Conditions: BRAF V600E Unresectable or Metastatic Melanoma BRAF V600E Metastatic NSCLC Melanoma
Keywords: NSCLC Melanoma BRAF V600E mutation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is a phase 1, multicenter, open-label, single-arm study to investigate the safety and tolerability of encorafenib 300 mg once daily (QD) monotherapy in adult Chinese participants with B-RAF Proto-oncogene, Serine/threonine Kinase V600E (BRAF V600E) mutant advanced solid tumors (unresectable metastatic melanoma or metastatic non-small cell lung cancer (NSCLC)), who are BRAF-inhibitor treatment-naïve and have failed the previous therapy(ies) in the metastatic setting or are not eligible to standard therapy. Participants will be eligible for the study based on identification of a BRAF V600E mutation in tumor tissue by a local National Medical Products Administration (NMPA) approved assay obtained prior to screening.

Detailed description:

Arms:
arm 1: Encorafenib hard capsule will be orally self-administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib will be administered once-daily (QD).

Interventions: intervention 1: Encorafenib
Intervention descriptions: intervention 1: oral capsule

Protocol document:
Prot_000.pdf: 
Document Type:  
Final Protocol 
Document Date:  
30 September 2021 
Study Title:  
Phase 1 Safety Study of Encorafenib in Chinese Patients With 
Advanced Metastatic BRAF V600E Mutant Solid Tumors 
Protocol Reference Number: W00090GE102 
NCT Number:  
NCT05003622 
 
 




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W00090GE102 
INVESTIGATOR SIGNATURE FORM 
Protocol Version 3.0 dated 30 September 2021. 
 
 
To conduct the study described in the protocol referenced above, in compliance with GCP, 
with applicable regulatory requirements and with the protocol agreed upon by the Sponsor 
and given approval / favorable opinion by the IRB/IEC. 
 
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 study-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 study. 
I have been informed that certain regulatory authorities require the sponsor to obtain and supply 
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. 
 
 
Investigator 
 
 
Date 
 
 


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Table of Contents 
 
Clinical Study Protocol ................................................................................................................. 1 
AGREEMENT PAGE ................................................................................................................... 2 
INVESTIGATOR SIGNATURE FORM .................................................................................... 3 
Table of Contents ........................................................................................................................... 4 
Tables .............................................................................................................................................. 9 
Figures ............................................................................................................................................ 9 
1. 
Protocol Summary ................................................................................................................ 10 
1.1. 
Synopsis ............................................................................................................................ 10 
1.2. 
Schedule of Activities ....................................................................................................... 13 
2. 
Introduction .......................................................................................................................... 17 
2.1. 
Background ...................................................................................................................... 17 
2.1.1. 
Disease Background ........................................................................................................ 17 
2.1.2. 
BRAF Mutations ............................................................................................................. 18 
2.1.3. 
Treatment Options for BRAF V600E Metastatic Melanoma and Non-small Cell Lung 
Cancer.............................................................................................................................. 18 
2.1.4. 
Encorafenib Therapy ....................................................................................................... 21 
2.2. 
Study Rationale ................................................................................................................ 23 
2.2.1. 
Rationale for Assessment of Encorafenib in the Study Population ................................ 23 
2.2.2. 
Rationale for Dose ........................................................................................................... 23 
2.3. 
Benefit/Risk Assessment .................................................................................................. 24 
2.3.1. 
Benefit Assessment ......................................................................................................... 24 
2.3.2. 
Risk Assessment .............................................................................................................. 25 
2.3.3. 
Overall Benefit/Risk Conclusion .................................................................................... 27 
3. 
Objectives and Endpoints .................................................................................................... 28 
4. 
Study Design ......................................................................................................................... 29 
4.1. 
Overall Design .................................................................................................................. 29 
4.1.1. 
Study Design Overview .................................................................................................. 29 
4.1.2. 
Study Procedures and Assessments................................................................................. 32 
4.2. 
Scientific Rationale for Study Design ............................................................................ 32 
4.3. 
Justification for Dose ....................................................................................................... 33 
4.4. 
End of Study Definition ................................................................................................... 33 


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5. 
Study Population .................................................................................................................. 34 
5.1. 
Inclusion Criteria ............................................................................................................. 34 
5.2. 
Exclusion Criteria ............................................................................................................ 35 
5.3. 
Lifestyle Considerations .................................................................................................. 38 
5.3.1. 
Contraception .................................................................................................................. 38 
5.3.2. 
Meals and Dietary Restrictions ....................................................................................... 39 
5.4. 
Screen Failures ................................................................................................................. 39 
6. 
Study Treatment ................................................................................................................... 40 
6.1. 
Study Treatment(s) Administered ................................................................................. 40 
6.2. 
Preparation/Handling/Storage/Accountability/Return/Destruction ........................... 42 
6.2.1. 
Accountability on Site and Return/Destruction .............................................................. 42 
6.2.2. 
Storage ............................................................................................................................. 42 
6.2.3. 
Expiry Date ..................................................................................................................... 43 
6.2.4. 
Return / destruction ......................................................................................................... 43 
6.2.5. 
Recall ............................................................................................................................... 43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ......................................... 44 
6.3.1. 
Blinding and Randomization ........................................................................................... 44 
6.3.2. 
Participant Numbering .................................................................................................... 44 
6.3.3. 
Allocation of Study Treatment and Dispensing .............................................................. 44 
6.4. 
Study Treatment Compliance ......................................................................................... 44 
6.5. 
Concomitant Medication and Therapeutic/Diagnostic Procedures ............................ 45 
6.5.1. 
Authorized Medications, Therapeutic and Diagnostic Procedures ................................. 46 
6.5.2. 
Prohibited Medications and Therapeutic/Diagnostic Procedures ................................... 47 
6.6. 
Dose Modification ............................................................................................................ 49 
6.6.1. 
Dose Interruptions ........................................................................................................... 50 
6.6.2. 
Dose Reductions .............................................................................................................. 50 
7. 
Discontinuation of Study Treatment and Participant Discontinuation/Withdrawal ..... 51 
7.1. 
Discontinuation of Study Treatment for Individual Participants ............................... 51 
7.1.1. 
Temporary Discontinuation and Rechallenge ................................................................. 51 
7.1.2. 
Permanent Study Treatment Discontinuation ................................................................. 51 
7.2. 
Participant Discontinuation/Withdrawal from the Study ........................................... 53 
7.3. 
Lost to Follow up ............................................................................................................. 54 


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8. 
Study Assessments and Procedures .................................................................................... 55 
8.1. 
Screening Assessments and Procedures ........................................................................ 55 
8.2. 
Efficacy Assessments ....................................................................................................... 56 
8.3. 
Safety Assessments .......................................................................................................... 57 
8.3.1. 
Adverse Events ................................................................................................................ 57 
8.3.2. 
Physical Examinations .................................................................................................... 57 
8.3.3. 
Dermatological Examination........................................................................................... 58 
8.3.4. 
Clinical Safety Laboratory Assessments ......................................................................... 58 
8.3.5. 
Pregnancy Testing ........................................................................................................... 60 
8.3.6. 
Vital Signs ....................................................................................................................... 60 
8.3.7. 
Electrocardiograms.......................................................................................................... 60 
8.3.8. 
Cardiac Function ............................................................................................................. 61 
8.3.9. 
Eastern Cooperative Oncology Group Performance Status ............................................ 61 
8.3.10. Other examinations/Chest, abdomen and pelvis CT scanner .......................................... 62 
8.4. 
Adverse Events and Serious Adverse Events ................................................................ 62 
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information ...................................................................................................................... 62 
8.4.2. 
Method of Detecting, Recording and Reporting Adverse Events and Serious Adverse 
Events .............................................................................................................................. 62 
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ............................................ 64 
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events .................................. 65 
8.4.5. 
Pregnancy ........................................................................................................................ 65 
8.4.6. 
Cardiovascular and Death Events ................................................................................... 67 
8.4.7. 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events .................................................................................. 67 
8.4.8. 
Adverse Events of Special Interest.................................................................................. 67 
8.5. 
Overdose ........................................................................................................................... 67 
8.6. 
Pharmacokinetics ............................................................................................................. 68 
8.6.1. 
Pharmacokinetic Samples ............................................................................................... 68 
8.6.2. 
Analytical Determination ................................................................................................ 69 
8.6.3. 
Pharmacokinetic Analysis ............................................................................................... 69 
8.7. 
Pharmacodynamics ......................................................................................................... 69 
8.8. 
Pharmacogenomics .......................................................................................................... 69 


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8.9. 
Other Exploratory Biomarker Assessment ................................................................... 69 
9. 
Statistical Considerations .................................................................................................... 70 
9.1. 
Statistical Hypotheses ...................................................................................................... 70 
9.2. 
Sample Size Determination ............................................................................................. 70 
9.3. 
Populations for Analyses ................................................................................................. 70 
9.4. 
Statistical Analyses .......................................................................................................... 71 
9.4.1. 
General Considerations ................................................................................................... 71 
9.4.2. 
Primary Endpoint ............................................................................................................ 71 
9.4.3. 
Secondary Endpoints ....................................................................................................... 72 
9.4.4. 
Other Analyse(s) ............................................................................................................. 73 
9.5. 
Compliance ....................................................................................................................... 74 
9.6. 
Interim/Initial Analyses .................................................................................................. 74 
9.7. 
Trial Steering Committee ............................................................................................... 74 
10. Supporting Documentation and Operational Considerations.......................................... 75 
10.1. Appendix 1: Regulatory, Ethical and Study Oversight Considerations ..................... 75 
10.1.1. Regulatory and Ethical Considerations ........................................................................... 75 
10.1.2. Early Study Termination ................................................................................................. 76 
10.1.3. Financial Disclosure ........................................................................................................ 76 
10.1.4. Informed Consent Process ............................................................................................... 77 
10.1.5. Data Protection ................................................................................................................ 78 
10.1.6. Communication with Sites .............................................................................................. 78 
10.1.7. Dissemination of Clinical Study Data ............................................................................. 78 
10.1.8. Data Quality Assurance ................................................................................................... 79 
10.1.9. Source Documents........................................................................................................... 84 
10.1.10. Study and Site Start and Closure ..................................................................................... 84 
10.1.11. Publication Policy ........................................................................................................... 85 
10.1.12. Insurance Policy .............................................................................................................. 85 
10.2. Appendix 2: Contraceptive Guidance ............................................................................ 87 
10.2.1. Definition of a Woman of Childbearing Potential and Fertile Men ................................ 87 
10.2.2. Contraceptive Guidance .................................................................................................. 88 
10.3. Appendix 3:  Non-exhaustive List of Concomitant Medications ................................. 89 
10.4. Appendix 4: Dose Modifications for Encorafenib-related Adverse Events ............... 96 


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10.5. Appendix 5: Snellen Equivalence (Visual Acuity Conversion Chart) ...................... 101 
10.6. Appendix 6: Study Treatment labelling ...................................................................... 102 
10.7. Appendix 7: Response Evaluation Criteria in Solid Tumors Version 1.1 ................ 103 
10.7.1. Methods of Measurement .............................................................................................. 103 
10.7.2. Measurability of Tumor at Baseline .............................................................................. 104 
10.7.3. Tumor Response Evaluation ......................................................................................... 105 
10.8. Appendix 8: Adverse Event Definitions ....................................................................... 112 
10.8.1. Definition of an Adverse Event ..................................................................................... 112 
10.8.2. Definition of a Serious Adverse Event .......................................................................... 113 
10.9. Appendix 9: Abbreviations ........................................................................................... 115 
10.10. Appendix 10: Protocol Amendment History ............................................................... 118 
10.11. Sponsor Personnel ......................................................................................................... 119 
 
 
 


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Tables 
 
Table 1: Schedule of Activities ..................................................................................................... 14 
Table 2: Important Risks of Encorafenib and the Respective Mitigation Strategy ....................... 25 
Table 3: Objectives and Endpoints in W00090GE102 ................................................................. 28 
Table 4: Criteria for Defining Dose Limiting Toxicities............................................................... 30 
Table 5: Detail of Study Treatment ............................................................................................... 40 
Table 6: The percentage of total red marrow present at different skeletal sites in a healthy adult49 
Table 7: Dose Reductions for Encorafenib ................................................................................... 50 
Table 8: Protocol-required Clinical Laboratory Safety Assessments............................................ 59 
Table 9: Eastern Cooperative Oncology Group Performance Status Scale .................................. 61 
Table 10: Process for Recording, Evaluating and Assessing Adverse Events and Serious Adverse 
Events ......................................................................................................................... 63 
Table 11: List of Cytochrome P450 Substrates to be used with Caution (CYP2C8, CYP2C9, 
CYP2C19 and CYP3A) .............................................................................................. 89 
Table 12: List of Cytochrome P450 substrates to be used with Caution (CYP2B6) .................... 90 
Table 13: List of Inhibitors of Uridine Diphosphate-glucuronosyl Transferase 1A1 to be used with 
Caution ....................................................................................................................... 90 
Table 14: Moderate Cytochrome P450 3A4 inhibitors to be Administered with Caution when 
co-administered with Encorafenib .............................................................................. 90 
Table 15: Breast Cancer Resistance Protein and P-glycoprotein inhibitors/inducers to be used with 
caution ........................................................................................................................ 91 
Table 16: Substrates of Breast Cancer Resistance Protein, Organic Anionic Transporters, Organic 
Anion Transporting Polypeptides, Organic Cationic Transporters and P-glycoprotein, to 
be administered with caution ...................................................................................... 91 
Table 17: List of Potential QT Prolonging Drugs ......................................................................... 92 
Table 18: Strong Cytochrome P450 3A4 Inhibitors and Strong/moderate Cytochrome P450 Inducers 
to be Prohibited when Co-administered with Encorafenib ......................................... 95 
Table 19: Recommended Dose Modifications for Encorafenib-related Adverse Events .............. 96 
Table 20: Timepoint Response: Participants with Target (± Non-target) Disease ...................... 110 
 
Figures 
 
Figure 1: Schema of 3+3 Design ................................................................................................... 29 
 
 


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1. Protocol Summary 
1.1. Synopsis 
Protocol Title:  
Multicenter, open-label, phase 1 study investigating the safety and tolerability of 
encorafenib monotherapy in BRAF V600E-mutated Chinese patients with advanced 
metastatic solid tumors (OCEAN I study) 
Short Title: 
Phase 1 safety study of encorafenib in Chinese patients with advanced metastatic 
BRAF V600E mutant solid tumors 
Rationale: 
 
B-RAF proto-oncogene, serine/threonine kinase (BRAF) mutations, which lead to 
constitutive activation of BRAF kinase and sustained rat sarcoma viral oncogene 
homologue 
(RAS)/proto-oncogene 
serine/threonine-protein 
kinase
(RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related 
kinase (ERK) pathway signaling resulting in increased cell proliferation and survival 
occur in approximately 25% of melanomas and 0.5 to 2.8% of non-small cell lung cancer 
(NSCLC)s in China. These data also showed that the V600E mutation was the most 
frequent BRAF mutation in both melanoma and NSCLC (89% and 32 to 86%, 
respectively). 
In real-world setting and clinical studies, melanoma and NSCLC patients with a B-RAF 
proto-oncogene, serine/threonine kinase V600E (BRAF V600E) mutation have 
unfavorable clinical outcome when treated with chemotherapy and immunotherapy 
compared to non-BRAF V600E and/or BRAF wild-type patients. Poor clinical outcome 
with chemotherapy has also been reported in Chinese populations. 
Encorafenib inhibits BRAF kinase, thereby inhibiting B-RAF proto-oncogene, 
serine/threonine kinase V600 (BRAF V600) positive cell growth. Encorafenib is 
registered in combination with the MEK inhibitor binimetinib in several jurisdictions 
for the treatment of patients with unresectable or metastatic melanoma with a 
BRAF V600E or BRAF V600K mutation, based on results from the phase 3 
COLUMBUS study [Dummer 2018a, Dummer 2018b]. It could therefore be anticipated 
that the efficacy of encorafenib in combination with binimetinib in other BRAF V600 
driven cancer types such as BRAF V600E mutant NSCLC may be similar than that 
observed with the combination of dabrafenib and trametinib. 
Tumor regression has been shown with encorafenib and binimetinib monotherapy in a 
BRAF-mutant human NSCLC xenograft model, and enhanced tumor regression was 
observed with the combination of encorafenib plus binimetinib. In a human xenograft 
melanoma mice model, encorafenib plus binimetinib combination treatment has delayed 
the emergence of resistance due to RAS/RAF/MEK/ERK pathway reactivation.  
The safety and tolerability of encorafenib as single agent or in combination with 
binimetinib is well-established in studies outside China. The overall safety profile of 
encorafenib is consistent with the respective mechanism of action and the known profile 






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1.2. Schedule of Activities  
The schedule of activities for all participants is shown in Table 1.  
 
in <33% of participants) and evaluation of the overall toxicity profile (based on deaths, 
treatment emergent SAEs, treatment emergent adverse events (TEAEs) leading to 
discontinuation and to dose interruption/reduction).  
The TSC will make a recommendation if the dose of encorafenib 300 mg QD is not 
deemed tolerable. 








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2. Introduction 
Encorafenib (Braftovi®; also known as PF-07263896, W0090, LGX818 or ONO-7702) is currently 
being developed in combination with binimetinib (Mektovi®), for the treatment of adult patients 
with metastatic melanoma and metastatic non-small cell lung cancer (NSCLC), who are B-RAF 
proto-oncogene, serine/threonine kinase (BRAF)- and mitogen-activated protein kinase 
(MEK)-inhibitor treatment-naïve and are either previously untreated or treated with one line of prior 
therapy in the metastatic setting. 
2.1. Background 
2.1.1. Disease Background 
 Melanoma 
Melanoma is a cancer that arises from melanocytes, the cells that produce the pigment melanin; 
however, in rare instances, it can originate in the eye or other non-skin organs. There is a clear 
association between ultraviolet light exposure and melanoma. Melanoma occurs predominantly in 
adults, and more than 50% of the cases arise in apparently normal areas of the skin. Despite being 
a rare form of skin cancer, melanoma accounts for nearly 75% of skin cancer deaths. 
About 80% of melanomas are detected in a localized stage and can be treated with surgical 
resection. When detected early, the 5-year survival rate of melanoma is above 90%; however, when 
melanoma is diagnosed after distant metastasis, the prognosis is, by contrast, very poor. The 5-year 
survival rate decreases to 15% with a median survival between 8 and 9 months [Jemal 2011]. 
Advanced melanoma is one of the most aggressive human malignancies.  
Both incidence of melanoma and mortality rate are rapidly increasing throughout the world, 
constituting a significant and growing health burden [Ferlay 2010]. The worldwide incidence of 
new cases of melanoma was 287,723 (1.6% of all new cancer cases) and number of deaths 60,712 
(0.6% of all cancers) in 2018. In China, there were 7,379 newly diagnosed cases accounting for 
0.17% of new cancer cases and 3,766 (0.13%) deaths [Bray 2018, Globocan 2018]. 
 Non-small Cell Lung Cancer 
Lung cancer is the most frequently diagnosed cancers and is also the leading cause of cancer-related 
death worldwide. It accounts for more than 2.1 million newly diagnosed cancer cases (11.6% of the 
total diagnosed cancer cases) and 1.76 million cancer-related deaths (18.4% of the total) worldwide 
every year [Bray 2018, Globocan 2018]. Lung cancer is a heterogenous disease clinically, 
biologically, histologically and molecularly. Non-small cell lung cancer, the predominant 


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histological subtype of lung cancer, accounts for approximately 85% of all cases, of which lung 
adenocarcinoma and lung squamous cell carcinoma are the most common subtypes [Herbst 2018]. 
Lung cancer accounts for approximately 18% of total diagnosed cancer in China. It is also the 
leading cause of cancer death in both males (26.4%) and females (20.3%) [Bray 2018, 
Globocan 2018]. It was estimated that there would be 774,323 new cases of lung cancer (~37% of 
global total) and 690,567 lung cancer deaths (~39% of global total) in 2018 [Feng 2019]. It is also 
estimated that mortality from lung cancer may increase by approximately 40% between 2015 and 
2030 [Cao and Chen 2019].  
Although the incidence of lung cancer (~35/100,000) is similar between China and the United States 
(US), the mortality rate of lung cancer in China (130.1/100,000) is 1.4 times greater than that in the 
US (91.0/100,000). This finding might be attributable to the lower early cancer detection rate and 
sub-standard treatment strategies provided by different regions in China [Feng 2019].  
The overall 5-year survival rate for advanced disease treated with chemotherapy remains poor, <2% 
[Cetin 2011]. In China, the age-standardized 5-year relative survival in men was 16.8% (62.5% 
worse than in thyroid cancer which has the highest survival rate) and 25.1% in women between 
2012 and 2015 [Cao and Chen 2019, Zeng 2018]. 
Non-small cell lung cancer, approximately 86% of total, is also the most predominant histological 
subtype of lung cancer with adenocarcinoma and squamous cell carcinoma as the most common 
subtypes [Gou 2014]. 
2.1.2. BRAF Mutations 
BRAF mutations, which lead to constitutive activation of BRAF kinase and sustained rat sarcoma 
viral 
oncogene 
homologue 
(RAS)/proto-oncogene 
serine/threonine-protein 
kinase 
(RAF)/MEK/extracellular signal-related kinase (ERK) pathway signaling resulting in increased cell 
proliferation and survival [Corcoran 2012] occur in approximately 25% of melanomas [Si 2012] 
and 0.5 to 2.8% of NSCLCs [Li 2014, Ding 2017, Lin 2019] in China. These data also showed that 
the V600E mutation was the most frequent BRAF mutation in both melanoma and NSCLC (89% 
and 32 to 86%, respectively). 
2.1.3. Treatment Options for BRAF V600E Metastatic Melanoma and 
Non-small Cell Lung Cancer  
In real-world setting and clinical studies, although some reports have correlated BRAF mutation in 
NSCLC with a poor outcome and reduced efficacy of platinum doublets [Barlesi 2016, 
Cardarella 2013, Marchetti 2011], the prognosis implication of B-RAF proto-oncogene, 
serine/threonine kinase V600E (BRAF V600E) mutation in NSCLC remains unclear. In a recent 
French matched study, BRAF mutation in exon 15 was not found to be a prognostic factor for 
progression-free survival (PFS) and overall survival (OS) in either first or second line 


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[Couraud 2019]. When treated with immunotherapy, NSCLC patients with a BRAF V600E 
mutation have unfavourable clinical outcome as compared to BRAF wild-type patients 
[Dudnik 2018, Mazieres, 2018, Rihawi, 2019, Tan 2019]. Poor clinical outcome with standard 
chemotherapy for NSCLC has also been reported in Chinese BRAF V600 NSCLC population 
[Ding 2017, Li 2015]. The heterogeneity of the disease, the rarity of the mutation, small patient 
numbers, and limited number of studies contribute to this lack of understanding [Baik 2017].  
In Chinese NSCLC population, retrospective studies have shown a trend in a shorter progression-
free survival (PFS) to first-line chemotherapy in patients with BRAF V600E mutant tumors 
compared to patients with non-BRAF V600E mutations (5.2 versus 6.4 months; hazard ratio [HR]: 
0.74 (0.29-1.94) p=0.561), an overall response rate (ORR) of 28.6% and disease control rate of 
78.6% was also observed in the BRAF mutant patients [Ding 2017]. In another retrospective study 
of lung adenocarcinoma patients [Li 2015], a trend in shorter median overall survival (OS) was also 
observed in BRAF V600E mutant patients (24.0 months; 95% confidence interval (CI): 20.6-27.5) 
compared to non-BRAF V600E patients (28.0 months; 95% CI: 22.7-33.3).  
Traditional options, such as chemotherapy, also lack substantial efficacy in melanoma. A novel 
immunotherapy, ipilimumab (Yervoy®, Bristol-Myers Squibb), an antibody against the cytotoxic 
T-lymphocyte antigen (anti-CTLA-4) was approved in the US in 2011, although melanoma that had 
spread to distant sites remained rarely curable.  
The discovery of the genetic underpinnings of melanoma and NSCLC and their characterization 
has uncovered potential targets for therapy, including BRAF mutations. BRAF inhibitors as 
monotherapy has demonstrated an acceptable safety profile along with a clinical activity in different 
indications.  
The BRAF inhibitor vemurafenib (Zelboraf®, Roche), has been approved in the US and Europe as 
a monotherapy for the treatment of adult patients with BRAF V600 unresectable or metastatic 
melanoma and is under investigation for treatment of NSCLC. In a phase 1 study with vemurafenib 
in 46 Chinese BRAF V600 mutant metastatic melanoma patients, the confirmed overall response 
rate (cORR) was 52.2% (95% CI: 37.0-67.1) with a median PFS of 8.3 months (95% CI: 5.7-10.9) 
and a median OS of 13.5 months (95% CI: 12.2-not estimable). The most common adverse events 
were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin 
level increase, melanocytic nevus and alopecia [Si, 2018]. Two patients (4%) had serious adverse 
events (SAEs): Grade 3 chest discomfort and Grade 3 uveitis, both were considered related to 
vemurafenib. The efficacy of vemurafenib in this Chinese phase 1 study was similar to that observed 
in the pivotal non-Chinese study [Chapman 2011, Chapman 2017] and has been approved for the 
treatment of patients with BRAF V600E mutant melanoma in China [Chinese guidelines for 
diagnosis and treatment of melanoma 2018]. 
Dabrafenib (Tafinlar®, Novartis) was approved for patients with BRAF V600E mutant advanced 
melanoma in the US in May 2013; it was further approved for use in Europe in August 2013. In a 
phase 2 study with dabrafenib in BRAF V600E mutant metastatic NSCLC, the cORR was 33% 
(95% CI: 23-45) with a median PFS of 5.5 months (95% CI: 3.4-7.3) and a median OS of 12.7 


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months (95% CI: 7.3-16.9). The most common adverse events were pyrexia, hyperkeratosis, 
asthenia, decreased appetite, cough, fatigue, skin papilloma, alopecia, dry skin, rash, vomiting and 
palmar-plantar erythrodysesthesia (PPE) syndrome1 [Planchard 2016a]. Similar efficacy results 
were observed with vemurafenib in BRAF V600 mutant NSCLC [Subbiah 2019] and in the 
retrospective European EURAF cohort [Gautschi, 2015]. 
Although studies have shown that BRAF-targeted therapy is effective in BRAF V600E mutant 
melanoma, data also indicate that the duration of response is often short lived, with resistance 
developing quickly, within approximately 6 months [Chapman 2011, Flaherty 2010, 
Flaherty 2012, Sosman 2012]. Re-activation RAS/RAF/MEK/ERK signaling occurs in the 
majority of cases of acquired resistance to BRAF inhibitors. In an attempt to delay resistance to 
BRAF inhibition, led to the development of combination treatments, including with MEK1/2-
inhibitors. 
Preclinical data has demonstrated the enhanced activity in combining BRAF and MEK inhibition 
in B-RAF proto-oncogene, serine/threonine kinase V600 (BRAF V600) driven tumors 
[Flaherty 2012, Joshi 2015, Stuart 2012]. This combination has been established as the standard 
of care in BRAF V600 mutant melanoma [Ascierto 2016, Dummer 2018a, Dummer 2018b, 
Long 2014, Robert 2016] and, has also been clinically validated in BRAF V600E mutant NSCLC 
[Planchard 2016b, Planchard 2017a, Planchard 2017b]. The combination of dabrafenib and the 
MEK inhihitor trametinib (Mekinist®, Novartis) was approved in the US in January 2014 for B-RAF 
proto-oncogene, serine/threonine kinase V600E/K (BRAF V600E/K) mutant metastatic melanoma 
and as an adjuvant treatment for BRAFV600E mutant Stage III melanoma after surgical resection in 
May 2018, based on the results of the COMBI-AD phase 3 study [Long 2017], making it the first 
oral regimen that prevents cancer relapse for node positive, BRAF mutant melanoma. The 
combination of dabrafenib with trametinib for BRAF V600 mutant advanced or metastatic NSCLC 
was approved in Europe in April 2017.  
To date, no targeted therapy for the treatment of BRAF V600E mutant NSCLC has been approved 
in China and vemurafenib is the only molecular-targeted drug approved for the treatment of patients 
with BRAF V600E mutant melanoma. Chemotherapy and immunotherapy remain standard therapy, 
i.e. same as that for NSCLC or melanoma without oncogenic driver mutations  depending on the 
accessibility and affordability of these drugs.  
As the BRAF V600E mutation implication in NSCLC and melanoma prognosis remains unclear 
with some data reporting unfavorable clinical outcome with chemotherapy and immunotherapy in 
Chinese BRAF V600 mutant melanoma and NSCLC population, there is an urgent medical need to 
provide effective and tolerable targeted therapy for these patients in China. 
                                                 
1 Also known as hand-foot skin reaction (HFSR) 


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2.1.4. Encorafenib Therapy 
Encorafenib is a potent and highly selective adenosine triphosphate (ATP)-competitive small 
molecule 
inhibitor 
of 
BRAF V600 
mutant 
kinase. 
Encorafenib 
suppresses 
the 
RAS/RAF/MEK/ERK pathway in tumor cell expressing BRAF V600 mutation.  
In a first-in-human phase 1 dose escalation and dose expansion study (CLGX818X2101), 
54 participants with locally advanced or metastatic BRAF V600 mutant melanoma initially received 
doses of encorafenib from 50 to 700 mg once daily (QD) or 75 to 150 mg twice daily. Dose limiting 
toxicities (DLTs) were reported in seven participants across the dose groups and were hand-foot 
skin reaction (HFSR), foot pain, fatigue, insomnia/asthenia, diarrhea/rash, facial paresis/confusion, 
and pain/neuralgia. All DLTs were reversible. The most common adverse events suspected to be 
related to encorafenib were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), 
pain in extremity, arthralgia, and fatigue. On the basis of the Bayesian model, the maximum 
tolerated dose (MTD) of encorafenib monotherapy was declared as 450 mg QD [Dummer 2013]. 
A further 33 participants were treated in the dose expansion phase; nine (33.3%) participants with 
melanoma and three (17.6%) participants with mCRC experienced at least one DLT during the first 
participants with melanoma 
treated at the MTD in the dose expansion phase were myalgia (33.3%), arthralgia (26.7%), fatigue 
(20.0%), asthenia (13.3%), and VIIth nerve paralysis and insomnia (6.7% each). Seven of the nine 
participants with a DLT required a dose reduction to 300 mg QD. Based on the early occurrence of 
these toxicities leading to dose reduction, the 300 mg QD dose was declared the recommended 
phase 2 dose (RP2D) for encorafenib monotherapy. The ORR for BRAF inhibitor-naïve and BRAF 
inhibitor-pretreated participants was 60.0% and 10.3% in the dose escalation phase and 60.0% and 
22.2% in the dose expansion phase. Progression-free survival and OS were assessed for participants 
in the dose expansion phase only. Median PFS was 12.4 months (95% CI: 7.4 not reached) and 
1.9 months (95% CI: 0.9 3.7) for BRAF inhibitor-naïve patients and BRAF inhibitor-pretreated 
participants. Median OS was not reached for BRAF inhibitor-naïve patients and was 9.7 months 
(95% CI: 3.68 10.84) for BRAF inhibitor-pretreated participants [Delord 2017]. 
In a large randomized phase 3 study in participants with advanced BRAFV600E/K mutant 
melanoma (CMEK162B2301, the COLUMBUS study) comparing encorafenib 300 mg QD with 
vemurafenib 960 mg twice daily, the PFS of 9.6 months (95% CI: 7.4-14.8) in the encorafenib group 
was longer than in vemurafenib group (7.3 months, 95% CI: 5.6-7.69). Encorafenib monotherapy 
provided a significant risk reduction to death (HR 0.76, 95% CI: 0.58-0.98, p=0.0033) and to 
progression (HR 0.68, 95% CI: 0.52-0.88, p=0.0038) compared to vemurafenib. The cORR was 
52% in the encorafenib group and 41% in the vemurafenib group [Dummer 2018b]. The efficacy 
results of vemurafenib in this study were consistent on all endpoints compared to the results in other 
pivotal studies of BRAF V600 mutant melanoma where vemurafenib was used as a control 
[Ascierto 2016, Larkin 2014, Robert 2015].  
The safety profile of encorafenib 300 mg QD monotherapy seen in the COLUMBUS study was 
comparable to those observed in the phase 1 dose escalation and dose expansion study 


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(CLGX818X2101) with the most common adverse events being alopecia (56%), PPE syndrome2 
(52%), arthralgia (44%), hyperkeratosis (39%), nausea (38%) and dry skin (30%) [Delord 2017, 
Dummer 2018b]. The safety and tolerability profile of encorafenib monotherapy was different to 
vemurafenib. Diarrhea, pyrexia and photosensitivity reaction were less frequently reported with 
encorafenib than with vemurafenib, and alopecia and PPE syndrome were more frequently reported 
the two treatment groups). 
These adverse events were generally low grade [Dummer 2018a, Dummer 2018b].  
The differentiated efficacy and safety profile of encorafenib is attributable to its unique 
pharmacological properties, i.e. its substantially longer dissociation half--life (T1/2diss) - more than 
30 hours as compared with 0.5 hour reported for vemurafenib [Koelblinger 2018, Stuart 2012]. 
The long T1/2diss translates into prolonged target suppression leading to an increased efficacy (on-
target effect) while reducing toxicity (off-target effect) as compared with other established BRAF 
inhibitors, such as cutaneous adverse reactions.  
The co-administration of encorafenib with the MEK1/2 inhibitor binimetinib has demonstrated 
additive or synergistic anti-proliferative activity in BRAF V600E mutant cell lines (including 
melanoma, colorectal, pancreatic and lung-derived). This additive or synergistic anti-tumor activity 
(growth inhibition and induction of tumor regression) was also demonstrated in BRAF V600E 
mutant human melanoma and NSCLC xenograft studies in mice (internal data). The results 
confirmed that encorafenib and binimetinib combination prevented the emergence of resistant 
melanoma tumors over the 4-month treatment duration of the study, resulting in enhanced antitumor 
activity and survival.  
To date, the antitumor effects of encorafenib monotherapy and the combination of encorafenib and 
binimetinib have been and is currently being clinically investigated in the following cancer types 
with BRAF V600 mutations: 
 
Advanced unresectable and metastatic BRAF V600E/K mutant melanoma (Study 
CMEK162B2301, COLUMBUS): encorafenib monotherapy, encorafenib plus binimetinib 
combination. 
 
Metastatic colorectal cancer with BRAF V600E mutation (Study ARRAY-818-301, 
BEACON): encorafenib plus cetuximab (doublet) and encorafenib plus cetuximab in 
combination with binimetinib (triplet) [Kopetz 2019]. 
 
Metastatic non-small cell lung cancer (NSCLC) with BRAFV600E mutation (Study ARRAY-
818-202, PHAROS):   encorafenib given in combination with binimetinib. 
Limited clinical data of encorafenib monotherapy or in combination with binimetinib is available 
specifically in Chinese BRAF V600E patients. Ethnic sensitivity analyses performed to date have 
shown showed no significant effect of ethnicity or race on the pharmacokinetics (PK) of encorafenib 
or binimetinib, administered as monotherapy or in combination. The evaluation on the impact of 
                                                 
2 Also known as hand-foot skin reaction (HFSR) 
 


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ethnicity on safety and efficacy did not show meaningful clinical difference between Asian and 
non-Asian. However, no definitive conclusions could be made due to the limited number of Asian 
participants treated.  
The purpose of this study is therefore to provide additional clinical safety and tolerability data with 
encorafenib 300 mg QD monotherapy in Chinese patients with BRAF V600E mutant melanoma or 
NSCLC to support further clinical development in combination with binimetinib. 
2.2. Study Rationale 
2.2.1. Rationale for Assessment of Encorafenib in the Study Population 
Tumor regression has been shown with encorafenib and binimetinib monotherapy in a 
BRAF-mutant human NSCLC xenograft model, and enhanced tumor regression was observed with 
encorafenib plus binimetinib combination. In human xenograft melanoma mice model, encorafenib 
plus binimetinib combination treatment has delayed the emergence of resistance due to 
RAS/RAF/MEK/ERK pathway reactivation.  
The safety and tolerability of encorafenib as single agent or in combination with binimetinib is 
well-established in studies outside China. The overall safety profile of encorafenib is consistent 
with the respective mechanism of action and the known profile of BRAF inhibitors. The 
differentiated efficacy and safety profile of encorafenib is attributable to its substantially longer 
T1/2diss (see Section 2.1.4).  
No targeted therapy for the treatment of BRAF V600E mutant NSCLC has been approved in China 
and vemurafenib is the only molecular-targeted drug approved for the treatment of patients with 
BRAF V600E mutant melanoma. Chemotherapy and immunotherapy (same as that for melanoma 
and NSCLC without oncogenic driver mutations) remain the standard treatment in China, 
depending on the accessibility and affordability of these drugs. There is therefore an urgent medical 
need for targeted therapy for Chinese melanoma and NSCLC patients with BRAF V600E mutation 
in the era of personalized healthcare. 
Limited clinical data of encorafenib monotherapy (or in combination with binimetinib) is available 
specifically in Chinese BRAF V600E mutant patients. This study therefore aims to provide 
additional clinical safety and tolerability data with encorafenib 300 mg QD monotherapy in Chinese 
patients with BRAF V600E mutant melanoma or NSCLC to support further clinical development in 
combination with binimetinib. 
2.2.2. Rationale for Dose  
The QD dosing regimen of encorafenib is based on the available PK data and its T1/2diss. Encorafenib 
300 mg QD has been determined to be the single agent RP2D in the clinical program.  


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In population PK analysis, ethnicity and/or race did not appear to have any major impact on the PK 
of encorafenib in Asian patients compared to non-Asian patients, with no resulting major 
differences in the safety and efficacy profiles between the two populations. Due to the limited 
number of patients, these findings should be interpreted with caution.  
2.3. Benefit/Risk Assessment 
The observed toxicities of encorafenib are generally of low grade, monitorable and manageable by 
treatment modification, interruption and discontinuation in conjunction with appropriate medical 
management. Detailed information regarding clinical safety and the known and expected benefits 
and risks, including reasonably expected adverse events, is provided in 
for encorafenib. Guidance on monitoring and dose modifications is provided in Section 6.6. 
2.3.1. Benefit Assessment 
In real-world setting and clinical studies, the implication of BRAF V600E mutation remains unclear, 
with some data reporting unfavorable clinical outcome with chemotherapy and immunotherapy in 
Chinese BRAF V600 mutant melanoma and NSCLC population compared to BRAF wild-type 
patients (see Section 2.1.3). 
Targeted therapy has not been approved for the treatment of BRAF V600E mutant NSCLC patients 
in China and vemurafenib is the only molecular-targeted drug approved for the treatment of 
BRAF V600E mutant melanoma. Given the implication of BRAF V600E mutation in melanoma and 
NSCLC, the prognosis remains unclear with some data reporting unfavorable clinical outcome with 
chemotherapy and immunotherapy; there is therefore an urgent medical need for efficacious and 
well-tolerated targeted therapies for BRAF V600 mutant melanoma and NSCLC patients in the era 
of personalized healthcare. 
BRAF inhibitor monotherapy has demonstrated an acceptable safety profile along with a clinical 
activity in different indications. The differentiated efficacy and safety profile of encorafenib 
compared to other BRAF inhibitors (see Section 2.1.4) is due to the longer T1/2-diss. The observed 
toxicities are generally of low grade, monitorable and manageable through appropriate medical 
intervention. 
Ethnic sensitivity analyses have shown that there are no significant effect of ethnicity or race on the 
PK of encorafenib administered as single agent or in combination with binimetinib.  
Outcomes from Study CMEK162B2301, COLUMBUS, demonstrated an overall survival benefit 
with both the combination therapy of encorafenib and binimetinib as well as with encorafenib 
monotherapy alone. However, it should be noted that in this study, while this was not the primary 
endpoint, the benefit was numerically (but not statistically) superior with the combination therapy 
compared to encorafenib monotherapy, suggesting that encorafenib is contributing significantly to 
the overall efficacy of the combination therapy of encorafenib and binimetinib [Dummer 2018b]. 






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Due to the substantially longer T1/2diss of encorafenib and consequently attenuated off-target effects, 
encorafenib has the potential to decrease BRAF inhibitor-related toxicities. Encorafenib has a 
differentiated safety profile compared to other BRAF inhibitors, which is mainly reflected in the 
lower incidence of pyrexia (dabrafenib-associated toxicity) and phototoxicity (vemurafenib-related 
toxicity). The majority of the observed toxicities with encorafenib are generally reversible and 
manageable by appropriate supportive medical care and/or dose modifications or discontinuation, 
and the risks will be mitigated through the implementation of the measures in Table 2 for clinical 
monitoring of participants during treatment. 
Ethnic factors do not appear to influence the safety profile of encorafenib. These findings will be 
confirmed in Chinese melanoma and NSCLC participants with a BRAF V600E mutation in this 
study prior to conducting further, larger studies of encorafenib in combination with binimetinib in 
the Chinese population.  
Review of the available safety data from post-marketing experience and clinical studies have not 
changed the benefit-risk profile of encorafenib which remains favorable when used in its approved 
indications and in accordance with the prescribing information. A review of individual case safety 
reports originating from Asian participants has shown that the pattern of adverse events related to 
study intervention grouped by Medical Dictionary for Regulatory Activities (MedDRA) is generally 
consistent with the global population. 
2.3.3. Overall Benefit/Risk Conclusion 
Taking into account the anticipated benefit and mitigating measures for the risks associated with 
encorafenib, the benefit of encorafenib treatment outweighs the potential risks for participants with 
BRAF V600E mutant melanoma and NSCLC in this study. The overall benefit/risk ratio is therefore 
deemed favorable. 
 
 




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4. Study Design 
4.1. Overall Design 
4.1.1. Study Design Overview 
This is a phase 1, multicenter, open-label, single-arm study to investigate the safety and tolerability 
of encorafenib monotherapy in adult Chinese participants with BRAF V600E mutant advanced solid 
tumors (unresectable metastatic melanoma or metastatic NSCLC) who are BRAF- and MEK-
inhibitor treatment-naïve and have failed the previous therapy(ies) for advanced metastatic disease 
or are not eligible to standard therapy. Participants will be eligible for the study based on 
identification of a BRAF V600E mutation in tumor tissue by a local National Medical Products 
Administration (NMPA) approved assay obtained prior to screening.  
All participants will receive a fixed flat oral dose of 300 mg encorafenib QD.  
It is planned to enrol up to six evaluable participants using a 3+3 design, shown in Figure 1. 
Figure 1: Schema of 3+3 Design 
 
Abbreviations: DLT = dose limiting toxicity; TSC = Trial Steering Committee 
 
Three participants will initially be enrolled and will be evaluated for DLTs during the first 
cycle of treatment (28 days) [the DLT evaluation period]: 






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4.1.2. Study Procedures and Assessments 
For each participant, the study will include: 
 
Screening: Participants with a locally determined BRAF V600E mutation will provide 
informed consent for screening and study procedures and assessments and will be screened 
for eligibility in the 28 days before the first dose of encorafenib. 
 
Treatment Period: Participants fulfilling all the eligibility criteria (see Section 5) will 
receive encorafenib 300 mg QD in 28 day (  7 days) cycles until death, disease progression4 
or one of the other predefined criteria for study treatment discontinuation is met (see 
Section 7.1). An end of treatment visit will be completed at the time of study treatment 
treatment).  
 
A 30-day Safety Follow-up: A safety follow-up visit will be performed approximately 
30 days after the last dose of study treatment or before the initiation of subsequent anticancer 
therapy, whichever occurs first. 
The schedule of activities for each participant is shown in Table 1.  
Tumor assessments will be performed by radiological imaging (including computed tomography 
[CT], magnetic resonance imaging [MRI], X-ray, different methods of whole-body bone scans). 
Tumor overall assessment (response, stable disease, progressive disease) will be determined locally 
by the investigator according to RECIST Version 1.1 (see Appendix 10.7). Tumor assessments will 
be performed at screening/baseline (within 28 days prior to the first dose of study treatment), then 
at least every 8 weeks (± 7 days) for the first 12 months, then at least every 12 weeks (± 7 days) 
until disease progression, withdrawal of consent for treatment, initiation of subsequent anticancer 
therapy, participant is lost to follow-up, or death (whichever occurs first). More frequently tumor 
assessments may be performed if needed. 
Safety assessments include monitoring of adverse events, DLTs, physical examinations, 
dermatological examinations, clinical laboratory safety tests (hematology, clinical chemistry, 
coagulation, urinalysis), vital signs, electrocardiograms (ECGs), and Eastern Co-operative 
Oncology Group (ECOG) performance status. 
Serial blood samples to characterize the PK profile of encorafenib and its metabolites (LHY746) 
will be collected from participants on the first day of treatment (Cycle 1 Day 1) and at steady state 
after 1 month treatment (Cycle 2 Day 1).  
4.2. Scientific Rationale for Study Design 
The study design involves a 3+3 approach (commonly used in conducting phase 1 oncology studies) 
that allows the assessment of DLTs but does not include a dose escalation or de-escalation 
                                                 
4 In special circumstances, continuation of treatment beyond disease progression may be allowed (see Section 6.1). 


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component. It is a well-established design for selecting a dose suitable for further investigation 
whilst minimising unnecessary exposure. In this study the design is employed to confirm the safety 
and tolerability of encorafenib 300 mg QD monotherapy in Chinese participants with BRAF V600E 
mutant melanoma or NSCLC to support further clinical development in combination with 
binimetinib. 
4.3. Justification for Dose 
The dose of encorafenib is 300 mg per oral (PO) QD, corresponding to its single agent RP2D. This 
dose has also been shown in clinical studies to result in tumor regression and clinical responses as 
a single agent [Dummer 2013, Gomez-Roca 2014] (see Section 2.1.4).  
Permitted dose modifications are detailed in Section 6.6. 
4.4. End of Study Definition 
The end of study is defined as the timepoint when the last participant enrolled has discontinued 
study treatment and completed the 30-day safety follow-up.  
 
 


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5. Study Population 
It is planned to treat up to six participants with metastatic BRAF V600E mutant melanoma or 
NSCLC who are BRAF inhibitor treatment-naïve and have failed the previous therapy(ies) for 
metastatic disease or are not eligible to standard therapy. The sample size rationale is provided in 
Section 9.2. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Each participant fulfilling all inclusion criteria and none of the exclusion criteria will be eligible.  
5.1. Inclusion Criteria 
All the following inclusion criteria must be met for a participant to be eligible for this study:  
 
Provide a signed and dated informed consent form (ICF). 
 
Chinese m
 
 
Documented histology- and/or cytology-confirmed metastatic melanoma or NSCLC 
(i.e. adenocarcinoma, large cell carcinoma, squamous cell carcinoma). 
 
Presence of BRAF V600E mutation as determined by a local laboratory with a NMPA 
approved BRAF test. 
 
BRAF inhibitor treatment-naïve participants and having failed the previous therapy(ies) for 
metastatic disease or are not eligible to standard therapy. 
Note:  
Alternative chemotherapy regimen is permitted if participants were platinum intolerant or 
ineligible. 
 
At least one tumor lesion as per investigator assessment according to RECIST Version 1.1, 
which has neither been irradiated nor biopsied during the screening period. The irradiated 
lesion is acceptable only if it is proven as disease progression deemed measurable prior to 
study. 
 
 
 
ECOG performance status of 0 or 1. 
 
Adequate hematologic function at screening and baseline characterized by the following: 
a. 
× 109/L. 
b. 
. 
c. 
× 109/L. 








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Known history of a positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). Testing for HIV must be performed at sites where 
mandated locally. 
 
Participants who have had major surgery (e.g. inpatient procedure with regional or general 
anesthesia) within 6 weeks prior to start of study treatment. 
 
Previous or concurrent malignancy within 2 years of study entry. 
Except: 
a. 
. 
b. 
Cured basal cell or squamous cell skin cancer. 
c. 
Gleason 6 prostate cancer. 
d. 
Treated in-situ carcinoma of cervix. 
 
that contraindicates the use of study treatment and may affect 
interpretation of results or that may render the participant at high risk from treatment 
complications. 
Note: 
Conditions are, in the opinion of the investigator, any medical or psychiatric conditions, 
metabolic dysfunction, physical examination finding or clinical laboratory finding suggesting 
disease/condition. 
 
Pregnant (confirmed by positive serum ß-HCG test), lactating or breast-feeding women. 
 
Is a family member of the Investigator or any associate, colleague, and employee assisting in 
the conduct of the study (secretary, nurse, technician). 
 
Is in a position likely to represent a conflict of interest. 
5.3. Lifestyle Considerations 
5.3.1. Contraception 
Women of childbearing potential must agree to take appropriate precautions to avoid pregnancy 
from screening through 30 days after the last dose of encorafenib. 
Male participants must agree to take appropriate precautions to avoid fathering a child and prevent 
exposure of seminal fluid to the partner from screening through 90 days after the last dose of 
encorafenib.  
The methods of contraception outlined in Appendix 10.2.2 are permitted under this protocol for use 
by the participant and his/her partner. These methods should be communicated to the participants 
and their understanding confirmed. 


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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 methods of contraception. 
5.3.2. Meals and Dietary Restrictions 
Participants must refrain from the consumption of grapefruit, pomegranates, star fruits, Seville 
oranges, lime, sour orange, citrus depressa, other local fruits or products containing the juice of any 
of these items from 7 days before the start of study treatment until after the final dose due to potential 
CYP3A4 interaction with encorafenib (see Section 6.5.1). Orange juice is allowed. 
There are no restrictions on dosing or PK sampling in relation to the timing of meals. 
5.4. Screen Failures 
Screen failures are defined as participants who sign the ICF but fail to meet one or more criteria 
required for participation in the study or do not complete the screening process. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to competent authorities. 
The following will be recorded in the electronic case report form (eCRF) for screen failures: 
 
Date of informed consent. 
 
Review of inclusion/exclusion criteria. 
 
Adverse events related to a study procedure during the screening period and any medications 
used to treat those adverse events. 
Participants who do not meet the criteria for participation in this study (screen failure) cannot be 
rescreened. However, if vital signs measured as per protocol do not initially fulfil inclusion 
criterion, an unscheduled assessment is authorized after 10 minutes of rest without considering this 
as rescreening. 
 
 




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Encorafenib will be orally self-administered. A fixed-flat dose of 300 mg PO encorafenib will be 
administered QD. Encorafenib should be taken daily in the morning at approximately the same time 
(± 2 hours) every day without regard to food. If a participant vomits at any time after dosing, the 
dose should not be re-administered. Doses of encorafenib that are omitted for adverse events or any 
other reason should not be made up during the day, or at the end of the dosing period.  
The first dose of encorafenib will be taken on Cycle 1 Day 1 and will then be continuously 
self-administered in 28-day cycles until death, disease progression, one of the other criteria for study 
treatment discontinuation is met (see Section 7.1) or the participant is lost to follow-up (see 
Section 7.3). On Day 1 of each cycle the encorafenib dose will be administered at the study site. 
Lifestyle considerations in relation to dosing are detailed in Section 5.3. There are no restrictions 
on dosing in relation to the timing of meals. 
Participants will receive a diary to document self-administration of encorafenib to include the dose, 
date of dosing (and time if applicable), if the participant vomited after dosing, if any doses were 
missed and the reason for the missed dose. One diary will be provided per cycle. On the days when 
encorafenib is administered at the study site, these details will be recorded in the eCRF by the study 
site personnel. 
Management of dose modifications (including dose interruptions and retreatment) are detailed in 
Section 6.6. 
Continuing study treatment beyond disease progression for any participant is only to be considered 
under special circumstances when it is believed that the participant may clinically benefit from 
continued treatment beyond progression. If it is judged by the investigator (in consultation with the 
sponsor) to be in the best interest of the participant, the participant may remain on study treatment 
as long he/she continues to benefit from the study treatment according to the investigator  
assessment. Special circumstances can be defined by e.g. mixed responses and appearance of new 
brain metastases (only) which is treatable with stereotactic radiotherapy or surgery but does not 
require whole brain radiotherapy. 
Treatment beyond progression is not allowed in the following cases: 
 
Participants with clear evidence of disease radiographic and clinical progression at multiple 
sites or clear evidence of new lesions outside the central nervous system. 
 
Participants with rapid progression of disease at critical anatomical sites (e.g. cord 
compression) requiring urgent alternative medical treatment cannot be dosed beyond 
progression. 
 
Participants who have clinically relevant worsening of laboratory values. 
 
Participants who have a clinically significant decline in ECOG performance status at time of 
progression. 


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6.2. Preparation/Handling/Storage/Accountability/Return/Destruction  
6.2.1. Accountability on Site and Return/Destruction 
Before the start of the study, the sponsor or designee will supply the study site with the number of 
study treatments units required for the study using Interactive Response Technology (IRT). 
Encorafenib will be supplied by the sponsor and sent to a local facility (sponsor designee) for 
storage prior to onward distribution to each study site prior to, and during the study. Full shipping, 
storage and handling details will be provided in the Pharmacy Manual. 
 
Labelled, packaged encorafenib will be shipped to each study site by the sponsor designee 
and will contain a temperature monitoring device. The investigator or designee must confirm 
appropriate temperature conditions have been maintained during transit for all study treatment 
received and any discrepancies are reported and resolved before use of the study treatment.  
 
Only participants enrolled in the study may receive study treatment and only authorized study 
site personnel may supply or administer study treatment. All study treatment must be stored 
according to Section 6.2.2. 
 
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation and record maintenance (dates 
and quantities of study treatment received, to whom study treatment is dispensed 
[participant-by-participant accounting] and accounts of returned and destroyed treatment). 
To ensure adequate records, all study treatment will be accounted for on an accountability 
inventory form as instructed by the sponsor according to Good Clinical Practice (GCP) 
(International Council on Harmonization [ICH] E6 (R2) [5.14]). 
Drug accountability must be performed by the clinical research associate (CRA) on a regular 
basis during the study according to the Monitoring Plan. The investigator must retain all 
unused or expired study treatment supplies until the CRA has confirmed the accountability 
records. If site policy prohibits holding study treatment supplies for CRA review, then a copy 
of the standard operating procedure for processing returns must be provided to the sponsor. 
 
At the end of the study, all used and unused study treatment including packaging should be 
noted and return/destruction is organized by the CRA. Further guidance and information for 
the final disposition of unused study treatments are provided in the Pharmacy Manual. 
6.2.2. Storage 
At the time of delivery to the site an accompanying letter will be provided with the details of storage 
conditions that should be respected. 


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As soon as the Pharmacist receives the study treatment, he/she will check the contents and 
immediately followed the instructions described in the Study Pharmacy Manual. Documents 
included in the parcel will be kept in the Investigator's file. .  
At the time of delivery to the site an accompanying letter will be provided with the details of storage 
conditions that should be respected. The CRA will ensure during the initiation visit that study 
treatments have been received in good conditions and the acknowledgment of receipt has been 
returned adequately. 
All study treatment must be stored in a secure, environmentally controlled and monitored (manual 
or automated) area in accordance with the labelled storage conditions and applicable regulatory 
requirements with access limited to the investigator and authorized study site personnel. 
Storage conditions will be described on the medication label. Detailed instructions for storage and 
handling of encorafenib will be detailed in the Study Pharmacy Manual. 
6.2.3. Expiry Date 
The investigator or designee should ensure that the study treatment expiry date has not been 
exceeded. If the expiry date has been exceeded, then the affected study treatment supplies must be 
quarantined to prevent them from being used. Accountability and final disposition will follow the 
process in Section 6.2.1.  
6.2.4. Return / destruction 
At the end of the study, all used and unused study treatments, including packaging should be 
tracked, and their return/destruction will be arranged by the CRA. 
The study treatment can be destroyed at the sponsor-designated local facilities or at a third party 
(on site) in accordance with local guidelines, as appropriate. 
Further guidance and information for the final disposition of unused study treatments will be 
provided in the Study Pharmacy Manual. 
6.2.5. Recall 
In case of recall of study treatment (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: 
 
Put all study treatments concerned by the recall in quarantine. 
 
Stop the administration of the concerned study treatments to the participants. 


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Inform the concerned participants that they must immediately stop taking these study 
treatments and bring them back. 
The study manager/CRA will organize the return of the recalled products to Pierre Fabre 
Médicament, according to the sponsor procedures. 
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Blinding and Randomization 
This is an open-label, single-arm, non-randomized study therefore no procedures for blinding or 
randomization are applicable. All participants will receive the same study treatment. 
6.3.2. Participant Numbering 
A participant will be considered enrolled into the study as soon as he/she has signed the ICF. All 
participants who provide informed consent will be assigned a unique participant code by an 
Interactive Response Technology (IRT) system. Once a participant is enrolled, he/she will be 
identified only by the assigned participant code. Once assigned, a participant code must not be 
reused for any other participant.  
The participant code will contain eight digits, corresponding to the country number, the site number 
provided written 
informed consent). 
6.3.3. Allocation of Study Treatment and Dispensing 
Allocation of boxes of encorafenib to each participant will be controlled by the IRT system. 
Encorafenib will be allocated on Day 1 of each cycle during the treatment period. Returned 
encorafenib should not be re-dispensed. 
Full information is described in the IRT Manual.  
6.4. Study Treatment Compliance 
As participants self-administer encorafenib at home, each participant will be reminded to bring back 
to the site any remaining encorafenib blisters and boxes (used or unused) from the previous cycle 
on Day 1 of the next cycle. Compliance with study treatment will be assessed on Day 1 of each 
cycle (from Cycle 2 onwards) by reviewing participant diary entries, accounting of returned study 
treatments and 
 interviews during the site visits and documented in the source 
documents and eCRF. Non-compliance from the prescribed dosage regimen should be recorded in 
the eCRF. 


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A record of the number of encorafenib capsules dispensed to and taken by each participant must be 
maintained and reconciled with study treatment and compliance records. The study treatment intake 
start and stop dates, including dates for study treatment delays and/or dose reductions will also be 
recorded in the eCRF. 
6.5. Concomitant Medication and Therapeutic/Diagnostic Procedures 
Any medication (including vaccines) other than study treatment (including non-prescription or 
prescription medicines or vitamins) taken in the period from 28 days before to the first 
administration of study treatment up to 30 days after the last dose of study treatment must be 
recorded. Any changes in dose of a medication during the study must also be recorded. The 
following information must be recorded in the eCRF: 
 
The name of the medication. 
 
The reason for prescription. 
 
The route of administration. 
 
The dose. 
 
The frequency. 
 
The duration (start date and end date). 
The participant must be told to notify the study site about any new therapies and dietary supplements 
taken after the start of the study treatment. 
Any therapeutic and diagnostic procedures (such as endoscopic examinations, diagnostics tests, 
ablation, surgical procedures, blood or platelet transfusions etc.) not planned by the study protocol 
must also be recorded. 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 eCRF (adverse events, 
medical history). The following information must be noted in the eCRF: 
 
The name of the procedure. 
 
The indication. 
 
The duration (start date and end date). 
Investigators should use caution when prescribing concomitant medications, as clinical experience 
with these compounds in participants with cancer is often limited. Investigators should contact the 
sponsor or designee when they are unsure whether a medication should be prescribed to a participant 
in the clinical study. 


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6.5.1. Authorized Medications, Therapeutic and Diagnostic Procedures  
In general, the use of any concomitant medications deemed necessary for the care of the participant 
is permitted, unless otherwise specified. Additional information regarding concomitant medications 
. 
Participants should be closely monitored for the occurrence of adverse events whilst taking 
permitted therapies requiring caution and/or action. 
 Authorized Therapies requiring Caution and/or Action  
Participants should be closely monitored for the occurrence of adverse events whilst taking these 
therapies. 
6.5.1.1.1. Cytochrome P450 and Uridine 5'-diphospho-glucuronosyltransferase 
Substrates and Inhibitors 
Encorafenib is a reversible inhibitor of CYP2B6, CYP2C9, CYP3A4 and uridine 5'-diphospho-
glucuronosyltransferase (UGT)1A1. It is also a time-dependent inhibitor of CYP3A4. Permitted 
medications to be used with caution in this study include those that are sensitive substrates of 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 (see Table 11 and Table 12) and UGT1A1 (see 
Table 13) or those substrates that have a narrow therapeutic index. 
There is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness of 
hormonal contraception methods. At least one form of non-hormonal contraception is therefore 
required during participation in this study (see Section 5.3.1). Caution should also be exercised in 
participants 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 (see Section 6.5.2). Concomitant 
use of moderate CYP3A4 inhibitors (see Table 14) while on study should be avoided. If use of 
moderate CYP3A4 inhibitors is unavoidable and no alternatives are available, short-term use 
 days) following discussion with the sponsor may be permitted with accompanying dose 
reduction to one-half of the encorafenib dose before use of moderate CYP3A4 inhibitors (or as close 
as can be achieved without exceeding the target dose). The encorafenib dose that was taken before 
initiating the CYP3A4 inhibitor may be resumed after the inhibitor has been discontinued for three 
to five elimination half-lives. Strong inhibitors of CYP2C19 should be used with caution when 
coadministered with encorafenib.  


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6.5.1.1.2. Transporter Substrate and Inhibitors 
In vitro data showed that encorafenib is a substrate of the transporter P-glycoprotein (P-gp) and a 
breast cancer resistance protein (BCRP) inhibitor. Use of medications that are known to inhibit or 
induce P-gp or BCRP should be used with caution (see Table 15). Encorafenib is also a potent 
inhibitor of the renal transporters, organic anionic transporter (OAT)1, 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, OCT2, OATP1B1 and OATP1B3 should be used 
with caution (see Table 16). 
6.5.1.1.3. 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 with concomitant medications 
with a known, conditional or possible risk to prolong the QT interval and/or induce Torsade de 
Pointes (see Table 17). Participants 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. 
6.5.2. Prohibited Medications and Therapeutic/Diagnostic Procedures 
The following therapies are prohibited during screening and the Treatment Period (unless otherwise 
noted). There are no prohibited therapies during the post-treatment Follow-up Period. None of the 
concomitant therapies and therapeutic/diagnostic procedures listed below are allowed during the 
treatment phase: 
 
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. 
 
Investigational drugs (other than study treatments) and devices. 
 
 of the 
bone marrow reserve). Calculation of the percentage of active bone marrow reserve can be 
performed using information in Table 6  [Hindorf, 2010]. 
Note: The participant must have clear measurable disease outside the radiated field. 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be considered 
on a case-by-case basis after consultation with the sponsor's medical monitor.  
Note: Administration of palliative radiation therapy will be considered clinical progression. 
 
Herbal preparations/medications. Participants should stop using herbal medications 
(


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susceptible to be a moderate or strong inhibitor or inducer of CYP3A4/5) 7 days before the 
first dose of study treatment. 
 
Concomitant systemic strong CYP3A4 inhibitors or moderate/strong inducers which are 
likely to significantly increase or decrease respectively encorafenib exposure (listed in 
Table 18). 
 
 


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Table 6: The percentage of total red marrow present at different skeletal sites in a healthy 
adult 
 
If another therapy and/or therapeutic/diagnostic procedure has to be prescribed in the interests of 
the 
 health, the decision to discontinue the participant from the study should be taken 
by the investigator. 
6.6. Dose Modification 
Participants will be monitored for adverse events throughout the study. The severity of adverse 
events will be graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events NCI CTCAE Version 4.03 [NCI CTCAE 2010].  
If a participant develops toxicity, the dose should be modified as outlined in Appendix 10.4. This 
table include criteria for interruption, reduction and discontinuation of study treatment. All dose 
modifications should be based on the worst preceding toxicity. All dosing interruptions and 
modifications must be recorded in the eCRF. 




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Following any dose reductions occurring due to toxicity, should investigators believe that it is the 
best interest of their patients, they may re-start and re-escalate doses, with close supervision and 
monitoring of their patients, except for the following circumstances of dose modification: 
 No dose re-escalation of encorafenib is allowed after a dose reduction due to prolonged 
 
  No dose re-
 
7. Discontinuation 
of 
Study 
Treatment 
and 
Participant 
Discontinuation/Withdrawal 
7.1. Discontinuation of Study Treatment for Individual Participants 
7.1.1. Temporary Discontinuation and Rechallenge 
Adverse events and clinically significant laboratory abnormalities leading to a dose interruption and 
the conditions for re-starting study treatment (rechallenge) are provided in Appendix 10.4. 
A treatment interruption occurs if at least one study treatment administration is missed, followed 
by a restart of the study treatment.  
It may be necessary for a participant to interrupt study treatment to allow for resolution of toxicity 
(see Section 6.6). Participants may resume treatment if no medical condition or other circumstance 
exists that, in the opinion of the investigator, would make the participant unsuitable for further 
participation in the study. 
Dose interruptions are also permitted in the case of medical/surgical events or logistical reasons not 
related to study treatment (e.g. elective surgery, unrelated medical events, vacation, holidays). 
Participants should be resumed on study treatment within 2 weeks (14 days) of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption will be 
documented in the eCRF. Dose interruptions of >4 weeks (28 consecutive days) are not allowed 
 medical monitor and study treatment must be permanently 
discontinued (see Section 7.1.2). 
7.1.2. Permanent Study Treatment Discontinuation 
Study treatment is to be administered until any of the following criteria for permanent 
discontinuation is met: 
 
Disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 (continuation of treatment beyond progression is permitted in special 
circumstances, see Section 6.1).  


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Clinical progression, as determined by the investigator in the absence of radiographic 
progression. 
 
Withdrawal of consent. Participants may choose to withdraw consent to continue study 
treatment but remain in the study to be followed for safety and disease progression. In this 
case, follow-up data will continue to be collected for this participant. Withdrawal of consent 
for study treatment may occur at any time without penalty of jeopardizing their healthcare or 
loss of benefits to which they are otherwise entitled. Participants who withdraw consent to 
study treatment and follow-up, will no longer receive study treatment or followed up within 
this study.  
 
Unacceptable adverse events or failure to tolerate study treatment:  
 
Grade 4 or life-threatening adverse event as outlined in Appendix 10.4 (except with 
 
 
Toxicity requiring more than the allowed number of dose reductions for encorafenib, 
(see Table 7). 
 
Occurrence of an adverse event that is related to study treatment and compromises the 
participant
-
judgement or 
 The medical 
monitor or delegate should immediately be informed by phone or e-mail and a report 
explaining the discontinuation will be forwarded to him/her as soon as possible. 
 
Initiation of subsequent anticancer therapy.  
 
Participant is non-compliant with study procedures or study treatment that in the judgment of 
the investigator or sponsor renders the participant unsuitable. 
 
Significant protocol deviation that, in the opinion of the investigator and/or sponsor, renders 
the participant unsuitable for further study treatment administration. 
 
Participant has missed >4 weeks (i.e., 28 consecutive days) of dosing (see Section 7.1.1). 
 
Participant becomes pregnant or begins breastfeeding. 
 
Participant is lost to follow-up. 
 
Defined end of the study (see Section 4.4) 
 
Termination of the study site or study by the sponsor/competent authority (described in 
Appendix 10.1.2 and Appendix 10.1.10). 
 
Physician decision. 
 
Other reasons (any unexpected event considered relevant by the investigator to be discussed 
case by case with the sponsor). 


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If a participant is withdrawn from study treatment, the date and reason of treatment discontinuation 
will be recorded in the eCRF. The participant will have an end of treatment visit followed by a 
30-day safety follow-up assessment.  
Data to be collected at the time of discontinuation of study treatment and follow-up and for any 
further evaluations that need to be completed are specified in Table 1. For participants who have 
discontinued study treatment for reasons other than disease progression, tumor assessments should 
continue to be performed (as per local review and standard of care) until the start of a new anticancer 
therapy, disease progression, death, loss to follow-
consent whichever occurs first.  
Participants who are discontinued from the study treatment due to a treatment-related adverse event 
zation. 
7.2. Participant Discontinuation/Withdrawal from the Study 
Participants may withdraw consent to  the study treatment and follow-up at their own request 
or be withdrawn at the discretion of the investigator (e.g. for safety, behavioural, compliance 
or administrative reasons) at any time and for any reason without prejudice to their future 
medical care. This is expected to be uncommon. The participant will be permanently 
discontinued both from study treatment and from the study at that time. 
At the time of withdrawing from the study, if possible, a 30-day safety follow-up visit should be 
conducted. Data to be collected at the time of discontinuation of study treatment and follow-up and 
for any further evaluations that need to be completed are specified Table 1. 
In all cases, the investigator should attempt to contact the participant as soon as possible for a final 
assessment in order to: 
 
Obtain the reason(s) for withdrawal and report it/them with the discontinuation date in the 
 
 
E
 
 
If necessary, take appropriate therapeutic measures: management of an adverse effect or 
concomitant disease, prescription of another treatment. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. Any blood 
or tissue samples collected up to the date of withdrawal of consent will be analyzed. No further 
data, except data in the public domain, may be solicited from or collected on the participant. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 


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7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. The following actions must be taken if a 
participant fails to return to the clinic for a required study visit: 
 
Study site personnel must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should continue 
in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designated study site 
personnel must make every effort to regain contact with the participant (where possible, three 
telephone calls and, if necessary, a certified letter to the parti
address or local equivalent methods). These contact attempts should be documented in the 
participant
 
 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 
 


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8. Study Assessments and Procedures 
Study procedures and their timing are summarized in the schedule of activities (Table 1). Adherence 
to the study design requirements, including those specified in the schedule of activities, is essential 
and required for study conduct. Additional, unscheduled visits or procedures may be performed at 
the discretion of the investigator (including samples for safety reasons or because of technical issues 
with the samples). Details must be recorded in the eCRF. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. Protocol waivers or exemptions are not allowed. The investigator will 
maintain a screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure, as applicable. 
Procedures conducted as part of the 
and obtained before provision of informed consent may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed within the 
timeframe defined in the schedule of assessments. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed one standard blood donation.  
8.1. Screening Assessments and Procedures 
Participants must undergo BRAF V600E local laboratory testing using an NMPA approved test 
prior to screening.  
All eligible participants will then undergo screening in the 28 days before the start of study 
treatment. Participants must provide informed consent for the study before any screening 
procedures to determine eligibility for participation in the study are performed (see 
Appendix 10.1.4). Participants will be registered for the study using IRT after informed consent is 
obtained (see Section 6.3).  
The following will be recorded at screening for all participants: 
 
Demographic variables (including age, sex and race). 
 
Disease history including stage, tumor location, organs involved and sites of metastases, 
baseline tumor mutation status including details of prior antineoplastic treatments including 
number of prior metastatic regimens.  
 
Other past and present medical history considered by the investigator to be significant. 
 
Smoking history. 


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Prior medications/procedures (to cover the 28 days before the first dose of study treatment). 
The following assessments will be performed: 
 
Physical examination, height and weight (see Section 8.3.2) and dermatological examination 
(see Section 8.3.3). 
 
Vital signs (see Section 8.3.6), ECG (see Section 8.3.7), cardiac function (see Section 8.3.8) 
tests and ECOG performance status (see Section 8.3.9). 
 
Local clinical laboratory blood tests: 
 
Safety tests (hematology, clinical chemistry and coagulation) (see Section 8.3.4). 
 
Viral serology tests for HBsAg and HCV Ab, (plus HIV in jurisdictions that specifically 
requiring it), and HBV DNA if HBsAg was positive or HCV RNA if HCV Ab positive.  
 
Pregnancy test in WOCBP (see Section 8.3.5). 
 
If required, analysis of follicle stimulating hormone (FSH) (see Appendix 10.2.1), to 
confirm postmenopausal status in females. 
Samples will be collected, handled and analyzed at the local laboratory according the study 
 
 
Urinalysis (see Section 8.3.4). 
 
Baseline tumor assessment of the chest, abdomen, pelvis and brain by CT/MRI plus bone or 
positron emission tomography (PET) scan if clinically indicated (see Section 8.2). 
Participant eligibility will be verified against the inclusion and exclusion criteria once all screening 
procedures are completed. When a participant is confirmed as eligible, they will be assigned to 
study treatment. 
8.2. Efficacy Assessments 
This study is not intended to formally assess efficacy, however, some efficacy assessment is 
necessary for the Investigator to assess continued benefit.  
Tumor response will be evaluated according to RECIST Version 1.1 (see Appendix 10.7). Tumor 
overall assessment (response, stable disease (SD), progressive disease (PD) will be determined 
locally by the investigator. 
Baseline disease assessments (imaging with a preference for CT and /or calliper measurements) will 
be performed at screening (in the 28-days before the first dose of study treatment up to Day -1) and 
as close as possible to the start of treatment.  
During the study, radiological assessments should be performed at least every two cycles (8 weeks) 
± 7 days for the first 12 months, then at least every three cycles (12 weeks) ± 7 days until disease 


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progression. A final assessment should be performed at the end of treatment visit, unless the 
previous assessment was performed in the last 30 days. More frequent radiological assessments 
may be performed if needed.  
According to RECIST Version 1.1, responses (complete response or partial response) should be 
confirmed by a repeat radiographic assessment no sooner than 4 weeks after the first documented 
response and no later than the next per-protocol scheduled imaging, whichever is clinically 
indicated.  
Additional imaging evaluations may be performed at any time if there is symptomatic evidence 
suggesting the possibility of disease progression based on clinical symptoms or physical 
examination. Following the 30-day safety follow up (when clinically appropriate) it is also 
recommended the participant be monitored with chest CT scans for cutaneous and non-cutaneous 
secondary malignancies for up to 6 months after the last study treatment dose or until initiation of 
another antineoplastic therapy. 
8.3. Safety Assessments 
8.3.1. Adverse Events 
Requirements for recording and reporting adverse events and SAEs are described in Section 8.4. 
8.3.2. Physical Examinations 
A physical examination will be carried out on each body system at screening and repeated on 
Cycle 1 Day 1 (if not performed within 72 hours before the first dose of study treatment), Cycle 1 
Days 8, 15 and 22, on Day 1 of each subsequent cycle, the end of treatment visit and the 30-day 
safety follow-up visit. Body weight will also be measured at each timepoint. Height will be 
measured at screening only. 
The physical examination at baseline should include general appearance, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological. Visual acuity should also be performed. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, skin, breast and pelvic examinations should be included. The 
physical examination at other timepoints should be targeted as clinically indicated. 
All physical examinations must be performed prior to study treatment administration. Significant 
findings in the i
on the medical history or adverse event 
eCRF pages. 


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8.3.3. Dermatological Examination 
Dermatological examinations will be performed to monitor for the possible development of 
keratoacanthoma and/or squamous cell carcinoma, as these have been reported to occur with 
selective BRAF inhibitor treatment [Flaherty 2010, Kefford 2010, Robert 2011]. This assessment 
will be performed at screening, Day 1 of each odd cycle (Cycle 3 onwards), the end of treatment 
visit and the 30-day safety follow-up visit. All assessments during the treatment phase should be 
made prior to study treatment administration. 
Following the 30-day safety follow-up (when clinically appropriate) it is recommended further 
dermatological examinations be performed every 8 weeks for up to 6 months after the last 
encorafenib dose or until initiation of another antineoplastic therapy.  
In case of occurrence of keratoacanthoma and/or squamous cell carcinoma, participants should 
undergo complete surgical excision of the skin lesion following study site standards. The evaluation 
may be done by the dermatologist if clinically indicated. 
8.3.4. Clinical Safety Laboratory Assessments 
Laboratory tests performed before the start of study treatment to determine eligibility or baseline 
status only (i.e. for viral serology and tests to confirm postmenopausal status for females) are 
detailed in Section 8.1. Pregnancy testing is detailed in Section 8.3.4. 
Blood samples for hematology, clinical chemistry, coagulation and urine samples for dipstick 
urinalysis will be taken at screening and repeated on Cycle 1 Day 1 (if not performed within 
72 hours before the first dose of study treatment), Cycle 1 Day 15, on Day 1 of each subsequent 
cycle, the end of treatment visit and the 30-day safety follow-up visit. Additional urinalysis tests 
will be performed on Cycle 1 Days 8 and 22.  
All assessments during the treatment phase should be made prior to study treatment administration. 
Blood samples for the chemistry panel will be taken under fasting conditions. 
The parameters to be assessed at each timepoint are listed in Table 8.  
Unscheduled clinical laboratory tests may be obtained at any time during the study at the 
i
 Laboratory test results required to make decisions regarding potential dose 
modifications (as specified in Section 6.6) should be reviewed before study treatment 
administration.  
Samples may be collected up to 48 hours prior to scheduled clinic visits. Results must be reviewed 
by the investigator prior to study treatment administration. 
Blood samples will be collected, handled and analyzed at the local laboratory according the study 
. Normal ranges from the laboratory will be used to identify abnormal 
values. Urinalysis will be performed in the clinic or at the local laboratory, according to study site 




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If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the aetiology should be identified, and the sponsor notified. 
If laboratory values from non-protocol specified laboratory assessments performed at the study 
 a change in participant management or are considered clinically 
significant by the investigator (e.g. adverse event, SAE or dose modification), then the results must 
be recorded in the eCRF. 
8.3.5. Pregnancy Testing 
Pregnancy tests will be performed on females determined to be WOCBP only (see 
Appendix 10.2.1
-HCG. 
A serum 
al laboratory at screening. Local urine 
pregnancy tests will be repeated on Cycle 2 Day 1, on Day 1 of each subsequent cycle, and at the 
end of treatment visit. Further tests may be performed at any time if pregnancy is suspected. All 
assessments during the treatment phase should be made prior to study treatment administration.  
The pregnancy tests at screening and predose on Cycle 1 Day 1 must be negative for inclusion. Any 
positive pregnancy tests during the treatment period will result in immediate discontinuation of 
study treatment (see Section 7.1). If any urine test cannot be confirmed as negative (e.g. an 
ambiguous result), a serum pregnancy test is also required. 
Pregnancies will be managed as defined in Section 8.4.5. 
8.3.6. Vital Signs 
Tympanic temperature, pulse rate, respiratory rate, systolic blood pressure and diastolic blood 
pressure will be measured using study site standard techniques at screening and repeated on Cycle 1 
Days 1, 8, 15 and 22, Day 1 of each subsequent cycle, the end of treatment visit and the 30-day 
safety follow-up visit. Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (e.g. television, cell 
phones). All assessments during the treatment phase should be made prior to study treatment 
administration and before blood collection for laboratory tests.  
Any treatment-emergent abnormal findings should be recorded as adverse events. 
8.3.7. Electrocardiograms 
12-lead ECGs will be performed at screening, Cycle 1 Day 8, 15 and 22, Day 1 of each subsequent 
even cycle (Cycle 2, 4, 6, 
) and the end of treatment visit.  
Three serial ECGs will be conducted within approximately 5 to 10 minutes total time. 12-lead ECGs 
should be preceded by at least 5 minutes of rest for the participant in a quiet setting without 




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8.3.10. Other examinations/Chest, abdomen and pelvis CT scanner 
Based on its mechanism of action, encorafenib may promote malignancies associated with 
activation of RAS through mutation or other mechanisms.  
A head and neck examination, chest/abdomen computerized tomography (CT) scan, anal and pelvic 
examinations (for women) and complete blood cell counts prior to initiation will be performed 
during and at the end of treatment as clinically appropriate. 
8.4. Adverse Events and Serious Adverse Events  
Adverse events and SAEs are defined in Appendix 10.8. Events meeting these definitions are also 
specified.  
8.4.1. Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All adverse events will be collected from when the participant first provides informed consent until 
the 30-day safety follow-up visit. If the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study and he/she considers the event to be 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor. 
8.4.2. Method of Detecting, Recording and Reporting Adverse Events and 
Serious Adverse Events 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate 
or the participant's legally authorized representative). Care will be taken not to introduce bias when 
detecting adverse events. Open-ended (participant
) and non-leading verbal 
questioning of the participant are the preferred methods. 
The investigator and designated study site personnel are responsible for detecting, documenting and 
recording events that meet the definition of an adverse event/SAE and remain responsible for 
following up events that are serious, considered related to the study treatment or study procedures, 
or that caused the participant to discontinue the study or study treatment (see Section 7). 
The records of adverse events must describe the nature (diagnosis, signs and symptoms), intensity, 
date/time of onset, date/time of end, outcome and actions taken with study treatment, relationship 
to study treatment (in the investigator's opinion) and whether the event is serious or not.  
The process of recording, evaluating and assessing adverse events/SAEs for intensity and causality 
is provided in Table 10. 
 
 






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examinations or consultation with other health care professionals. If a participant dies during 
participation in the study or during the follow-up period, the investigator will provide the sponsor 
with a copy of any post-mortem findings, including histopathology.  
All SAEs will be followed until resolution, stabilization, the event is otherwise explained or the 
participant is lost to follow-up (as defined in Section 7.3).  
The investigator will submit any new or updated SAE data to the 
Division within 24 hours receipt of the information. New or updated information will be entered on 
the SAE eCRF page (or provided on a new paper SAE form, if required). 
8.4.4. Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study treatment 
under clinical investigation are met.  
The sponsor has a legal responsibility to notify the competent authority about the safety of a study 
treatment under clinical investigation. The sponsor will comply with country-specific requirements 
relating to safety reporting to the competent authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC) and investigators. 
An SAE is determined to be a suspected unexpected serious adverse reactions (SUSAR) if it meets 
all the following criteria: 
 
Unexpected (i.e. nature or severity of which is not consistent with the study treatment 
description [e.g. Investigator's Brochure for an unapproved investigational product or locally 
approved Product Information for a marketed product]).  
 
Serious. 
 
Assessed to be related to study treatment. 
Safety reports must be prepared for SUSARs according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
An investigator who receives a safety report describing a SAE or other specific safety information 
(e.g. summary or listing of SAEs) from the sponsor will review and then file it along with the 
and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5. Pregnancy 
Contraceptive requirements for female and male participants are specified in Section 5.3.1.  




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Any poststudy pregnancy-related SAE considered related to the study treatment by the 
investigator will be reported to the sponsor as described in Section 8.4.2. While the 
investigator is not obligated to actively seek this information in former study participants, 
he/she or she may learn of an SAE through spontaneous reporting. 
If pregnancy is suspected during treatment period, the study treatment(s) should be temporarily 
discontinued (see Section 7.1.1) immediately until the result of the pregnancy testing is known. If 
pregnancy is confirmed, then the study treatment should be permanently discontinued (see 
Section 7.1.2) in an appropriate manner and the participant discontinued from the study.  
8.4.6. Cardiovascular and Death Events 
Cardiovascular and death events will be recorded and reported as specified in Section 8.4.1 to 
Section 8.4.4. 
8.4.7. Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as Adverse Events or Serious Adverse Events 
Progression of malignancy (including fatal outcomes) will be documented as part of the efficacy 
assessment (see definition of an adverse event in Appendix 8) and will not be reported according to 
the standard process for recording and reporting of adverse events unless either of the following 
conditions applies, then the event must be recorded and reported as an adverse event (instead of a 
disease-related event): 
 
expected for the individual participant. 
OR 
 
The investigator considers that there is a reasonable possibility that the event was related to 
study treatment. 
8.4.8. Adverse Events of Special Interest  
Adverse events of special interest will be defined in the Statistical Analysis Plan (SAP).  
8.5. Overdose 
Any dose of study treatment greater than 
 assigned dose according to protocol 
recommendations will be considered an overdose. The sponsor does not recommend specific 
treatment for an overdose.  
In the event of an overdose, the investigator or designated physician should: 


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Contact the medical monitor immediately. 
 
Monitor renal function as well as adverse reactions.  
 
In the absence of seriousness criteria, the overdose, and associated adverse events if any, are 
reported only on the adverse event eCRF page. If the definition of seriousness criteria is met, 
the SAE eCRF page must be also completed and transmitted to the sponsor. 
 
Document the quantity of the excess dose as well as the duration of the overdose in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.6. Pharmacokinetics 
8.6.1. Pharmacokinetic Samples 
Blood samples of approximately 4 mL will be collected to characterize the PK profile of 
encorafenib and its metabolite (LHY746) on the first day of treatment (Cycle 1 Day 1) and at steady 
state after 1 month treatment (Cycle 2 Day 1). Serial blood samples will be taken predose and 
1 (±10 minutes), 2 (±10 minutes), 4 (±30 minutes) and 6 (±30 minutes) hours postdose on both days 
(total 10 samples per participant). Each blood sample will be drawn by direct venipuncture or via 
an indwelling catheter: If an indwelling catheter is used for blood collection, approximately 1 mL 
will be drawn and discarded before sampling. Care must be taken to collect blood slowly without 
causing hemolysis. 
The following will be recorded: 
 
Cycle 1 Day 1: date and time of the first encorafenib dose and exact date and time of each 
sample. 
 
Cycle 2 Day 1: date and time of the last previous encorafenib dose before Cycle 2 Day 1 
(i.e. Cycle 1 Day 28) 
of each sample.  
Study visits for PK sampling should be scheduled in the morning so that correct predose and 
postdose PK blood samples can be collected. The encorafenib dose on PK visit days should be 
taken at the study site, only after collecting the predose PK sample. 
If a participant experiences an adverse event that results in an unscheduled visit or meets the criteria 
for an SAE, a further blood sample should be collected, if feasible, if less than 24 hours have elapsed 
since the last dose. On Cycle 1 Day 1 and Cycle 2 Day 1, if vomiting occurs, the exact time of the 
first vomiting episode within the first 4 hours postdose on that day must be noted. If a vomiting 
episode occurs within the first 4 hours postdose of encorafenib during the day of the last dose prior 
to collection of PK samples (except for Cycle 1 Day1), the exact time (whenever possible) must be 
noted in the eCRF.  


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Each sample will be divided into aliquots (for primary aliquots for PK analysis and back-ups). 
Samples will be stored at the study site at -20°C. Primary aliquots will be shipped to central 
laboratory on the day of collection and back-ups within 28 days of collection.  
Complete information regarding blood sample collection and processing, handling and shipment 
will be provided in the Laboratory Manual. The primary and back-up aliquots will be shipped 
separately. The samples will be stored at the central laboratory at -70°C until transfer to the 
third-party bioanalytical laboratory for analytical determination.  
8.6.2. Analytical Determination 
Analytical determination of plasma concentrations of encorafenib and LHY746 will be carried out 
at a designated third-party bioanalytical laboratory using validated liquid chromatography tandem 
mass spectrometry (LC/MS-MS) methods.  
8.6.3. Pharmacokinetic Analysis 
Encorafenib and LHY746 concentrations will be transmitted by the bioanalytical laboratory to the 
subcontractor in charge of PK analysis. Non-compartmental (e.g. area under the curve [AUC], 
maximum concentration [Cmax] and minimum concentration [Cmin]) and population PK analyses (as 
appropriate) will be performed (see Section 9.4.3.2).  
8.7. Pharmacodynamics 
Not applicable. Pharmacodynamics will not be assessed in the study. 
8.8. Pharmacogenomics 
Not applicable. Pharmacogenomics will not be assessed in the study. 
8.9. Other Exploratory Biomarker Assessment 
Not applicable. Biomarkers will not be assessed in the study. 
 
 




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9.4. Statistical Analyses 
9.4.1. General Considerations  
All data will be listed. This section summarizes the descriptive analyses planned on these data.  
A SAP will be prepared by the sponsor (or designee) and finalized prior to first participant first 
visit. This plan will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses. Any major 
modifications will also be described in a protocol amendment. 
Statistical analysis will be performed after database lock or data snapshot (see Section 10.1.8.3.5), 
using statistical analysis software (SAS®) Version 9.4 or higher, according to the SAP. 
In general, following descriptive methods will be used to present all relevant data: 
 
Continuous data will be presented using number of observations, number of missing, mean, 
standard deviations, median, quartiles, minimum and maximum. 95% CIs will be presented 
if relevant. 
 
Categorical data will be summarized using number of observations, frequencies, percentages 
and number of missing. Unless otherwise specified, the calculation of proportions will be 
based on the non-missing data. Counts of missing observations will be excluded from the 
denominator if not otherwise specified in the SAP. 
Baseline is defined as the last completed and available assessment prior to date of first dose of study 
treatment. If an assessment that is planned to be performed prior to the first dose of study treatment 
in the protocol is performed on the same day as the first dose of treatment and the time is unknown, 
it will be assumed that it was performed prior to study treatment administration and will be 
considered as baseline assessment.  
The Clinical Study Report will be written based on all data at the end of the study. 
9.4.2. Primary Endpoint 
The primary endpoint is the incidence of DLTs experienced during Cycle 1 of encorafenib 
treatment. A DLT is defined as any adverse event or abnormal laboratory value assessed as 
unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies 
that satisfies at least one of the criteria listed in Table 4 (see Section 4.1.1). 
The occurrence of DLTs will be summarized descriptively for the DDS.  


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9.4.3. Secondary Endpoints 
 Safety  
All safety analyses will be performed on the SAF. 
9.4.3.1.1. Study Treatment Exposure 
The duration of study treatment exposure in weeks, actual and relative dose intensity will be 
summarized. The number of participants with dose modifications will be presented. The actual daily 
doses and reasons for dose modification will be listed.  
Further details will be provided in the SAP. 
9.4.3.1.2. Adverse Events 
All analyses of adverse events will be further detailed in the SAP. 
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 (relative to its 
previous status). All adverse events will be coded using the MedDRA terminology according to 
Appendix 10.1.8.3.4 and the verbatim term, system organ class (SOC) and preferred term presented. 
A TEAE is defined as any event that first occurred or worsens from the first study treatment 
administration date up to the last administration date + 30 days (inclusive).  
Incidence tables will display the number and percentage of participants with TEAEs and number of 
TEAEs by SOC and preferred term. Further summaries will be provided by maximum severity 
(based on NCI CTCAE grades, where applicable) and relationship to study treatment. A participant 
with multiple occurrences of an adverse event will only be counted under the maximum NCI 
CTCAE grade or worse relationship for this event. 
Summaries of Grade 3 and 4 TEAEs, SAEs and adverse events resulting in study treatment 
discontinuation, study treatment modification or study discontinuation and adverse events leading 
to additional therapy will also be separately presented by SOC and preferred term. 
Summaries for deaths on-study will be provided.  
Adverse events of special interest will be identified, defined in the SAP and summarized. 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 treatment. For each specific 
category, number and percentage of participants with at least one event will be reported, if relevant. 
Additional analyses may be defined.  


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9.4.3.1.3. Clinical Safety Laboratory Evaluation 
Clinical safety laboratory parameters will be graded using graded using NCI CTCAE Version 4.03, 
where possible and presented in shift tables or scatterplots of baseline grade versus maximum grade 
on study, if relevant. For laboratory parameters that cannot be graded using NCI CTCAE 
Version 4.03, shift tables of normal-abnormal will be provided. Summaries of clinically notable  
measurements will also be provided. The definitions of clinically notable  will be provided in the 
SAP. 
For other laboratory parameters that cannot be graded using NCI CTCAE, shift tables of 
normal-abnormal will be presented. 
9.4.3.1.4. Other Safety Data   
Vital signs, physical examination, dermatological examination, ECG and ECOG performance status 
data will be summarized descriptively over time for values and changes from baseline and/or with 
shift tables or scatterplots, if relevant. Summaries of clinically notable measurements will also be 
provided. Definitions will be detailed in the SAP. 
Results for each ECG parameter will be summarized and reviewed for clinically notable 
abnormalities according to predefined criteria as outlined in the SAP. 
 Pharmacokinetics 
PK analyses will be performed on the PK Set. 
Descriptive statistics of encorafenib and LHY746 plasma concentrations will be reported and 
presented graphically. A non-compartmental analysis will be performed (e.g. AUC, Cmax and Cmin). 
Descriptive statistics of non-compartmental PK parameters of encorafenib and LHY746 will be 
reported. Details of the analyses will be included in the SAP or in a PK Analysis Plan. 
If appropriate and possible, the generated PK data will be pooled with data from other studies to 
enrich the full population PK analysis planned for encorafenib. Details of these analyses will be 
provided in a specific standalone modelling plan. The modelling results will be reported in a separate 
report. 
9.4.4. Other Analyse(s)  
Concomitant medications/therapies will be summarized by Anatomical Therapeutic Classification 
System term and preferred term. Analyses will be performed on the SAF. The number of 
participants with at least one concomitant procedure will be tabulated by summarized by SOC and 
preferred term, if applicable.  


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Summaries will include those medications/therapies and therapeutic/diagnostic procedures starting 
on or after the start of study treatment or starting before the start of study treatment and continuing 
after the start of study treatment.  
Any other medication or procedure starting and ending before the first study treatment 
administration will be listed.  
Other analyses will be described in the SAP. 
9.5. Compliance 
Compliance is described in Section 6.4. 
9.6. Interim/Initial Analyses  
There are no interim analyses planned. 
9.7. Trial Steering Committee  
The TSC will analyse the available safety data in order to evaluate the tolerability of encorafenib 
300 mg QD.  
The TSC will assess any toxicities as significant or not once the first three participants (and six 
participants if required) have fully completed the first cycle of treatment (28 days). The tolerability 
assessment will be based on the DLT rate (DLTs observed in <33% of participants) and evaluation 
of the overall toxicity profile (based on deaths, treatment emergent SAEs, TEAEs leading to 
discontinuation and to dose interruption/reduction). The TSC will make a recommendation if the 
dose of encorafenib is not deemed tolerable. 
The TSC membership, data to be reviewed, timing of the planned reviews as well as the operating 
procedures will be described in the TSC Charter.  
 


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10. Supporting Documentation and Operational Considerations 
10.1. Appendix 1: Regulatory, Ethical and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines. 
 
Applicable ICH GCP Guidelines. 
 
Applicable laws and regulations. 
 
The protocol, protocol amendments, ICF, Investigator  Brochure and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. In that case, an amendment will be submitted within the period 
defined by local regulations. 
 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies and procedures established by 
the IRB/IEC. 
 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable) and all other applicable local 
regulations. 
 
The screening of participants does not start before the approval of the IRB/IEC has been 
obtained and the study authorized by the competent authority (or notified to the competent 
authority, depending on the national regulations). 
 
 


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10.1.2. Early Study Termination 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the competent authorities and any Contract Research Organizations 
(CRO[s]) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
 Early Study Termination decided by the Sponsor 
The sponsor may discontinue the study at any time for any of the following reasons: 
 
Emerging adverse events of such a serious nature that continuation of the study becomes 
unacceptable. 
 
Recruitment rate too low to expect completion of the study in its present form within the 
period foreseen for inclusions. 
 
Deviations from ICH GCP and/or regulations. 
 
Decision to stop development of the study treatment. 
If the study is prematurely discontinued, all study data must be returned to Pierre Fabre 
Médicament. In addition, the study site must conduct final disposition of all unused study treatments 
in accordance with study procedures. 
 Early Study Termination decided by the Competent Authorities 
The competent authorities may suspend or prohibit a study if it considers that the conditions of 
authorization are not being met or has doubt about the safety or scientific validity of the study. 
10.1.3. Financial Disclosure 
Investigators and co-investigators will provide the sponsor with sufficient, accurate financial 
information (as requested) to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate competent authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
The funding of research is supported by the sponsor (e.g. investigator fees, study costs, participant 
compensation for travel expenses). 
By signing the protocol, the investigator declares no conflict of interest. 


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10.1.4. Informed Consent Process 
 
Written information about the study must be given to each participant and/or their legally 
authorized representative 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 ICH GCP. 
It must also describe the measures taken to safeguard participant
personal data, according to the European Union (EU) General Data Protection Regulation 
(2016/679). 
 
The investigator or designated study site personnel will explain the nature of the study, 
including the restraints and risks, to the participant or his/her legally authorized representative 
and answer all questions regarding the study. They will be given a sufficient time to consider 
the study before consenting. 
 
Participants must be informed that taking part in the study is voluntary. Participants or their 
legally authorized representative  will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, the IRB/IEC or 
study site and EU General Data Protection Regulation (2016/679). Participants will provide 
written informed consent before any study-specific procedures are carried out. 
 
The medical records must include statements that the applicable written informed consent was 
obtained for screening and the dates obtained. The investigator or his/her designee obtaining 
the informed consent must also sign the ICFs. 
 
The participant must be reconsented to confirm his/her agreement to continue participating if 
the written information is amended during the study due to new information becoming 
available that may be relevant to the participan
 or due 
to amendments to the protocol. 
 
Participants that are re-screened must also be re-consented. 
 
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 participant.  
 
As soon as consent is signed, the participant will be given a personal card to be kept all along 
the study duration and providing the following information: participant's name, sponsor's 
name, study code, (if applicable), date of start and expected date of end of the study (if 
applicable), complete address of the study site with the name and emergency phone number 
of the Investigator.  
 
In the event of pregnancy during the study additional informed consent will be sought 
(required within 72 hours) from the pregnant female (female study participant or partner of a 
male study participant) to allow the investigator to follow the pregnancy to outcome and to 
provide pregnancy information to the sponsor. 


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10.1.5. Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or datasets 
that are transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law and EU General Data Protection Regulation 
(2016/679). The level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the ICF. 
The participant must be informed that his/her medical records may be examined by clinical quality 
assurance auditors or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members and by inspectors from competent authorities. 
10.1.6. Communication with Sites 
Sites will be updated regularly about study status. Relevant information and important decisions 
regarding the study will be communicated to all sites in parallel in writing in a timely manner. 
In case of emergency requiring implementation of urgent measures with regards to participant 
safety, the sites will first be contacted by telephone by the sponsor medical monitor or designee, 
with the information confirmed in writing. A Safety Monitoring Plan will be also written with 
regards to SAE management and communication. 
10.1.7. Dissemination of Clinical Study Data 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the sponsor. The investigator may use this 
information for the purposes of the study only. 
It is understood by the investigator that the sponsor will use information obtained in this clinical 
study in connection with the clinical development program and therefore may disclose it as required 
to other clinical investigators and to regulatory authorities. In order to allow the use of the 
information derived from this clinical study, the investigator understands that he/she has an 
obligation to provide complete test results and all data obtained during this study to the sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only be 
undertaken with written consent from the sponsor. 
Clinical Study Report: 
Data analysis and Clinical Study R
responsibility. 


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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, statistical and PK integrated report. It must be signed by the sponsor  
medically qualified representative signatory and the co-ordinating investigator. 
Study Results Communication:  
Within a maximum period of 12 months after study completion, global results of the research are 
communicated to the investigator.  
The participant can ask the investigator for the results, according to local regulations.  
For clinical studies that are part of a marketing authorization application, the results have to be 
published on the Chinese website www.chinadrugtrials.org.cn within 12 months of completion of 
the clinical study (at a minimum, the clinical study results information shall include synopsis 
content of the Clinical Study Report as specified in ICH E3) as per Center of Drug Evaluation 
regulation Regulations for the registration and information publicity of drug clinical trials  (2020 
NO. 9) and on the European Medicines Agency (EMA) website. In that case, the documents will be 
anonymized to ensure data protection of individuals according to legislation (EMA/90915/2016). 
The final Clinical Study Report, if part of a Common Technical Document dossier, will be 
anonymized as part of data protection regulations for further public communication to the EMA 
gate. 
A lay summary of the study results will be authored in local languages as part of the EU 
regulation 536/2014. 
10.1.8. Data Quality Assurance 
All participant data relating to the study will be recorded in an eCRF unless transmitted to the 
sponsor or designee electronically (e.g. central laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF. 
The sponsor assumes accountability for actions delegated to other individuals (e.g. CROs). 
 Audit 
The investigator must permit study-related monitoring, audits, IRB/IEC review and competent 
authority inspections. 


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pendent of and separate from monitoring or quality control 
activities, is to evaluate study 
operating procedures, ICH GCP and the applicable regulatory requirements. Audits may be 
conducted by th
signee at each relevant 
location where activities dedicated to the clinical study 
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. The practical conditions for the 
or designee. 
 Inspection 
The competent authority may inspect any study 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 
agree to provide direct access to source documents. 
 Data Management 
The sponsor or designee is responsible for the data management of this study, including quality 
checks of the data. Data management will be subcontracted to a CRO under the supervision of the 
s
data manager of the Pierre Fabre Médicament Biometry Department. All clinical data 
related to the study will be collected and saved in a computerized database according to the 
procedures in Appendix 10.1.8.3.1 to Appendix 10.1.8.3.6. Full details are provided in the Data 
Management Plan. 
10.1.8.3.1. Electronic Case Report Form 
An eCRF will be developed for this study. The eCRF (Medidata Rave®) will be used to record all 
participant data required by the protocol. The hosting of this web-based electronic data capture will 
be subcontracted to Medidata Solutions, Inc. 
The eCRF should be compliant with local regulations, compliant with 21CFR Part 11, fully 
validated and include an access control and a traceability system for data corrections (audit trail).  
Before the start of the study, the investigator will complete a Delegation of Significant Study-related 
Duties Form. The signature and initials of all persons in charge of eCRF completion should be 
recorded on this form. Each person involved in eCRF completion, review, correction and/or 
validation will be trained and then will have an individual login and access code to the eCRF. An 
eCRF user guide will be available for investigators/study site personal involved in eCRF completion 
and CRAs.  
Data from study assessments and procedures outlined in Section 8 will be recorded in the source 
documents and the eCRF by the investigator and designated study site personnel. All information 
entered into the eCRF will be recorded from source documents. The investigator is responsible for 
the management and accuracy of the information entered into the eCRF.  


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An eCRF must be completed for each participant enrolled in the study (i.e. ICF signed). 
10.1.8.3.2. Central/External Data  
Results of local laboratory testing will be entered into the eCRF. 
The following electronic data are not reported in the eCRF by the investigator and will be transferred 
to data management for validation and integration into the study database according to the 
specifications given by the data manager. These data will be captured and handled in accordance 
with ICH GCP guidelines: 
 
Centrally analyzed PK samples:  
Actual dates and times of blood collections will be entered in the eCRF. Validated results 
from bioanalysis of encorafenib concentrations in plasma will be transmitted by the 
third-party bioanalytical laboratory to the subcontractor in charge of PK analysis. The 
encorafenib concentrations and final PK parameters will be uploaded in the final database 
from an electronic data file respectively provided by the bioanalytical laboratory and the 
subcontractor. 
10.1.8.3.3. Data Cleaning 
Manual and electronic edit checks used for data cleaning are described in the study Data Validation 
Plan. Upon approval, the edit checks and listings will be programmed. The CRO data management 
will follow the cleaning of the data over the course of the study. The investigator will be asked to 
record the date, time and author of the changes. 
10.1.8.3.4. Data Coding 
Adverse events, concomitant diseases, concomitant therapeutic/diagnostic procedures and 
medical/surgical histories will be coded using MedDRA (latest version in use) and prior and 
concomitant medications will be coded using the World Health Organization (WHO) DRUG 
GLOBAL dictionary (latest version in use), plus the respective user guides and sponsor specific 
guidelines. The coding will be validated by a CRO physician 
 
10.1.8.3.5. Database Lock 
Analysis will be based either on database lock or database snapshot. 
A snapshot consists of a stable view of the data i.e. an extract of the database done at a specific 
timepoint. The specific timepoint will be defined in the TSC Charter as well as the list of critical 
variables. 


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As data will not be locked in the eCRF, entry of additional data and changes in eCRF will be deemed 
possible after the timepoint the snapshot was made. These changes will not be tracked.   
All snapshots will be stored in SAS® format on a sponsor-dedicated secured server. 
The validated database will be locked upon request of the s
data manager following the 
completion of all steps required, i.e. entry, reception and check of all data, resolution of all queries, 
validation of the coding, clinical and safety databases reconciliation and data review/Validation 
Committee meeting performed. 
Subsequent changes to the database will then only be made only by written agreement of the 
sponsor. 
10.1.8.3.6. Data Storage 
Data, as well as their modifications, will be saved and kept available upon request of the sponsor. 
The s
data manager will assume storage of the locked clinical database in SAS® format on 
a secured server. 
Electronic capture of all eCRFs will be sent in portable document format (PDF) format to the 
sponsor and then stored on a dedicated secured server by the sponsor.  
A CD-ROM (or similar storage support) containing the PDF version of all eCRFs of the site 
(including audit trail) will be archived by the study site. 
 Study Monitoring 
Monitoring details describing strategy (e.g. risk-based initiatives in operations and quality such as 
risk management and mitigation strategies and analytical risk-based monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote or on-site monitoring) are provided in Monitoring Plan. 
Representatives of the sponsor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized study site personnel are accurate, complete and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP and all applicable regulatory requirements. 
On-site visits will be carried out by a representative of the sponsor (CRA and/or study manager) 
before study initiation and at regular intervals (as defined in the Monitoring Plan) throughout the 
study. Additional visits and communication by telephone, fax or meeting may be performed if 
necessary. Any site visit performed by representatives of the sponsor will be recorded in the 
investigator's site file.  


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10.1.8.4.1. Site Pre-selection Visit 
Before selecting a study site 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, recruitment, 
environment), technical means and study site personnel to carry out the study. This includes a check 
that the study site has all the necessary equipment to conduct the study (e.g. sample processing and 
storage, study treatment storage, ECGs) and where applicable, appropriate calibration has been 
performed. 
10.1.8.4.2. Initiation Visit 
Before the start of the study at all investigation sites, an initiation visit will be carried out by the 
CRA to check at least that: 
 
The investigator has received: 
 
The protocol, administrative and financial agreement signed by all parties. 
 
The written statement of IRB/IEC approval and the list of its members and their 
functions. 
 
The written statement of competent authority approval. 
 
The original signed and dated curriculum vitae of the investigator(s) has been collected. 
 
Local laboratory normal ranges have been collected.  
 
All study materials are available at 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 will also provide training on the study protocol requirements and study specific 
procedures.  
10.1.8.4.3. Routine Monitoring Visits 
Throughout the study, regular monitoring visits will be carried out by the CRA to check compliance 
with ICH GCP, participant informed consent, strict application of the protocol, conformity of the 
data entered in the eCRF with the source documents and ensure its correct completion, adverse 
event reporting, proper retention, storage and management of the study treatment as well as the 
source and other study-related documents.  
10.1.8.4.4. Close-out Visit 
At the end of the study, a final visit will be carried out by the CRA to: 
 
Verify that the eCRFs are complete and all queries are resolved. 


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Control the accountability of intact and used study treatment units and destroy or return them 
to Pierre Fabre Médicament, or delegated warehouse, for 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 regulatory obligations, study document archiving process and 
duration. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 25 years after study completion unless local regulations or study site 
policies require a longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
10.1.9. Source Documents 
 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the study site. 
 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Current medical 
records must also be available. 
 
Definition of what constitutes source data can be found in the Source Data Agreement. 
In accordance to the requirements of ICH GCP, all sponsor representatives (study manager, CRA 
and auditors) have to be given a 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 keep professional confidentiality with 
regards to the participant data. 
10.1.10. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The sponsor designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. 
A study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed (see Appendix 10.1.8.4.4). 
The investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 


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Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures or ICH GCP guidelines. 
 
Inadequate recruitment of participants by the investigator. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRB/IEC, the competent authorities, and any CROs used in the study of the reason 
for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate participant therapy 
and/or follow-up. 
10.1.11. Publication Policy 
The results of this study, which are the property of the sponsor and considered as confidential, may 
be published or presented at scientific meetings. The investigator must agree to submit all 
manuscripts or abstracts to the sponsor before submission. This allows the sponsor to protect 
proprietary information and to provide comments. Publication or communication relating to results 
of the study, in written or oral form, shall comply with the following provisions: 
 
Any communication or publication project must be provided to the sponsor for review at least 
60 days before 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 he deems appropriate to establish and preserve his proprietary rights. 
The sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a co-ordinating investigator 
will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. In case of a multicenter study, the sponsor shall 
their participation in the design of the protocol as well as their recruitment of eligible and analysable 
participants. 
10.1.12. Insurance Policy 
In accordance with the provisions of the law and ICH GCP, the sponsor has an insurance policy 
intended to guarantee against possible damage resulting from the research. 


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The studies and/or experiments performed on behalf of the sponsor 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 
 insurance.  
 
 


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10.2. Appendix 2: Contraceptive Guidance  
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. The following guidance is 
adapted from the guidelines of the Clinical Trials Facilitation Group [CTFG 2014].  
10.2.1. Definition of a Woman of Childbearing Potential and Fertile Men 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study treatment, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
 
Premenarchal. 
 
Premenopausal female with one of the following: 
 
Documented hysterectomy. 
 
Documented bilateral salpingectomy. 
 
Documented bilateral oophorectomy. 
For participants with permanent infertility due to an alternate medical cause other than the 
above, (e.g. mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the study 
: 
medical records, medical examination or medical history interview. 
 
Postmenopausal female: 
 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
 
High FSH levels in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, confirmation with more 
than one measurement is required.  
 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 


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For the purpose of this guidance, a man is considered fertile after puberty unless permanently sterile 
by bilateral orchidectomy. 
10.2.2. Contraceptive Guidance 
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly are considered as highly effective birth control methods. Such 
methods include: 
 
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. 
 
Intrauterine hormone-releasing system. 
 
Bilateral tubal occlusion. 
 
Vasectomized partner. 
 
Sexual abstinence. 
Acceptable birth control methods that result in a failure rate of more than 1% per year 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. 
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. 


























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10.5. Appendix 5: Snellen Equivalence (Visual Acuity Conversion Chart) 
Taken from Holladay 2004. 
 
 
 
 
 


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10.6. Appendix 6: Study Treatment labelling 
Study treatment unit kit box and blisters will be labelled in compliance with local requirements, 
according to the following rules: 
Study Treatment unit kit box labelling: 
a) Name and address of the sponsor 
b) Pharmaceutical dosage form, route of administration, quantity of dosage units, name/identifier 
and strength/potency 
c) Packaging batch number 
d) Trial reference code allowing identification of the study (Protocol number) 
e) Treatment number  
f) Name of the investigator (will be added at time of shipment) 
g) Directions for use (reference may be made to the IB or other explanatory document intended 
for the trial participant or person administering the product)  
h) 
 
i) Storage conditions  
j) Expiry date as month/year (MM/YYYY) or (YYYY/MM) 
k) 
 
The kit box labelling contains a tear-off flap with the following information: Name of sponsor, 
Protocol number, Packaging batch number and Treatment number. 
 
Study Treatment blisters: 
a) Name of the sponsor 
b) Pharmaceutical dosage form, quantity of dosage units, name/identifier and strength/potency 
c) Packaging batch number 
d) Protocol number 
e) Treatment number  
f) Expiry date as month/year (MM/YYYY) or (YYYY/MM) 
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. 
 
 


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10.7. Appendix 7: Response Evaluation Criteria in Solid Tumors 
Version 1.1 
Taken from Eisenhaur 2009. 
10.7.1. Methods of Measurement 
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 start of study treatment and 
never more than 28 days before the first dose. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the treatment phase and follow-up phase (if 
applicable). 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 examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
documentation by color 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 


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obtained or to determine relapse in studies where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the ULN, however, they must normalize for a participant to be considered in 
complete response (CR). 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 partial response (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. 
10.7.2. 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 
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 
-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion and inflammatory breast disease, lymphangitic involvement of skin or 


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lung, abdominal masses/abdominal organomegaly identified by physical examination that is 
not measurable by reproducible imaging techniques. 
 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. 
 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same participant, 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. 
10.7.3. Tumor Response Evaluation 
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 (see Appendix 10.7.2.1).  


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 Baseline D
T
Non-
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 participants 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.  
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 
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, sagittal 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 
 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 
details to follow). In addition, it is possible to record multiple non-target lesions involving the same 
 


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 Response Criteria 
Tumor Response for Target and Non-target Lesions 
 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for 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 
CR 
criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case 
report forms 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. 
. 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 
hen this occurs, it is important that a value be recorded on the 
eCRF. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If 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 


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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-
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 
 
 
Evaluation of Non-target Lesions 
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). 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. The 
appearance of one or more new lesions is also considered progression. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
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 participant also has measurable disease
-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 
-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 participant has only non-measurable disease. This circumstance arises in some 
phase 3studies 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 participants for unequivocal 


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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 
in lymphangitic disease from localized to widespread or may be described in protocols as 
participant 
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 participant
PR or CR. 
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 participant who has visceral disease at baseline and while on study has a CT or MRI 
brain scan ordered which reveals metastases. The participant
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 fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments 
need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning 
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 
-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 




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The BOR is determined once all the data for the participant are known.  
*For example, a participant 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 timepoint response, the 
 best response depends on the 
subsequent assessments. For example, a participant 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 participant 
lost to follow-up after the first SD assessment would be considered not evaluable.  
Special Notes on Response Assessment 
(<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 participants with CR may not 
 
Participants with a global deterioration of health status requiring discontinuation of study treatment 
discontinuation of study treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study treatment. The objective response status of such 
participants is to be determined by evaluation of target and non-target disease. 
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 CR depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before assigning a status of CR. 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. 
 
 
















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SAP_001.pdf: 
Document Type:  
Final Statistical Analysis Plan 
Document Date:  
06 July 2022 
Study Title:  
Phase 1 Safety Study of Encorafenib in Chinese Patients With 
Advanced Metastatic BRAF V600E Mutant Solid Tumors 
Protocol Reference Number: W00090GE102 
NCT Number:  
NCT05003622