also 
tabulated in an individual data listing. 
In addition, blood pressure (systolic, diastolic and both combined) shift table based on NCI-CTCAE 
v4.03 grade for hypertension at baseline and worst post-baseline values will be produced: 
• Systolic BP (SBP) only (mmHg): 
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o Grade 0: < 120  
o Grade 1: 120-139 
o Grade 2: 140-159 
o Grade 3: ≥ 160 
o No Grade 4 or 5 
• Diastolic BP (DBP) only (mmHg): 
o Grade 0: < 80 
o Grade 1: 80-89 
o Grade 2: 90-99 
o Grade 3: ≥ 100 
• Systolic and diastolic BP combined (mmHg). Maximum grade based on SBP and DBP 
values will be considered: 
o Grade 0: SBP < 120 and DBP < 80 
o Grade 1: SBP in 120-139 or DBP in 80-89 
o Grade 2: SBP in 140-159 or DBP in 90-99 
o Grade 3: SBP ≥ 160 or DBP ≥ 100 
o No Grade 4 or 5 
Clinically notable values will be flagged in the individual data listings of vital signs in appendix 16 
of the ICH report. 
15.5. ECG 
Automatic corrections for QTcF will be used, whenever available. Otherwise QTcF will be 
calculated as QT / (60/HR)1/3 (rounded to the nearest integer). 
Values of QTcF will be classified as following: 
QTc Categories (ms) 
≤450 
451-480 
481-500 
>500 
 
 
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Changes from baseline of QTcF will be classified as following: 
QTc change from 
baseline(ms) 
≤30 
31-60 
>60 
 
The number and percentage of patients with at least one clinically notable ECG abnormalities (see 
Appendix 4) will be tabulated by type of abnormalities. 
Patients with clinically notable QTcF values >500 ms and changes from baseline >60 ms will be 
listed including the corresponding notable values and abnormality findings. 
15.6. MUGA/ECHOCARDIOGRAM  
Left Ventricular Ejection Fraction (LVEF) abnormalities will be defined by grade according to NCI-
CTCAE version 4.03. Patient will be considered as having a LVEF abnormality if the worst post-
baseline value is grade 2, 3 or 4 according to the following classification (as defined in NCI-CTCAE 
version 4.03):  
- 
Grade 0: Non-missing value below Grade 2  
- 
Grade 2: 40% ≤ LVEF value ≤ 50% or -20% < absolute change from baseline  ≤ -10%  
- 
Grade 3: 20% ≤ LVEF value < 40% or absolute change from baseline  ≤ -20% 
- 
Grade 4: LVEF value <  20%. 
The following summaries will be produced for LVEF:  
• Incidence of worst post-baseline LVEF value with NCI-CTCAE version 4.03 grades. 
• Shift tables using NCI-CTCAE version 4.03 grades to compare baseline to the worst post-
baseline LVEF value with NCI-CTCAE version 4.03 grades.  
• Time to LVEF abnormalities will be presented as KM plots if at least 10 patients with 
abnormality are observed. Patients with no LVEF abnormality will be censored at their last 
on-treatment LVEF examination date. Patients with no adequate post-baseline LVEF 
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assessment will be censored at their date of first study treatment administration. Two types 
of abnormalities will be considered: 
o LVEF value < 50%;  
o LVEF value < 50% and/or absolute change from baseline ≤ -10% .  
Different modalities to assess LVEF might be used for the same patient, change from baseline and 
shift table will be provided regardless of the modality. 
Patients with abnormalities (grade 2 or above NCI-CTCAE version 4.03) will be tabulated in an 
individual listing. 
15.7. ECOG PS 
ECOG PS will be summarized descriptively by time windows for each score category. Shift table 
to compare baseline to the worst post-baseline score will be produced. 
15.8. PHYSICAL EXAMINATION 
The results on physical examination will not be tabulated as used to detect potential AE. They will 
be only listed in appendix 16 of the ICH report. 
15.9. DERMATOLOGIC EXAMINATION 
Number of patients with post-Baseline skin abnormalities will be summarized by type of 
abnormalities (keratoacanthoma, squamous cell carcinoma, other). 
15.10. OPHTHALMIC EXAMINATION 
All ophthalmic examinations will be listed: 
• Visual assessment performed by the investigator: General inspection, Motility examination, 
Alignment examination, Visual disturbance 
• Full ophthalmic examination: Tonometry, Visual acuity, Fundoscopy, Slit lamp, Optical 
Coherence Tomography (OCT), Fluorescein Angiography  
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General inspection, Motility examination, Alignment examination, Visual disturbance: 
For each considered category, the number of subjects with at least one newly occurring 
abnormalities (whatever the clinical significance) will be described, on the subjects at risk of 
developing the abnormality. Subjects at risk of developing the abnormality will be defined as 
subjects. with baseline not missing and not being abnormal (whatever the clinical significance) in 
both eyes, and with at least one post-baseline value). 
Same analysis will be performed for the number of subjects with at least one newly occurring 
clinically significant abnormalities. Subjects at risk of developing the abnormality will be defined 
as subjects with baseline not missing and not being clinically significantly abnormal in both eyes, 
and with at least one post-baseline value). 
Subjects with newly occurring abnormalities in general inspection, motility examination, alignment 
examination and visual disturbance respectively will be tabulated in a listing of individual data. 
 Visual acuity  
Visual acuity will be measured using the Snellen visual acuity. This is determined by establishing 
the smallest optotypes that can be identified correctly by the patient at a given observation distance. 
Snellen visual acuity will be reported as a Snellen fraction (m/M) in which the numerator (m) 
indicates the test distance and the denominator (M) indicates the distance at which the gap of the 
equivalent Landolt ring subtends 1 minute of arc. For each timepoint, the LogMAR score will be 
calculated as –log(m/M). LogMAR is a notation of visual loss since positive logMAR values 
indicate reduced vision, while normal vision is indicated by negative logMAR numbers.  
Total visual acuity score will also be assessed identifying clinically meaningful deterioration in 
visual acuity (LogMAR increase). LogMAR results will be summarized in a shift table from 
Baseline score (≤0, >0 to <0.1, 0.1 to <0.2, 0.2 to <0.3 and ≥0.3) to worst post-baseline value (≤0 
(no deterioration), >0 to <0.1, 0.1 to <0.2, 0.2 to <0.3 and ≥0.3). 
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Ophthalmic events (AESI from groupings “Retinopathy excluding RVO” and “Retinal vein 
occlusion”) occurring within -15 days to 30 days of the worst logMAR score (<=0, 0 to <0.1, 0.1 to 
<0.2, 0.2 to <0.3 or ≥0.3) will be presented by preferred term and worst logMAR score.  
Patients with ≥ 0.2 LogMAR increase (visual loss) will be listed by patient and timepoint including 
the Snellen fraction and logMAR score.  
All Snellen fraction and logMAR scores will be listed by eye in appendix 16 of the ICH report. 
Intraocular pressure  
Number and percentage of patients with clinically intraocular pressure above 30 mmHg will be 
summarized by time windows. For patients with such values, a listing will also be provided.  
Optical Coherence Tomography (OCT) and Fluorescein Angiography (FA)  
The clinical outcome presented in the listing combine the clinical observation (present, not 
clinically significant and clinically significant) and the eye involvement (unilateral or bilateral). For 
each considered category, the number of subjects with at least one newly occurring abnormalities 
(whatever the clinical significance and clinically significant abnormalities) will be described by 
type of abnormality, on the subjects at risk of developing the abnormality (i.e. with baseline not 
missing and not being significantly abnormal in both eyes, and with at least one post-baseline 
value). Patients without baseline assessment will also be considered at risk at baseline of developing 
a new abnormality.3 For each considered category in each assessment (OCT and FA), newly 
occurring abnormalities will be provided. 
Fundoscopy and slit lamp  
For each considered category (fundoscopy and slit lamp), the number of subjects with at least one 
newly occurring abnormalities (whatever the clinical significance) will be described by type of 
abnormality, on the subjects at risk of developing the abnormality. Subjects at risk of developing 
 
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the abnormality will be defined as subjects with baseline not missing and not being abnormal 
(whatever the clinical significance) in both eyes, and with at least one post-baseline value). 
Same analysis will be performed for the number of subjects with at least one newly occurring 
clinically significant abnormalities. Subjects at risk of developing the abnormality will be defined 
as subjects with baseline not missing and not being clinically significantly abnormal in both eyes, 
and with at least one post-baseline value). 
Subjects with newly occurring abnormalities in fundoscopy and slit lamp respectively will be 
tabulated in a listing of individual data. 
15.11. CONCOMITANT THERAPIES AND THERAPEUTIC / DIAGNOSTIC 
PROCEDURES  
 
Concomitant therapies (as described in PRIOR AND CONCOMITANT THERAPY eCRF page) 
prior to and after the start of the study treatment will be tabulated from a descriptive perspective by 
therapeutic area according to the WHO-DRUG dictionary using the "anatomical therapeutic 
chemical (ATC) classification (ATC2, ATC4 and Preferred Term) for the FAS and according to the 
first study treatment administration: 
• starting between informed consent signature and start of study treatment, and ending prior 
to the start of study treatment,  
• starting prior to the start of study treatment and continuing after the start of study treatment,  
• starting on or after the start of study treatment but no later than 30 days (included) after last 
dose of study drug.  
The number and percentage of subjects with at least one concomitant therapeutic / diagnostic 
procedure (as described in MEDICAL AND SURGICAL PROCEDURES eCRF pages) will be 
tabulated by SOC and PT using the MedDRA terminology and according to the first study treatment 
administration. 
The number and percentage of subjects with at least one antineoplastic therapy since study treatment 
discontinuation (as described in ANTI-NEOPLASTIC THERAPY SINCE STUDY TREATMENT 
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DISCONTINUATION - MEDICATION eCRF page) will be described by treatment intent 
(palliative, curative, unknown). 
The number and percentage of subjects with at least one single agent since study treatment 
discontinuation (as described in ANTI-NEOPLASTIC THERAPY SINCE STUDY TREATMENT 
DISCONTINUATION - MEDICATION eCRF page) will be provided by WHO-DRUG ATC2, 
ATC4 and Preferred Term. 
The number of patients with at least one combination identified in Appendix 1 with start dates 
within the same month or treatments taken in parallel despite being started within the same one 
month interval will be tabulated.The number and percentage of subjects with at least one 
antineoplastic surgery since study treatment discontinuation (as described in ANTI-NEOPLASTIC 
THERAPY SINCE STUDY TREATMENT DISCONTINUATION - SURGERY eCRF page) will 
be described by treatment intent, location of surgery and result. Location will be classified as done 
for primary tumor location (cf. Table 9). 
The number and percentage of subjects with at least one antineoplastic surgery since study treatment 
discontinuation (as described in ANTI-NEOPLASTIC THERAPY SINCE STUDY TREATMENT 
DISCONTINUATION – SURGERY eCRF page) will be tabulated by SOC and PT using the 
MedDRA terminology.  
The number and percentage of subjects with at least one antineoplastic radiotherapy since study 
treatment discontinuation (as described in ANTI-NEOPLASTIC THERAPY SINCE STUDY 
TREATMENT DISCONTINUATION – RADIOTHERAPY eCRF page) will be tabulated by 
treatment intent (palliative, curative, unknown), best overall response and procedure linked to 
Chemotherapy (No/Yes). 
Time to subsequent therapy (TST) will be defined as the time from the first study treatment 
administration to the initiation of subsequent antineoplastic therapy or death. TST will be described 
using survival curves according to the Kaplan Meier method and reporting estimated median (in 
months) with 95% CI, 25th and 75th percentiles and KM estimated probabilities with corresponding 
95% CIs at several time points (every 2 months up to 14 months). 
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Table 17: Censoring rules for TST 
In the below table, “subsequent antineoplastic therapy” refers to any additional secondary antineoplastic 
medication or anti-cancer surgery or radiotherapy. 
 
 
Situation 
Event Date 
Outcome 
A 
Initiation of subsequent antineoplastic therapy 
Start date of subsequent 
antineoplastic therapy  
Event 
B 
Death at any time after the first study treatment 
administration 
Date of death 
Event 
C 
Patient alive without starting a subsequent antineoplastic 
therapy  
Date of last contact  
Censored 
PFS after next line of treatment (PFS2) will be defined as the time from the first study treatment 
administration to the earlier of death at any time after the first study treatment administration or 
progression after the start of subsequent anticancer therapy. 
PFS2 will be described using survival curves according to the Kaplan Meier method and reporting 
estimated median (in months) with 95% CI, 25th and 75th percentiles and KM estimated probabilities 
with corresponding 95% CIs at several time points (every 2 months up to 14 months). 
Table 18: Censoring rules for PFS2 
In the below table, “subsequent antineoplastic therapy” refers to any additional secondary antineoplastic 
medication or anti-cancer surgery or radiotherapy. 
 
 
Situation 
Event Date 
Outcome 
A 
Progression after start of subsequent antineoplastic therapy 
Date of progression  
Event 
B1 
Death at any time after the first study treatment 
administration and before the start of any subsequent 
antineoplastic therapy, after zero or one missed/inadequate 
tumor assessment while on the Study  
Date of death  
Event 
B2 
Death at any time after the first study treatment 
administration and before the start of any subsequent 
antineoplastic therapy, after 2 or more missed/inadequate 
tumor assessments while on the Study  
Date of last contact 
Censored 
B3 
Death after the start of any subsequent antineoplastic 
therapy 
Date of death  
Event 
C 
Patient alive and without progression on their subsequent 
antineoplastic therapy 
Date of last contact 
Censored 
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Situation 
Event Date 
Outcome 
D 
Patient alive, without starting a subsequent antineoplastic 
therapy 
Date of last contact 
Censored 
 
Procedures related to COVID-19 pandemic (e.g. quarantine, patient isolation, testing, etc) will be 
listed on an individual basis, with reported term, MedDRA Preferred Term (PT) and Lowest Level 
Term (LLT), and dates, day relative to first study treatment administration and status with respect 
to the study treatment period. Procedures related to COVID-19 are reported in the eCRF with a 
prefix “COVID19” and will be coded using appropriate MedDRA codes. Prefix will not be 
displayed in the listing. 
 
16. QUALITY OF LIFE ANALYSIS  
Quality of Life will be evaluated through the EORTC QLQ-C30, EQ-5D-5L QoL and PGIC 
questionnaires on the FAS. 
The number of patients completing the questionnaires and the number of missing or incomplete 
assessments will be summarized for each time window. Compliance for each questionnaire is 
described in  
Table 19. 
 
Table 19: Patient Reported Outcomes Compliance 
 
Status 
Questionnaire 
Missing 
Incomplete assessment 
Complete assessment 
EORTC QLQ-C30 
0 question answered 
1 to 29 questions answered 
30 questions answered 
EQ-5D-5L 
0 question answered 
1 to 5 questions answered 
6 questions answered 
PGIC 
0 question answered 
NA 
1 question answered 
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16.1. EORTC QLQ-C30 SCORING 
Following the European Organisation for Research and Treatment of Cancer (EORTC) 
recommendations [12], fifteen scores will be derived from the initial 30 questions of the QLQ-C30 
questionnaire: 
a global health-related quality of life scale, 
five functional scales: physical, role, cognitive, emotional, social, 
nine symptom scales: nausea and vomiting, pain, fatigue, dyspnoea, insomnia, appetite loss, 
constipation, diarrhoea, financial difficulties. 
They will be the health-related quality of life parameters of the analysis on QLQ-C30 questionnaire. 
Of note, a higher value in functional scales (resp. Global Health Status) will reflect a better level of 
function (resp. quality of life), but for “symptoms” scales a higher value will reveal a deterioration 
of the condition. 
Each scale in the EORTC QLQ-C30 questionnaire will be scored (0 to 100) according to the 
EORTC recommendations in the EORTC QLQ-C30 Scoring Manual. The scoring method is 
summarized below. In this summary Qi refers to the ith question on the EORTC QLQ-C30, and 
score value correspondence is ["1" = "Not at All", "2" = "A Little", "3" = "Quite a Bit", "4" = "Very 
Much"] for Q1 to Q28. 
 
 
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Table 20: EORTC QLQ-C30 questionnaire scoring 
 
Raw score 
Analysed Score 
Functional scales 
Physical functioning:  
(Q1+Q2+Q3+Q4+Q5)/5 
(1 – (raw score -1) / 3) * 100 
Role functioning: 
 
(Q6+Q7)/2 
(1 – (raw score -1) / 3) * 100 
Emotional functioning: 
 
(Q21+Q22+Q23+Q24)/4 
(1 – (raw score -1) / 3) * 100 
Cognitive functioning 
(Q20+Q25)/2 
(1 – (raw score -1) / 3) * 100 
Social functioning 
(Q26+Q27)/2 
(1 – (raw score -1) / 3) * 100 
Global health status: 
Global health status/QOL 
(Q29+Q30)/2 
((raw score -1) / 6) * 100 
Symptom scales/Items: 
Fatigue 
(Q10+Q12+Q18) / 3 
((raw score -1) / 3) * 100 
Nausea and vomiting  
(Q14+Q15) / 2 
((raw score -1) / 3) * 100 
Pain 
(Q9+Q19) / 2 
((raw score -1) / 3) * 100 
Dyspnoea 
Q8 
((raw score -1) / 3) * 100 
Insomnia 
Q11 
((raw score -1) / 3) * 100 
Appetite loss 
Q13 
((raw score -1) / 3) * 100 
Constipation 
Q16 
((raw score -1) / 3) * 100 
Diarrhoea 
Q17 
((raw score -1) / 3) * 100 
Financial difficulties 
Q28 
((raw score -1) / 3) * 100 
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Descriptive statistics will be used to summarize the 15 scores values and changes from baseline by 
time windows on the FAS. Figures will be displayed for scores changes by time windows. 
16.2. EQ-5D-5L 
The EQ-5D-5L[13] contains 1 item for each of 5 dimensions health-related quality of life (mobility, 
self-care, usual activities, pain or discomfort, and anxiety or depression).  
Each dimension has 5 levels: Level 1 indicating no problems, Level 2 indicating slight problems, 
Level 3 indicating moderate problems, Level 4 indicating severe problems and Level 5 indicating 
extreme problems.  
Descriptive statistics will be used to summarize the scored scales at each time window. 
For each dimension, the EQ-5D-5L levels will be also described as dichotomised into 'no problems' 
(i.e. level 1) and 'problems' (i.e. levels 2 to 5) by time windows. 
The EQ-5D-5L VAS records the patient’s self-rated health on a vertical visual analogue scale 
numbered from 0 to 100, where the endpoints are labelled ‘The best health you can imagine’ (i.e. 
100) and ‘The worst health you can imagine’ (i.e. 0).  
Descriptive statistics for EQ-5D-5L VAS values and changes will be tabulated by time windows on 
the FAS. Figure will be displayed for EQ-5D-5L VAS changes from baseline by time windows. 
16.3. PGIC 
PGIC score will be summarized using descriptive statistics by time windows on the FAS. 
 
 
 
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17. BIOMARKERS ANALYSIS 
The relationship between protein levels, mutations and clinical outcomes will be explored.  
Descriptive statistics for values and changes from baseline in tumor markers blood CEA and CA19-
9 will be tabulated by time windows on the FAS. 
The primary endpoint and the corresponding 95% CI will be presented by the microsatellite 
instability (MSI) status subgroups, CEA subgroups and CA19-9 subgroups as described in section 
0. Scatter plots highlighting individual results will display baseline CEA vs baseline CA19-9 
Levels, each BOCR being identified differently, on the FAS. 
The relationship between changes in blood CEA and CA19-9 and radiographic response to 
treatment will be investigated. Descriptive statistics for percentage change from baseline to nadir 
in blood CEA and CA19-9 will be tabulated for each type of response (BOCR) on the FAS. The 
nadir corresponds to the lowest post-baseline blood CEA value recorded for a patient during the 
study. 
All the blood and tissue biomarkers analyses will be exploratory. They will not be part of the CSR, 
outside the analysis specified above, but summarized in a separate report under the supervision of 
translational medicine department. 
18. HEALTHCARE RESOURCE UTILIZATION 
Descriptive statistics of hospitalizations occurring during the treatment period (i.e. from first 
treatment administration date up to last administration date + 30 days included) will be provided.  
The number of patients hospitalized, the number of hospitalizations by patient, the cumulative 
duration of hospitalization by patient, the total number and duration of hospitalizations, the facility 
used and hospital discharge disposition will be summarized descriptively on the FAS. 
For hospitalization that are “ongoing” at the cut-off date, the end date will be imputed to the last 
contact date to compute the duration.  
 
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19. PHARMACOKINETICS ANALYSIS 
Blood samples for encorafenib, binimetinib and the active metabolite of binimetinib (AR00426032) 
plasma concentration measurements will be performed as follow: 
 
 
Cycle 1 Day 1 
Cycle 2 Day 1 
Time after encorafenib/ 
binimetinib dosing on 
designated dosing days (h) 
2 
6 
0 
(Pre-dose) 
2 
PK sample for 
encorafenib, binimetinib 
and AR00426032  
x 
x 
x 
x 
Abbreviations: h = hours; PK = pharmacokinetic 
PK samples will be collected on Cycle 1 Day 1 postdose (encorafenib/binimetinib) at 2 h (± 10 min) and 6 h (± 30 min). PK 
samples will be collected on Cycle 2 Day 1 predose (just prior to encorafenib/binimetinib dose) and postdose at 2 h (± 10 min). 
Blood samples for encorafenib/binimetinib PK will be processed to collect plasma. 
 
 
Blood samples for serum Cetuximab concentration measurements will be performed as follow: 
 
Cycle 1 Day 1 
Cycle 2 Day 1 
Time after the start of 
cetuximab infusion on 
designated dosing days (h) 
2 
6 
0 
(Pre-infusion) 
2 
PK sample for cetuximab  
x 
x 
x 
x 
Abbreviations: h = hours; PK = pharmacokinetic 
PK samples will be collected on Cycle 1 Day 1 post-infusion (cetuximab) at 2 h (± 10 min) and 6 h (± 30 min). PK samples will 
be collected on Cycle 2 Day 1 pre-infusion (just prior to infusion of cetuximab) and post-infusion at 2 h (± 10 min). Blood 
samples for cetuximab PK will be processed to obtain serum. Time points are based on the start of infusion. 
 
The pharmacokinetic set (cf section 7) will be used to perform the PK analysis. 
 
19.1. DESCRIPTIVE STATISTICS 
The plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib 
(AR00426032) and the serum concentrations of Cetuximab will be tabulated with their related 
descriptive statistics.  
Individual concentrations tables will be presented by drug-related analyte (i.e encorafenib, 
binimetinib, AR00426032 and cetuximab), by dose (if applicable) and by nominal time points, with 
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descriptive statistics as number of available data (N), arithmetic mean, StD, CV, geometric mean, 
geometric CV, median, [min – max] according to the following rules.   
Values reported as ‘NS’ (no sample) will be set to ‘missing’. 
Encorafenib, binimetinib and AR00426032 concentrations will be flagged and excluded from the 
descriptive statistics if a vomiting episode occurs within the first 4 hours post-dosing of during the 
day of the last dose prior to collection of PK samples. 
Concentrations will be flagged and excluded from the descriptive statistics if the actual sampling 
time is outside the nominal sampling time predefined window (i.e T2h ±10 min and T6h ± 30 min). 
For calculated statistics, by time point, if more than (or equal) half of values are not BLQ, statistics 
will be calculated considering BLQ values as missing data, but Min value will take into account 
BLQ (i.e Min = BLQ). If more than half of values are BLQ: arithmetic and geometric means, StD, 
CV geometric CV, median will not be calculated and only Min (BLQ) and Max values will be 
presented. By time point, if all the concentration values are BLQ, the corresponding statistics will 
be indicated as not applicable (NA). 
19.2. POPULATION PK AND EXPOSURE RESPONSE ANALYSES 
PK parameters for encorafenib, binimetinib, AR00426032 and cetuximab may be generated by a 
compartmental approach such as a population approach, as appropriate. Details of these analyses 
and of the incorporation of prior information to support the model building will be provided in a 
specific standalone modeling plan. Results of these analyses will be provided in a separate report. 
 
 
 
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20. CHANGES TO THE STATISTICAL ANALYSIS PLAN SINCE 
PROTOCOL WRITING  
The following modifications were made to statistical analyses compared to those envisaged in the 
Version 1 of the protocol dated May 25th, 2018: 
In SAP Version 1: 
- 
Addition of analysis of the best percent change in tumor measurements from baseline added 
- 
Addition of analyses on the duration of follow-up added 
- 
Removal of over time analyses for safety data 
- 
Addition of analyses (demographic and disease characteristics, primary and secondary 
outcomes measures, treatment exposure, AE and laboratory data analyses) for the subgroup 
of subjects in Japan. 
- 
Addition of analysis of “Time to disease progression under next regimen” 
In SAP Version 2: 
- 
Definition of cut-off for Stage 1/Stage 2 analysis was completed with a footnote, to 
explicitly mention discontinued subjects.  
- 
Study flow-chart updated following protocol amendment V5. 
- 
Following protocol amendment V5: Wording updated for time point for futility analysis, for 
Stage 2 analysis. 
- 
Following protocol amendment V5: Update of the paragraph on the lack of confirmation of 
mutation / discordance between local and central (threshold before requirement to perform 
assessment using central laboratory). 
- 
Following protocol amendment V5: List of labs parameters completed (Myoglobin, Serum 
CK isoenzymes).  
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Following protocol amendment V5: Add analysis of new visual assessments performed 
(General inspection, Motility examination, Alignment examination, Visual disturbance) 
In SAP Version 3: 
- 
No change compared to analyses planned in the initial version of the protocol.  
o Clarifications were added to avoid any ambiguity for programming 
o Two variables were added (disease characteristics), following iDSMC 
recommendations provided after the first iDSMC meeting. 
o Analysis of “Time to disease progression under next regimen” detailed into “Time 
to subsequent therapy” (TST) and “Progression under next line of treatment” (PFS2) 
o Exploratory analysis of the primary endpoint was added after Steering Committee at 
Stage 1 (excluding the patients with no metastases at inclusion)  
In SAP Version 4: 
- 
Definition of PP set was clarified to explicitly mention that subjects with no central 
confirmation of the BRAF V600E status will be excluded from the PP set. (It was initially 
considered that it will be a protocol deviation, but this is). 
- 
Exploratory analysis of the primary endpoint was added to assess impact of the USM 
implemented during the COVID-19 pandemic  
- 
No change compared to analyses planned in the initial version of the protocol for:  
o Clarifications were added to avoid any ambiguity for programming 
o Some parameters were added in demographics and disease characteristics  
o Additional analyses (protocol deviations, AEs, procedures) to describe impact of 
COVID-19 pandemic on the study 
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o Analyses were updated in accordance with USM implemented during COVID-19 
pandemic (Protocol V8): take into account in exposure derivations for cetuximab + 
add an exploratory analysis of the primary endpoint 
o Description of additional items collected in the eCRF (prior surgeries, stomies) were 
added 
o A section was added to detail how to handle central imaging data sent by the vendor 
 
21. DATA PROCESSING 
Version 9.4 of SAS Software for windows will be used to perform the statistical procedures. 
 
 
 
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22. REFERENCE 
[1] 
E.A. Eisenhauer and al. 
 
New response evaluation criteria in solid tumours:Revised RECIST guideline 
(version 1.1) 
European journal of cancer (2009). 45:228-247 
 
[2] 
Peter C. O'Brien; Thomas R. Fleming 
 
A Multiple Testing Procedure for Clinical Trials. 
 
Biometrics . (1979). 35:549–556 
 
[3] 
East® version 6.4 manual (2016). Cytel Inc. Cambridge, MA USA.  
[4] 
Clopper CJ, Pearson ES 
 
The Use of Confidence or Fiducial Limits Illustrated in the Case of the Binomial. 
Biometrika; (1934), 26(4): 404-413 
 
[5] 
Brookmeyer R and Crowley J 
 
A Confidence Interval for the Median Survival Time.  
 
Biometrics (1982). 38: 29 – 41 
 
[6] 
Schemper M, Smith TL 
 
A note on quantifying follow-up in studies of failure time.  
 
Controlled Clinical Trials (1996), 17: 343-346 
 
[7] 
Kalbfleisch JD, Prentice RL 
 
The Statistical Analysis of Failure Time Data.  
 
Wiley Series in Probability and Statistics (2002) 
 
[8] 
Binimetinib Investigator’s Brochure edition 15 – 20 MARCH 2018 
 
[9] 
Encorafenib Investigator’s Brochure edition 09 – 03 AUGUST 2017  
 
[10] 
Cetuximab  Summary Of Product Characteristics 
 
[11]  
Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarryhthmic Drugs, Center for Drug Evaluation 
and Research, Food and Drug Administration, Rockville, MD.  
https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-
gen/documents/document/ucm073153.pdf  
 
[12] 
EORTC QLQ-C30 Scoring Manual  
 
[13] 
EQ-5D-5L_UserGuide_2015  
 
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23. APPENDIX 
 
Appendix 1: Prior or subsequent antineoplastic therapy Combinations 
Appendix 2: Conventions related to Adverse Events 
Appendix 3: Specific groupings of adverse events  
Appendix 4: Vital signs and ECG clinically notable abnormalities  
Appendix 5: Tables, Figures and Listings (TFL) 
Appendix 6: Signature Page of SAP version 4 
 
  
 
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APPENDIX 2 
CONVENTIONS RELATED TO ADVERSE EVENTS 
 
 
  
2.1) Conventions relative to Treatment Emergent Adverse Events (TEAEs) 
 
Onset Day of AE = Day_[Start date of AE – Date of first administration  +1]  if start date ≥ Date of first administration   
                            = Day_[Start date of AE – Date of first administration]  if start date < Date of first administration   
     
____________        = severity 
 
 
Before 
treatment  
Onset day < 0 
During treatment (On study drug) 
Onset day > Day1 
After treatment 
Onset day> 30 
days 
Type of AE 
Number of 
AE 
occurrenc
es 
Number of 
TEAE 
occurrences 
AE00 
 
AE 
 
 
 
 
 
  
 
 
1 
0 
 
 
 
 
 
 
 
 
  
 
 
AE01 
 
 
 
 
 
 
 
  
 
AE 
1 
0 
 
 
 
 
 
 
 
 
  
        > 30 days and 
           not related     
                 
AE 
 
 
AE02 
 
AE 
 
 
 
 
 
  
 
              
1 
0 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
AE 
 
  
 
 
 
AE03 
 
AE 
 
 
 
 
 
  
 
2 
0 
 
 
 
 
 
 
 
 
  
 
 
 
AE04 
 
AE 
 
 
 
 
 
  
           AE 
 
 
 
 
 
 
 
 
 
AE 
  
 
> 30 days 
and not 
related 
2 
0 
 
 
 
 
 
 
 
 
  
 
 
 
 
AE06 
 
AE 
 
 
 
TEAE 
 
  
 
 
2 
1 
 
 
 
 
 
 
 
 
  
 
      TEAE 
 
 
AE07 
 
 
 
 
 
 
TEAE 
  
 
1 
1 
 
 
AE08 
 
 
AE 
 
 
 
 
 
TEAE 
  
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
TEAE 
 
 
 
 
AE09 
 
 
 
 
 
 
AE 
  
 
2 
1 
 
 
 
 
 
 
 
TEAE 
  
 
 
 
AE10 
 
AE 
 
 
 
 
 
 
         TEAE 
3 
2 
 
 
 
 
 
AE 
 
 
TEAE 
  
> 30 days 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 TEAE 
 
TEAE 
 
 
 
AE11 
 
AE 
 
 
 
 
TEAE 
  
  
> 30 days 
and related 
 
4 
3 
 
 
 
 
 
AE 
 
 
 
 
 
 
 
 
AE12 
 
AE 
 
 
 
 
 
 | SAE 
 
              
 
2 
 
1 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 3 
SPECIFIC GROUPINGS OF ADVERSE EVENTS 
 
 
Encorafenib, Binimetinib and Cetuximab Adverse Events of Special Interest are displayed in the 
excel file: ANCHOR_Statistical_Analysis_Plan_AESI.xls. Last version of this file will be used for 
analysis. 
Note: Any update of this list (e.g. modification of a title) without impact on the statistical analysis 
described in this plan will not lead to a new version of the statistical analysis plan. 
 
 
 
 
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APPENDIX 4 
VITAL SIGNS AND ECG CLINICALLY 
NOTABLE ABNORMALITIES 
 
 
Table 1: Vital signs clinically notable values 
Parameter 
Clinically notable values 
SBP 
SBP ≥ 160 mmHg and increase from Baseline ≥ 20 mmHg 
SBP ≤ 90 mmHg and decrease from Baseline ≥ 20 mmHg 
DBP 
DBP ≥ 100 mmHg and increase from Baseline ≥ 15 mmHg 
DBP ≤ 50 mmHg and decrease from Baseline ≥ 15 mmHg 
HR 
HR ≥ 120 bpm and increase from Baseline ≥ 15 bpm 
HR ≤ 50 bpm and decrease from Baseline ≥ 15 bpm 
Weight 
Weight increase ≥ 10 % from baseline 
Weight decrease ≥ 20 % from baseline 
Body 
temperature 
Body temperature ≥ 37.5 C  
Body temperature ≤ 36 C 
  
Table 2: ECG clinically notable values or changes [11] 
Parameter 
Clinically notable values or changes 
QTcF 
Value in 451-480 ms 
Value in 481-500ms 
Value > 500 ms 
Increase from Baseline in 31-60 ms 
Increase from Baseline > 60 ms 
Heart rate 
HR > 100 bpm 
HR < 60 bpm  
 
 
 
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APPENDIX 5 
TABLES, FIGURES AND LISTINGS 
 
 
The 
list 
of 
TFLs 
to 
be 
produced 
is 
displayed 
in 
the 
excel 
file: 
ANCHOR_SAP_Appendix5_TFL.xls. Last version of this file will be used for analysis. 
Note: Any update of this list (e.g. modification of a title) without impact on the statistical analysis 
described in this plan will not lead to a new version of the statistical analysis plan. 
 
The stage 2 analysis (if considered as primary analysis) will include all analyses listed (except 
PK and Healthcare resource utilization analyses that will be performed once at the end of 
study).   
 
 
Each output name (.rtf) will end with the population reference (including 16.2 listings), for instance:  
• 
Table 11_2_1_1 (Demographics on ES): T11_2_1_1_demo_ES.RTF 
• 
Table 
12_1_1_1 
(Duration 
of 
Exposure 
to 
Encorafenib 
on 
FAS): 
T12_1_1_1_enco_expos_FAS.RTF 
Tables, figures and listings that will be performed for the subgroup of subjects in Japan separately 
at the time of the primary analysis (i.e. Stage 2 or at Stage 1 if study stops for futility), will have 
RTF reference ended with “[Population]_JAP”. For instance: 
• 
Table 
11_2_1_1 
(Demographics 
on 
ES, 
only 
Japanese 
subjects): 
T11_2_1_1_demo_ES_JAP.RTF 
• 
Table 
12_1_1_1 
(Duration 
of 
Exposure 
to 
Encorafenib 
on 
FAS): 
T12_1_1_1_enco_expos_FAS_JAP.RTF 
 
 
It should be mentioned in the Titles: 
• 
The analysis (IDSMC, Stage 1, Stage 2 or EOS),  
• 
When analyses are performed on the subgroup of Japanese subjects   
For instance, for the description of demographics characteristics performed on the FAS (Title in the 
TFL list is: “Demographics [FAS]”), Title should display: 
• IDSMC analysis: “Demographics [FAS, IDSMC x]” 
• Stage x analysis: “Demographics [FAS, Stage x]” 
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• EOS analysis: “Demographics [FAS, EOS]” 
• Stage x analysis on the subgroup of Japanese subjects: “Demographics – Japanese Subjects 
[FAS, Stage x]” 
 
 
 
 
 
 
 
 
 
 
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