A Phase I/II Study of Binimetinib With Encorafenib in Patients With Non-V600 Activating BRAF Mutant Advanced Malignancies
Phase: PHASE1
Conditions: Advanced BRAF Mutant Cancers
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
MSK PROTOCOL COVER SHEET 
Phase I/II Study of Binimetinib with Encorafenib in Patients with non-V600 Activating 
BRAF Mutant Advanced Malignancies 
Dr. Rona Yaeger/Early Drug Development: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................ 9 
4.1 
Design ............................................................................................................................. 9 
4.2 
Intervention .................................................................................................................... 10 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 10 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 18 
6.1 
Subject Inclusion Criteria ............................................................................................... 18 
6.2 
Subject Exclusion Criteria .............................................................................................. 20 
7.0 
RECRUITMENT PLAN ..................................................................................................... 21 
8.0 
PRETREATMENT EVALUATION .................................................................................... 22 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 23 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................. 34 
11.0 
TOXICITIES/SIDE EFFECTS............................................................................................ 37 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 39 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 40 
14.0 
BIOSTATISTICS ............................................................................................................... 40 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES42 
15.1 
Research Participant Registration .................................................................................. 42 
15.2 
Randomization............................................................................................................... 42 
16.0 
DAT A M ANAGEMENT ISSUES ....................................................................................... 42 
16.1 
Quality Assurance ......................................................................................................... 43 
16.2 
Data and Safety Monitoring............................................................................................ 43 
17.0 
PROTECTION OF HUMAN SUBJECTS ........................................................................... 43 
17.1 
Privacy .......................................................................................................................... 44 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 44 
17.2.1 
 45 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 45 
19.0 
REFERENCES ................................................................................................................. 46 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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1275 York Avenue 
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20.0 
APPENDICES ................................................................................................................... 47 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a phase I/II study of higher dose MEK inhibitor treatment together with RAF inhibitor 
treatment to target advanced cancers with non-V600 BRAF activating alterations. The goal 
of this trial is to test the safety and efficacy of an innovative combination aimed to more 
profoundly inhibit ERK signaling in tumors. In this regimen, the RAF inhibitor encorafenib 
serves to increase ERK pathway inhibition by (1) contributing a modest inhibition of mutant 
BRAF and by (2) opposing the toxicity of the MEK inhibitor binimetinib in normal tissues to 
allow treatment with a higher dose of binimetinib. 
The trial includes an evaluation of the safety of the planned combination in a limited 
escalation followed by an efficacy evaluation of the dosing schedule that is deemed safe in a 
Simon’s 2-stage design (Figure 1). 
Figure 1. Study Schema 
 
 
 
 
 
Abbreviations: QD, once daily; BID, twice daily; d, days; DLT, dose-limiting toxicity 
Please note that the expansion phase includes initial patients treated at the level 2 dosing of 
encorafenib plus binimetinib on an intermittent schedule of 3 weeks on/ 1 week off and 
patients treated with amended, continuous dosing of study drugs. Drug dosing schedule was 
amended during the trial because several patients reported good tolerance of continuous 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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dosing during the first three weeks and symptomatic improvement but recrudescence of 
symptoms during the week off drug. 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 Primary Objectives 
Phase I: To evaluate the tolerability and safety profile of encorafenib 450 mg oral once daily 
(QD) with binimetinib 60 mg oral twice daily (BID) in patients with advanced malignancies 
harboring non-V600 activating BRAF alterations by evaluating dose-limiting toxicities (DLTs). 
Two dosing schedules will be evaluated. Initially patients were treated with intermittent 
dosing with treatment for 21 days on and 7 days off. Based on several patients reporting 
good tolerance of the continuous dosing and increased symptoms, including pain and 
fatigue, during the one week off and the absence of any dose limiting ophthalmologic toxicity, 
the dosing schedule was changed during the trial to a continuous schedule of encorafenib 
and binimetinib. 
Phase II: To obtain preliminary evidence of efficacy measured by objective response rate . 
2.2 Secondary Objectives 
Phase II: 
To determine progression free survival (PFS) for patients with advanced cancer with non- 
V600 activating BRAF mutations treated with encorafenib and binimetinib. 
To determine overall survival (OS) for patients with advanced cancer with non-V600 
activating BRAF mutations treated with encorafenib and binimetinib. 
To determine safety, tolerability, and adverse event profile of this regimen. 
2.3 Exploratory Objectives 
Phase II: 
2.31 To evaluate degree of ERK pathway inhibition with encorafenib and binimetinib in tumor 
tissue in day 7 on-treatment biopsies and correlate with objective response rate. 
Pharmacodynamic (PD) markers will consist of (1) RNA expression of the ERK 
transcriptional output genes DUSP6, SPRY2, and ETV1 and (2) immunohistochemical 
analysis of phosphorylated ERK expression. 
2.32 To evaluate changes in mutant BRAF circulating free DNA (cfDNA) detection with 
treatment and correlate with the objective response rate. 
2.33 To evaluate the full tumor genomic profile with a multi-gene next-generation sequencing 
(NGS) assay and correlate with the objective response rate. 
3.0 
BACKGROUND AND RATIONALE 
The MAPK (mitogen-activated protein kinase) signaling pathway is the most commonly 
activated oncogenic pathway in human cancer. Selective BRAF inhibitors have 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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revolutionized the treatment of BRAF V600 mutant tumors, including melanoma, lung cancer, 
and anaplastic thyroid cancers1-3. But the success of selective RAF inhibitors has been the 
exception, as the efficacy of MEK and ERK inhibitors has been limited by toxicity and inability 
to adequately inhibit the target4, 5. Non-V600 BRAF activating mutants, a heterogeneous 
group of genomic alterations, depend on ERK activation but are unaddressed by existing 
therapeutic strategies. Signaling in these tumors (Figure 2) consists of activated mutant 
BRAF dimers that turn on the MAPK cascade by activating MEK, which activates ERK, which 
then acts on cytosolic and nuclear targets to regulate cellular proliferation, survival, and 
differentiation. 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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Figure 2. Diagram for signaling in physiologic conditions versus in cells with activated 
non-V600 BRAF mutants 
 
 
Non-V600 BRAF mutations and fusions are common in human cancer. In both published 
series and our own institutional sequencing effort, which has now profiled more than 20,000 
cancers using the multi-gene exon-capture NGS platform MSK-IMPACT [Memorial Sloan 
Kettering-Integrated Mutation Profiling of Actionable Cancer Targets], among BRAF 
alterations, they account for approximately 75% of alterations in lung cancers, 10-20% in 
melanomas, and 30% in colorectal cancers6. In total, we have prospectively identified 
approximately 200 patients with non-V600 activating BRAF mutation or fusion, RAS wild-type 
tumors, through MSK-IMPACT analysis. 
Pharmacodynamic analysis of tumor samples from patients with BRAF V600E melanoma 
treated in the phase 1 study of vemurfenib indicate that profound ERK inhibition is required 
for response to MAPK pathway inhibitors.7 Inadequate continuous dosing of MAPK inhibitors 
leads to insufficient pathway inhibition for responses. A threshold of ERK inhibition is 
required for effect on tumor growth. This explains the limited activity seen with MEK or ERK 
inhibitors alone, where dose escalation is limited by a narrow therapeutic index.4,9,15 To more 
effectively inhibit ERK signaling in these tumors, we plan to study a combination strategy that 
applies RAF inhibitors as a tool to oppose the toxicity of MEK inhibitors in normal tissues to 
titrate up the MEK inhibitor so as to better block ERK signaling in the tumor. Current RAF 
inhibitors (vemurafenib, dabrafenib, encorafenib) selectively inhibit BRAF V600 mutants, 
which signal as monomers in steady state. In RAF wild-type tissues, these drugs cause 
“paradoxical activation” and increase phosphorylated ERK levels by transactivation of one 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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protomer in the RAF dimer pair7. These drugs, however, do not cause paradoxical ERK 
activation in non-V600 activating BRAF mutants8. In these tumors, the mutant BRAF dimers 
are constitutively activated and thus not activated further by RAF inhibitors. Instead binding 
of RAF inhibitor to one site in the dimer pair, leads to inhibition of that protomer and a modest 
inhibition of ERK. Consistent with this understanding, treatment with the RAF inhibitor 
vemurafenib does not accelerate the growth of cell lines and patient derived xenografts 
(PDXs) with non-V600 BRAF alterations that we have generated from patients with activating 
non-V600 BRAF alterations (Figure 3). 
Figure 3. Effect of RAF inhibitor treatment on the growth of patient-derived xenografts 
(PDXs) with non-V600 activating BRAF mutants. Five mice are included in each arm. 
 
 
In the recent phase I trial of the ERK inhibitor BVD-523, treatment was associated with 
sporadic durable objective responses in patients with BRAF non-V600 mutant cancers, 
however, PD and pharmacokinetic (PK) data suggest that treatment exposure at maximally 
tolerated doses (MTDs) may be too low to effectively abrogate ERK signaling in many 
patients9. This narrow therapeutic window is likely the result of the lack of selectivity of ERK 
inhibition for mutant (cancerous) versus wild-type (healthy) tissues. These observations 
provide a strong rationale to leverage the paradoxical activation induced by first-generation 
BRAF inhibitors to oppose the inhibition of ERK in normal tissues with the goal of improving 
drug tolerance and therapeutic index. Therefore, we hypothesize that adding the RAF 
inhibitor encorafenib to the MEK inhibitor binimetinib will reduce toxicity related to inhibition of 
MAPK signaling in healthy tissue while having no deleterious effect on inhibiting MAPK 
signaling in non-V600 BRAF mutant or fusion tumors, allowing dose escalation to achieve a 
higher dose and better efficacy. 
Preclinical data demonstrate the safety and efficacy of this approach. Treatment was tested 
in a cell line and xenograft generated from a patient’s colon tumor with a BRAF K601E 
activating mutation. Exposure of the BRAF K601E colon cancer cells in vitro to vemurafenib 
does not change levels of phospho-ERK; exposure to the selective ERK inhibitor 
(Sch772984) leads to suppression of ERK signaling, with decreased levels of the activated 
downstream protein phospho-RSK; and combination treatment leads to continued inhibition 
of ERK signaling (Figure 4A). The PDX was expanded in mice for four treatment groups: 
vehicle control, vemurafenib, ERK inhibitor at the MTD in mice of 50 mg/kg daily, or the 
combination of these two drugs at these doses or with a high dose of the ERK inhibitor of 75 
mg/kg daily, previously found to be too toxic in mice (Figure 4B). All treatments were well- 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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tolerated with no change in weight in the treated mice. Treatment with vemurafenib alone 
resulted in slowed but continued tumor growth, the ERK inhibitor prevented tumor growth, 
and combined ERK and RAF inhibition led to tumor regression. Notably, the combination of 
vemurafenib with the higher dose ERK inhibitor resulted in profound tumor regression in all 
mice treated. These data suggest that with concurrent RAF and ERK inhibitor treatment, we 
may be able to deliver an ERK inhibitor dose in vivo that sufficiently inhibits ERK signaling for 
tumor regression and improved clinical efficacy. 
Figure 4. Effect of RAF and ERK inhibition on signaling and growth of BRAF K601E 
colon cancer patient derived cells. 
 
Abbreviations: vem, vemurafenib; hr, hour; IP, intraperitoneal 
Thus, the goal of this study is to increase ERK inhibition in non-V600 BRAF mutant tumors 
by using a RAF inhibitor to (1) oppose the effect of the MEK inhibitor in normal tissues (to 
allow uptitration of the MEK inhibitor) and (2) modestly inhibit ERK signaling and thus have 
an additive effect on pathway inhibition. In this study, for dose level 2, binimetinib will be 
administered in an intermittent schedule. Previous publications and our experiences in the 
clinic suggest that pulsatile dosing may maintain the MEK inhibitor dose to inhibit ERK 
sufficiently in the tumor and allow normal tissues to recover from toxic effects.10,11 As 
profound ERK inhibition is required for tumor regression7, an intermittent schedule may allow 
sufficient ERK inhibition in tumor tissue with time for recovery of normal tissues, rather than 
continuous inadequate target inhibition with a continuous lower-dose administration of MEK 
inhibitors.10 The clinical experience with binimetinib is summarized in section 5.1. Because 
ocular toxicity, which is not clearly modulated by RAF inhibitors, limited continuous dosing at 
higher dose levels, dose level 2 consists of an intermitternt schedule of binimetinib. 
Encorafenib is also given on an intermittent schedule, so that dosing of encorafenib and 
binimetinib coincide. As the potential inhibitory effect of encorafenib likely varies by BRAF 
alterations, giving encorafenib on the same schedule as binimetinib will prevent unopposed 
RAF inhibitor therapy in these tumors and further limit the potential for ERK activation from 
encorafenib treatment. After four patients were treated at dose level 2, the dosing schedule 
was modified to continuous treatment of both binimetinib and encorafenib based on the 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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absence of dose limiting ophthalmologic symptoms and increased patient symptoms during 
the week off treatment. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This phase I/II study consists of a Phase I part followed by an efficacy analysis (Phase II) of 
the dosing schedule deemed safe in patients with advanced cancer with activating non-V600 
BRAF mutant tumors. All patients must have had prior sequencing of their tumor with 
identification of activating non-V600 BRAF mutants. Patients will be initially enrolled to the 
approved dose of encorafenib 450 mg oral QD and binimetinib 45 mg PO BID, dose level 1. 
If we confirm this dose level is safely tolerated in the study population, we will then escalate 
treatment to dose level 2 with the novel dosing regimen of encorafenib 450 mg oral QD 21 
days on/ 7 days off and binimetinib 60 mg oral BID 21 days on/7 days off. 
Specifically three patients will be enrolled to dose level 1, If none of these patients 
experience a DLT in the first 28 days, then these three patients will start cycle 2 at dose level 
2. If one patient experiences a DLT at dose level 1, then dose level 1 will be expanded with 
three additional patients. If there is 0-1 DLT in these six patients in the first 28 days, then we 
will enroll subsequent patients at dose level 2. If two of the three first patients enrolled to 
dose level 1 experience a DLT or if 2 of the 6 patients treated at dose level 1 experience a 
DLT, then we will not escalate treatment to dose level 2. 
Three patients will be enrolled to dose level 2 and if 0 or 1 patient experiences a DLT in the 
first 28 days, then we will expand this dose level to include an additional three patients. If 
one or fewer patients experience DLTs in the first 28 day treatment cycle, then we will 
declare that this dose can be safely given in this population and phase II portion will proceed 
with this regimen. If 2 or more patients experience DLTs in the first 28 days, then the phase 
II portion will enroll patients at the dose 1 level. 
The phase II part has a 2-stage design for efficacy assessment. Seventeen patients will be 
included in the first stage and if 3 or more responses are observed, then the second stage 
will proceed to enroll an additional 15 patients. As patients in the phase I part of the start will 
start at the lower dose level 1, they will not be included in the stage one efficacy cohort. At 
the end of the study, if 8 or more responses are observed the regimen would be considered 
promising for further study. 
Safety will be evaluated using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), Version 5, based on recorded adverse events (AEs), physical 
examinations, and clinical laboratory assessments. Patients will be evaluated for response 
by computer tomography (CT) or MRI every 8 weeks. Response will be determined using 
RECIST (version 1.1 criteria). Clinical endpoints to be evaluated will include overall 
response rate (ORR), (PFS, OS, and AEs. 
All patients will be asked to undergo an optional pre-treatment and day 7 optional on- 
treatment biopsy for planned PD and correlative studies. Additional research studies include 
blood collection every 4 weeks to monitor circulating tumor DNA (ctDNA) fraction. 

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We estimate that we will accrue about 1-2 patients per month and 16 patients a year. The 
trial recruitement will take 2-3 years. 
4.2 
Intervention 
Treatment will consist of encorafenib 450 mg oral QD and binimetinib 60 mg oral BID . The 
dosing schedule was modified from intermittent dosing of 21 days on/ 7 days off after several 
patients reported good tolerance of continuous dosing during the first three weeks and 
symptomatic improvement but recrudescence of symptoms during the week off drug. A 
regimen of encorafenib 450 mg oral QD together with binimetinib 45 mg oral BID has already 
been found safe and is now approved by the United States Food and Drug Administration 
(FDA) as a treatment for BRAF V600 mutated melanoma. This trial aims to raise the MEK 
inhibitor dose by giving treatment together with a RAF inhibitor. Unlike in the treatment of 
BRAF V600 mutant tumors, the primary active drug in this trial of non-V600 activating BRAF 
mutants is the MEK inhibitor binimetinib. Patients will receive treatment until objective 
progression of disease or unacceptable toxicity. Patients may continue treatment beyond 
progression if they are receiving clinical benefit from treatment. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Patients will be treated with the combination of binimetinib and encorafenib. 
5.1 Overview of Binimetinib 
Binimetinib (also known as MEK162 or ARRY-438162) is a potent and selective allosteric, 
adenosine triphosphate (ATP)-uncompetitive inhibitor of MEK1/2. Binimetinib is currently 
being investigated as a single agent and in combination with a variety of other agents, 
including inhibitors of, BRAF, and cyclin-dependent kinase 4/6, Programmed cell death- 
1/programmed death-ligand 1(PD-1/PD-L1), and cytotoxic chemotherapy in patients with 
selected advanced or metastatic solid tumors, including melanoma, ovarian, and colorectal 
cancers. 
Binimetinib is manufactured by Array BioPharma and is supplied as film-coated tablets in a 
dosage strength of 15 mg. The film-coated tablets consist of binimetinib drug substance; 
colloidal silicon dioxide/silica colloidal anhydrous; croscarmellose sodium; lactose 
monohydrate; magnesium stearate; microcrystalline cellulose/cellulose, microcrystalline; and 
a commercial film coating. The tablet is ovaloid biconvex (capsule shaped), yellow to dark 
yellow in color. Binimetinib film-coated tablets should be stored at room temperature, not 
above 25°C and protected from light. Tablets are packaged in square, high-density 
polyethylene bottles that are induction sealed and closed with a polyporplyene, child- 
resistant screw cap. Binimetinib bottles will be labelled, at a minimum, with the lot number, 
contents (number of tablets), dosage strength, and storage conditions. Binimetinib should be 
dispensed to patients in the bottles provided by Array BioPharma and should not be 
repackaged at the site or pharmacy. 
Binimetinib Nonclinical Safety Pharmacology and Toxicology 
Acute, subchronic, chronic and reproductive toxicity, genotoxicity and phototoxicity studies 
were completed in rats and monkeys to support the chronic administration of binimetinib to 
adult patients. There was no evidence of a genotoxic potential in vitro or in vivo. The adverse 

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effects of MEK inhibitors in humans are similar to those observed in rats and monkeys, with 
the exception of ocular findings and soft tissue mineralization (rats only). These adverse 
effects include gastrointestinal (GI) intolerance and diarrhea, rash (skin findings in rats only), 
retinal events (only seen in humans) and retinal vein occlusion (RVO) (rarely seen in 
humans). In vitro and in vivo phototoxicity studies conducted in mice indicate that binimetinib 
has a low risk of weak phototoxic potential at therapeutic doses. There has been no evidence 
of phototoxicity or photosensitivity in human beings treated with binimetinib for cancer or for 
rheumatoid arthritis. In the 6-month study in rats, there was a slight trend for increased 
kidney mineralization by mid-study onward at ≥ 1 mg/kg/day in females and ≥ 3 mg/kg/day in 
males. Treatment-related skin effects and kidney mineralization defined the lowest- 
observable-adverse-effect level (LOAEL) of 1 or 3 mg/kg (females and males, respectively). 
The MTD was defined by morbidity and mortality associated with dose-related increases in 
soft tissue mineralization and bone marrow atrophy-necrosis that occurred at doses of 
≥ 100 mg/kg in the 28-day study. There were no observations on gross pathological 
examination; mineralization was only detected microscopically within the small arteries and 
arterioles in the affected organs. 
Daily oral administration of binimetinib to juvenile Sprague-Dawley rats on postnatal Day 10 
through 40 was not tolerated at doses ≥ 10 mg/kg/day. The MTD in juvenile rats was 3 
mg/kg, and the no-observable-adverse-effect level (NOAEL) was 1 mg/kg/day. The 
exposure-based safety index attained at the MTD and NOAEL were very similar to those 
attained in adult rats. 
Embryo-fetal development studies showed evidence of teratogenicity in rabbits (ventricular 
septal defects and pulmonary trunk alterations) and reduced fetal body weight in rats and 
rabbits. Given these observed effects, binimetinib should not be used in pregnant women. 
Clinical Experience with Binimetinib 
As of 20 January 2018, a total of 2816 healthy subjects and patients have received 
binimetinib as monotherapy or in combination with other agents, including 229 healthy 
subjects, 17 subjects with hepatic dysfunction, 6 subjects with renal dysfunction, 164 patients 
with rheumatoid arthiritis, and 2400 patients with advanced cancer.Detailed information 
regarding clinical studies of binimetinib is presented in the Investigator’s Brochure. 
Clinical Pharmacokinetics 
The PKs of binimetinib are characterized by moderate to high variability, accumulation of 
approximately 1.5-fold and steady-state concentrations reached within 15 days, with a 
median terminal half-life (t1/2) of approximately 9 hours. Food-effect clinical studies have 
indicated that the influence of food on the PK of binimetinib is mild and not clinically relevant. 
A drug-interaction study with the proton-pump inhibitor rabeprazole indicates binimetinib can 
be administered in the presence of stomach pH-altering agents. Binimetinib is primarily 
metabolized by glucuronidation pathways (mainly via uridine diphosphate glucuronosyl 
transferase [UGT]1A1, 1A3 and 1A9); however, the impact of UGT1A1 inhibitors or inducers 
has not been clinically assessed. In vitro studies also demonstrated that binimetinib is a P- 
glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, but the effects of 
inhibitors of these substrates on the PK of binimetinib in vivo are unknown. 

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In vitro, binimetinib has the potential to inhibit CYP2B6; however, in vivo inhibition of 
CYP2B6 is anticipated to not be clinically significant. Binimetinib has also induced CYP3A in 
vitro, but this induction was not confirmed in a clinical drug-drug interaction (DDI) study. 
In dedicated clinical studies to evaluate hepatic and renal impairment, an increase in 
binimetinib exposure was observed in subjects with moderate and severe hepatic impairment 
and in subjects with severe renal impairment. 
Clinical data supporting binimetinib dose 
The trial ARRAY-162-111, a phase I dose-escalation study in patients with advanced solid 
tumors followed by expansion cohorts in patients with advanced or metastatic biliary cancer 
or KRAS- or BRAF-mutant metastatic colorectal cancer, evaluated the safety and tolerability 
of increasing doses of binimetinib. In this study, 19 patients with advanced solid tumors 
received binimetinib in the dose escalation phase and 15 were evaluable for dose-escalation 
decisions. Dose levels and information about DLTs are listed in Table 1. 
Table 1: Dose-Limiting Toxicities in the Phase I study of Binimetinib, ARRAY-162-111 
Dose Level 
(no. of pts with DLTs/no. of evaluable 
patients in cohort) 
Dose-limiting Toxicity 
30 mg BID (0/3) 
No DLT observed 
45 mg BID (0/3) 
No DLT observed 
60 mg BID (0/6) 
No DLT observed 
80 mg BID (2/3) 
Grade 3 dermatitis acneiform 
Grade 3 chorioretinopathy 
Abbreviations: BID, twice daily; DLT, dose-limiting toxicity; mg, milligram(s); no., 
number; pts., patients 
 
Based on the escalation, the MTD of binimetinib was declared to be 60 mg oral BID dosed 
continously. Following determination of the MTD in the dose-escalation phase, 74 patients 
were enrolled in the expansion phase, including 28 patients in the biliary cancer cohort, 31 
patients in KRAS-mutant colorectal cancer cohort and 15 patients in the BRAF-mutant 
colorectal cancer cohort. After initiation of the expansion phase, a higher-than-expected 
frequency of ocular AEs affected the ability to treat patients continuously at the MTD, thus a 
reduced dose of 45 mg BID was implemented for the remainder of newly enrolled patients in 
the expansion phase cohorts. The ocular toxicity that limited dosing occurred after the first 
28-days on treatment. Based on this toxicity profile, the current study initially tested an 
intermittent schedule of binimetinib at the higher dose of 60 mg to allow recovery from ocular 
effects during the fourth week of each cycle while binimetinib is held. However, the dosing 
schedule was changed to continuous treatement after several patients reported good 
tolerance of continuous dosing during the first three weeks and symptomatic improvement 
but recrudescence of symptoms during the week off drug. 
Clinical Safety 
Available clinical data indicate a predictable safety profile consistent with that reported for 
other allosteric MEK1/2 inhibitors. The most frequent treatment-emergent AEs by Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term in patients receiving binimetinib 

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include rash, dermatitis acneiform, nausea, vomiting, diarrhea, peripheral edema, fatigue, 
and creatine kinase (CK) elevation. Other clinically relevant toxicities are retinal events, 
increased blood pressure, decreased ejection fraction, and noninfectious 
pneumonitis/interstitial lung disease, all of which should be monitored closely with 
appropriate diagnostic evaluations. These observed AEs are generally reversible and 
manageable by appropriate supportive medical care and/or dose modifications. 
Pooled AE data from 2 single-agent clinical studies of binimetinib (CMEK162X2201 45 mg 
BID continuous dosing [N = 158] and CMEK162A2301 [N = 269]) are presented in Table in 
order to provide a detailed assessment of the safety of binimetinib in patients with metastatic 
melanoma (including NRAS-mutant and BRAF-mutant) naïve to prior MEK inhibitors who 
received single-agent binimetinib at the recommended single-agent dose of 45 mg BID 
(“binimetinib 45 mg population”; N = 427). 
Table 2: Adverse Events Regardless of Causality Reported in ≥ 10.0% of Patients by 
Preferred Term (Pooled Data from Studies of Single-agent Binimetinib 45 mg BID in 
Patients with Melanoma) 
 
45 mg BID 
N = 427 
Preferred term 
All Grades 
n (%) 
Grade 3/4 
n (%) 
Any AE 
427 (100) 
285 (66.7) 
Blood CK increased 
191 (44.7) 
89 (20.8) 
Diarrhea 
182 (42.6) 
8 (1.8) 
Dermatitis acneiform 
177 (41.5) 
11 (2.6) 
Edema peripheral 
174 (40.7 
3 (0.7) 
Rash 
146 (34.2) 
13 (3.0) 
Nausea 
128 (30.0) 
5 (1.2) 
Fatigue 
114 (26.7) 
15 (3.5) 
Vomiting 
84 (19.7) 
8 (1.9) 
Constipation 
65 (15.2) 
2 (0.5) 
Hypertension 
64 (15.0) 
34 (8.0) 
Asthenia 
60 (14.1) 
8 (1.9) 
AST increased 
59 (13.8) 
9 (2.1) 
Pruritus 
58 (13.6) 
4 (0.9) 
Decreased appetite 
55 (12.9) 
2 (0.5) 
Pyrexia 
53 (12.4) 
0 
Dry skin 
45 (10.5) 
0 
Dyspnoea 
44 (10.3) 
6 (1.4) 
Ejection fraction decreased 
44 (10.3) 
15 (3.5) 
Retinal detachment 
44 (10.3) 
0 
Abbreviations: AE, adverse event; AST, aspartate aminotransferase; CK, creatinine 
kinase; mg, milligram(s); n or N, number 
Data cutoff date CMEK162X2201 06 Nov 2015; CMEK162A2301 18 Mar 2016 
Further information can be found in the binimetinib Investigator’s Brochure. 

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IRB Number: 18-547 A(13) 
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5.2 Overview of Encorafenib 
Encorafenib (also known as LGX818) is a highly selective ATP-competitive small-molecule 
RAF kinase inhibitor, which suppresses the RAS/RAF/MEK/ERK pathway in tumor cells 
expressing BRAF V600E. Similar to other selective small-molecule RAF kinase inhibitors, 
encorafenib inhibits CRAF (half maximal inhibitory concentration [IC50] = 0.30 nM), BRAF 
(IC50 = 0.47 nM), as well as BRAF V600E (IC50 = 0.35 nM) in cell-free assays. However, this 
class of inhibitor does not inhibit RAS/RAF/MEK/ERK signaling in cells expressing BRAFwt. In 
the human melanoma cell line A375, which expresses BRAF V600E, encorafenib potently 
inhibits phospho-MEK (half maximal effective concentration [EC50] = 2 nM), phospho-ERK 
(EC50 = 3 nM), and proliferation (EC50 = 4 nM), resulting in cell cycle arrest and apoptosis. 
Given the high degree of selectivity against other kinases, encorafenib has no 
antiproliferative activity in tumor cell lines that express wild-type BRAF and is highly selective 
for BRAF mutations in cell lines containing V600E/D/K, with the greatest sensitivity observed 
in BRAF V600E melanoma and colorectal cancer (CRC) lineages. 
Encorafenib has been evaluated in multiple human tumor xenograft models grown in nude 
mice. Similar to the in vitro profile, the antitumor activity was restricted to tumors expressing 
BRAF V600E, while there was no antitumor effect in xenograft models expressing wild-type 
BRAF or CRAF. Nonclinical in vivo data suggest that encorafenib has a wide therapeutic 
index and that regression of BRAF V600E human melanoma tumor xenografts is associated 
with a strong and sustained inhibition of the RAF/MEK/ERK pathway. 
Encorafenib is manufactured by Array BioPharma and is supplied as hard gelatin capsules in 
a dosage strength of 75 mg. Encorafenib capsules consist of encorafenib drug substance 
and the following excipients: copovidone, poloxamer 188, succinic acid, microcrystalline 
cellulose, colloid silicon dioxide, crospovidone, and magnesium stearate of vegetable origin. 
The capsule shell is commercially available and contains gelatin and titanium dioxide as well 
as iron oxide red, yellow or black depending on the particular strength. Encorafenib capsules 
should be stored at room temperature, not above 25°C and protected from moisture. 
Capsules are packaged in square, high-density polyethylene bottles that are induction sealed 
and closed with a polyporplyene, child-resistant screw cap. Encorafenib bottles will be 
labelled, at a minimum, with the lot number, contents (number of tablets), dosage strength, 
and storage conditions. Encorafenib should be dispensed to patients in the bottles provided 
by Array BioPharma and should not be repackaged at the site or pharmacy. 
Nonclinical Safety Pharmacology and Toxicology 
In 1- to 4-week toxicology studies in rats and cynomolgus monkeys, encorafenib was well 
tolerated at systemic exposures which result in tumor regression in mouse xenograft studies. 
Findings included hyperplasia and hyperkeratosis in the skin (plantar surface of feet) and 
non-glandular stomach in the rat. An absence of the later stages of spermatid maturation in 
male rats was also observed. Significant mortality/morbidity was observed mostly in female 
rats at the highest dose of 400 mg/kg/day, a dose well above the MTD in rats. 
In the 13-week toxicology study in monkeys, the only test article-related finding was blister- 
like lesions identified over the macular region of the retina, observed in 2 monkeys treated at 
a dose of 60 mg/kg/day. Exposure (maximum area under the curve [AUC] from time 0 to 24 
hours achieved in the study at any time point) in the 2 affected monkeys was 5- to 8-fold and 

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4- to 6-fold that achieved at the 300 and 450 mg QD dose levels, respectively, in humans at 
steady state in Clinical Study CLGX818X2101. One of the animals with this finding showed 
evidence of recovery. Histopathology examination of the affected eyes suggested that the 
findings were similar to the retinopathy associated with MEK inhibitors. 
Nonclinical safety pharmacology results did not indicate a risk for QT prolongation based on: 
the findings of the Good Laboratory Practice (GLP) human ether-a-go-go-related gene 
assay, on electrocardiogram (ECG) evaluations in the GLP monkey cardiovascular telemetry 
study, and the GLP 4- and 13-week toxicology studies in monkeys. Also, there were no 
clinical signs in the 4-or 13-week GLP-compliant studies in the rat and monkey that would 
indicate an effect on the central nervous system or respiratory system. 
The GLP Ames and chromosomal aberration assays as well as a rat micronucleus study 
indicated that encorafenib is not genotoxic. 
Encorafenib showed a potential for phototoxicity in a screen 3T3 neutral red uptake in vitro 
assay. In patients treated with encorafenib, as a single-agent, in the range of doses of 300 to 
450 mg QD, the incidence of photosensitivity was 2.9% and 5.6% in the melanoma and 
colorectal cohorts, respectively of Study CLGX818X2101 and 3.6% in the single-agent 
encorafenib arm of Clinical Study CMEK162B2301. 
Pharmacokinetics and Metabolism 
Encorafenib is a relatively potent reversible inhibitor of CYP2B6, CYP2C9, and CYP3A4/5 
and a weak (IC50 ≥ 20 µM) reversible inhibitor of CYP1A2, CYP2C8, CYP2C19, and 
CYP2D6. Encorafenib induced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary 
hepatocytes and was found to potently induce CYP3A4 mRNA in vitro with EC50 values of 
10.2 μM. Furthermore, encorafenib inhibits UGT1A1 and is a substrate of P-glycoprotein (P- 
gp) with high apparent passive permeability. It is also a weak inhibitor of breast cancer 
resistance protein (BCRP) (IC50=10 to 25 µM). Finally, encorafenib inhibits the renal organic 
anion transporter (OAT) OAT1, OAT3, and OCT2 and the hepatic transporters, organic 
anion-transporting polypeptide (OATP)1B1 and OATP1B3. 
Encorafenib is primarily metabolized by CYP3A4 (> 50%) and to lesser degrees by CYP2D6 
and CYP2C19. 
In a Phase I study in patients with locally advanced or metastatic BRAF V600E melanoma 
(Study CLGX818X2101, dose escalation phase), encorafenib was rapidly absorbed and 
plasma concentrations reached their peak on average at 2 hours postdose. Elimination was 
also rapid, with a terminal half-life (t1/2) of 2 to 4 hours. Apparent systemic clearance (CL/F) 
and apparent volume of distribution (Vz/F) were moderate. After multiple QD administrations, 
steady-state appeared to have been reached by Day 15, with lower exposures than on Day 
1, consistent with what would be expected with auto-induction of CYP3A4. At doses tested in 
the study (50, 100, 150, 200, 300, 450, 550 or 700 mg QD and 75, 100, and 150 mg BID), 
the average concentrations of encorafenib were above the predicted efficacious 
concentrations based on nonclinical xenograft models (0.135 μg/mL). 
Additional details are provided in the encorafenib Investigator’s Brochure. 

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Clinical Safety 
The experience of encorafenib as a single agent includes 97 healthy subjects and 7 subjects 
with hepatic impairment in 5 studies (CLGX818A2101, ARRAY-162-105, ARRAY-818-101, 
ARRAY-818-102 and ARRAY-818-105) and 410 patients with cancer in 4 studies 
(CLGX818X2101, CLGX818X2102 [single-agent encorafenib part], CMEK162B2301 
[single-agent encorafenib arm] and CLGX818AUS03). In single-agent studies, the most 
frequently reported AEs were dermatological, gastrointestinal, musculoskeletal, fatigue, 
asthenia and headache. 
The largest encorafenib single-agent treatment population to date is from the Phase III Study 
CMEK162B2301 (also known as COLUMBUS)12. In the encorafenib arm, the most common 
AEs (> 25.0% of patients) were alopecia, palmar-plantar erythrodysesthesia syndrome, 
arthralgia, nausea, hyperkeratosis, dry skin, myalgia, vomiting, headache, palmoplantar 
keratoderma and fatigue (Table 3). Grade 3 or 4 AEs were reported for 127 patients (66.1%) 
in the encorafenib arm, the most common of which were palmar-plantar erythrodysesthesia 
syndrome (13.5%), myalgia (9.9%) and arthralgia (9.4%). 
The most frequently observed AEs of special interest in patients in studies with encorafenib 
as a single-agent or in a dual combination are currently mostly characterized as acute renal 
failure events (including blood creatinine increased), dermatologic events (rash and skin 
events other than rash events), facial paresis, fatigue/asthenia events, GI events, headache 
events, heart rate increased (including atrial fibrillation and tachycardia), liver events, 
musculoskeletal disorders/pain events, ocular events (retinal events, vascular eye events 
and other eye events) and secondary neoplasms. 
5.3 Overview of the Combination of Encorafenib and Binimetinib 
 
Nonclinical Pharmacokinetics and Metabolism 
Although the in vitro data suggest a potential for encorafenib to affect the PK of binimetinib- 
based inhibition of UGT1A1, no significant drug-drug interaction was observed up to the 
highest doses tested in Clinical Study CMEK162X2110 (800 mg QD encorafenib in 
combination with 45 mg BID of binimetinib). 
Clinical Experience 
In phase 1 studies, patients have received binimetinib at 45 mg PO BID, together with 
escalating doses of encorafenib (50, 100, 200, 400, 450, 600, or 800 mg QD). The 
recommended Phase 2 dose for encorafenib in combination with binimetinib was based on a 
Phase 1b/2 combination study (CMEK162X2110). In this trial, patients received binimetinib 
at 45 mg PO BID, together with escalating doses of encorafenib at the following dose levels: 
50 mg (N=6), 100 mg (N=5), 200 mg (N=4), 400 mg (N=5), 450 mg (N=13), 600 mg (N=8), or 
800 mg (N=6). Two separate dose combinations were recommended for the Phase 2 
expansion in BRAF V600 mutated melanoma patients as was allowed per protocol with a 
total of 64 patients receiving 600 mg QD encorafenib as the starting dose and 15 patients 
receiving 450 mg QD as the encorafenib starting dose. Three patients receiving encorafenib 
600 mg QD + binimetinib 45 mg BID experienced significant increases in creatinine levels. 
Although there were potential confounding factors in two of the patients that may have 

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contributed to the creatinine abnormalities, in the absence of strong evidence of better 
efficacy at the higher dose and observed responses at encorafenib doses as low as 50 mg 
QD, all patients were switched to or started on the lower recommended dose of encorafenib 
450 mg QD + binimetinib 45 mg BID for the remainder of the Phase 2. Thirty-five patients 
had their encorafenib dose switched from 600 mg to 450 mg with this protocol change and 
an additional 8 patients had their doses reduced from 600 mg to 450 mg due to adverse 
effects. 
The combination of encorafenib and binimetinib is now approved by the FDA for BRAF V600 
mutated melanoma based on the COLUMBUS study (CMEK162B2301). 
In this study, Combo 450 (encorafenib 450 mg QD plus binimetinib 45 mg BID) demonstrated 
a favorable efficacy and safety profile in patients with BRAF V600-mutant melanoma10. 
Combo 450 significantly improved PFS versus vemurafenib alone, with the median PFS 
being 14.9 months for Combo 450 versus 7.3 months for vemurafenib (hazard ratio [HR] 
[95% confidence interval (CI)], 0.54 [0.41, 0.71]; P<0.001). In addition, the median PFS of 
14.9 months in the Combo 450 arm was improved compared with the encorafenib 
monotherapy arm in which the median PFS was 9.6 months (HR [95% CI], 0.75 [0.56, 1.00]; 
P=0.051). The local assessment of PFS in the Combo 450 and encorafenib monotherapy 
arms was consistent with the result by blinded independent assessment (HR [95% CI], 0.68 
[0.52, 0.90]; P=0.006). Encorafenib 300 mg QD alone improved PFS vs vemurafenib (HR 
[95% CI], 0.68 [0.52, 0.90]; P=0.007). Objective response rate was greater in the Combo 450 
arm (63.0% [55.8, 69.9]) compared with 50.5% (43.3, 57.8) in the encorafenib arm and 
40.3% (33.3, 47.6) in the vemurafenib arm. The median duration of response was also 
greater in the Combo 450 arm (16.6 months [12.7, 20.4]) compared with 14.9 months (11.0, 
not evaluable) in the encorafenib arm and 12.5 months (6.9, 16.9) in the vemurafenib arm. 
Maintenance of quality of life was improved with Combo 450 compared with vemurafenib 
alone and encorafenib alone as measured by the Functional Assessment of Cancer Therapy 
Melanoma scale and the European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (also known as EORTC QLQ-C30) Global Health 
Status score. 
The tolerability profile of Combo 450 was favorable compared with monotherapy with 
vemurafenib or encorafenib alone, resulting in higher relative dose intensity for Combo 450. 
The most common AEs are summarized in Table 3. 
Table 3: 
Adverse Events by Preferred Term (Study CMEK162B2301 Part 1) 
 
Preferred Term 
Combo 450 
n=192 
Median Duration of 
Exposure: 51 weeks 
Encorafenib 300 mg 
n=192 
Median Duration of 
Exposure: 31 weeks 
Vemurafenib 
n=186 
Median Duration of 
Exposure: 27 weeks 
Any 
Grade 
% 
Grade 3/4 
% 
Any 
Grade 
% 
Grade 3/4 
% 
Any 
Grade 
% 
Grade 3/4 
% 

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Total 
98 
58 
>99 
66 
>99 
63 
Nausea 
41 
2 
39 
4 
34 
2 
Diarrhea 
36 
3 
14 
2 
34 
2 
Vomiting 
30 
2 
27 
5 
15 
1 
Fatigue 
29 
2 
25 
1 
31 
2 
Arthralgia 
26 
1 
44 
9 
45 
6 
Blood CK increased 
23 
7 
1 
0 
2 
0 
Headache 
22 
2 
27 
3 
19 
1 
Pyrexia 
18 
4 
15 
1 
28 
0 
GGT increased 
15 
9 
11 
5 
11 
3 
Alopecia 
14 
0 
56 
0 
37 
0 
Hyperkeratosis 
14 
1 
38 
4 
29 
0 
Dry skin 
14 
0 
30 
0 
23 
0 
Myalgia 
14 
0 
28 
10 
18 
1 
Rash 
14 
1 
21 
2 
29 
3 
Hypertension 
11 
6 
6 
3 
11 
3 
Palmoplantar keratoderma 
9 
0 
26 
2 
16 
1 
Palmar-plantar 
erythrodysesthesia 
syndrome 
7 
0 
51 
14 
14 
1 
Abbreviations: AE, adverse event; BID, twice daily; CK, creatinine kinase; Combo 450, encorafenib 
450 mg QD + binimetinib 45 mg BID; GGT, gamma-glutamyltransferase; QD, once daily. 
Note: All-cause AEs (>25% in any treatment group) or Grade 3/4 AEs (>5% in any treatment group) 
are shown. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
Patients participating in this study will have advanced cancer with non-V600 BRAF activating 
alterations. 
6.1 
Subject Inclusion Criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patient has signed the Informed Consent (ICF) prior to any screening 
procedures being performed and is able to comply with protocol requirements 
2. Age ≥ 18 years at the time of informed consent 
3. Metastatic or advanced-stage malignant tumors confirmed histologically for 
whom no standard therapy is considered to be appropriate by the investigator 
4. Patients must have at least one other lesion that is measurable by 
RECIST criteria. 

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5. Patient’s tumor must harbor an activating BRAF mutation (listed in Table 4 
or approved by the study Principal Investigator) or a fusion involving the 
kinase domain of BRAF 
 
Table 4. Mechanistically validated activating non-V600 BRAF mutants 
P367L/S 
G464V/E 
G469A/V/R 
L485W 
N486_A489delinsK 
N486_P490del 
E586K 
L597Q/V/S 
T599TT/TS 
T599I/K 
V600_K601delinsE 
K601E/N/T 
K601_S602delinsNT 
BRAF kinase duplication 
Fusions involving BRAF kinase domain 
 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status < 2 
7. Adequate bone marrow, organ function and laboratory parameters: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 
• 
Hemoglobin (Hgb) ≥ 8 g/dL with or without transfusions, 
• 
Platelets (PLT) ≥ 75 x 109/L without transfusions, 
• 
AST and/or ALT ≤ 2.5 × upper limit of normal (ULN); patient with liver metastases 
≤ 5 ×ULN, 
• 
Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL 
(Note: Patients who have a total bilirubin level > 1.5 x ULN will be allowed if their 
indirect bilirubin level is ≤ 1.5 x ULN) 
• 
Serum Creatinine ≤ 1.5 x ULN, or calculated creatinine clearance (determined as 
per Cockcroft-Gault) ≥ 50 mL/min at screening 
8. Adequate cardiac function: 
• 
left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated 
acquisition (MUGA) scan or echocardiogram, 
• 
QTc interval ≤ 480 ms (preferably the mean from triplicate ECGs) ; 
9. Able to take oral medications; 
10. Patient is deemed by the Investigator to have the initiative and means to be compliant 
with the protocol (treatment and follow-up) 
11. Female patients are either postmenopausal for at least 1 year, are surgically sterile 
for at least 6 weeks, or must agree to take appropriate precautions to avoid 
pregnancy from screening through 30 days after the last dose of study 
drug/treatmentif of childbearing potential (Note: Permitted contraception methods 
listed in Section 9.3 should be communicated to the patients and their understanding 

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confirmed. For females of childbearing potential, the pregnancy test result must be 
negative at screening.) 
12. Males must agree to take appropriate precautions to avoid fathering a child from 
screening through 90 days following the end of therapy. (Note: Permitted 
contraception methods listed in Section 9.3 should be communicated to the patients 
and their understanding confirmed.) 
6.2 
Subject Exclusion Criteria 
Patients meeting any of the following criteria are excluded from the study: 
1. Any symptomatic brain metastasis (Note: Patients previously treated or untreated for 
this condition who are asymptomatic in the absence of corticosteroid and anti- 
epileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with 
imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) 
demonstrating no current evidence of progressive brain metastases at screening.) 
2. History or current evidence of retinal vein occlusion (RVO) or current risk factors to 
RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes); history of retinal degenerative disease 
3. Leptomeningeal disease 
4. Previous or concurrent malignancy within 2 years of study entry, with the following 
exceptions: adequately treated basal or squamous cell skin cancer, superficial 
bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, 
early stage breast cancer, or other noninvasive or indolent malignancy 
5. Impaired cardiovascular function or clinically significant cardiovascular diseases, 
including any of the following: 
• 
History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 
months prior to screening, 
• 
Symptomatic chronic heart failure (i.e. Grade 2 or higher), history or current 
evidence of clinically significant cardiac arrhythmia and/or conduction 
abnormality < 6 months prior to screening except atrial fibrillation and 
paroxysmal supraventricular tachycardia; 
6. Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 
150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite current therapY. 
7. Known positive serology for HIV (Human Immunodeficiency Virus), active hepatitis B, 
and/or active hepatitis C infection 
8. Impaired GI function or disease that may significantly alter the absorption of 
encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, 
malabsorption syndrome, small bowel resection with decreased intestinal absorption) 
9. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first 
dose of study treatment. Examples include transient ischemic attacks, 
cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) 
deep vein thrombosis or pulmonary emboli. 
Note: Patients with either deep vein thrombosis or pulmonary emboli that does 
not result in hemodynamic instability are allowed to enroll as long as they are 
on a stable dose of anticoagulants for at least 4 weeks. 

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Note: Patients with thromboembolic events related to indwelling catheters or 
other procedures may be enrolled.Concurrent neuromuscular disorder that is 
associated with the potential of elevated CK (e.g., inflammatory myopathies, 
muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy). 
10. Any other condition that would, in the Investigator’s judgement, contraindicate the 
patient’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to 
swallow medications, social/psychological issues, etc. 
11. Patients who have undergone surgery ≤ 3 weeks prior to starting study drug or who 
have not yet recovered from side effects of such procedure 
12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test 
13. Medical, psychiatric, cognitive, or other conditions that may compromise the patient’s 
ability to understand the patient information, give informed consent, comply with the 
study protocol or complete the study 
14. Prior treatment with any RAF, MEK, or ERK inhibitors (such as vemurafenib, 
dabrafenib, encorafenib; trametinib, cobimetinib, binimetinib, selumetinib; or BVD- 
523, respectively) 
 
7.0 
RECRUITMENT PLAN 
As part of the Memorial Sloan Kettering-Integrated Mutation Profiling for Actionable Cancer 
Targets (MSK-IMPACT) initiative which started in 2014, every patient at MSK with advanced 
cancer has the opportunity for tumor NGS performed at our institution, generating routine 
information on BRAF alterations. Furthermore, samples without identified genomic drivers 
can be selected by pathology for further testing with the Archer FusionPlex assay, a NGS 
RNA-based methodology for fusion and alternative isoform testing. In this assay, cDNA 
libraries are made from RNA and subjected to anchored multiple PCRs (polymerase chain 
reactions) with primers for a set of kinase genes with potential activating structural variants. 
This allows for breakpoint identification and transcript sequencing, whether the partner gene 
is known or novel. The assay is thus designed to identify fusions, including fusions involving 
the BRAF gene. As of mid-year 2018, about 27,500 patient tumor samples have been 
analyzed by the MSK clinical molecular pathology laboratory with NGS. To facilitate accrual, 
a notification system will be set up where the investigators will be notified of all new cases of 
patients with appropriate BRAF alterations as potential candidates for this clinical trial. In 
total, we have prospectively identified at MSK approximately 200 patients with non-V600 
activating BRAF mutation or fusion, RAS wild-type tumors, through MSK-IMPACT analysis. 
Therefore the maximal accrual of 38 patients should be highly feasible. We anticipate that 
accrual will take 2-3 years depending on the sample size in this 2-stage design. Every effort 
will be made to maximize recruitment of patients, including women and minorities. Patients 
will undergo formal informed consent process through designated consenting professionals 
on the study. Patients will be given time to understand and make informed decisions. A copy 
of the signed and dated consent form will be given to each patient to take home. Patients 
will not be paid for this study. The study drugs, encorafeninb and binimetinib, will be 

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delivered to patients without charge as Array BioPharma has agreed to provide treatment for 
the study. 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center 
(MSKCC). If the investigator is a member of the treatment team, s/he will screen their 
patient’s medical records for suitable research study participants and discuss the study and 
their potential for enrolling in the research study. Potential subjects contacted by their 
treating physician will be referred to the investigator/research staff of the study. The principal 
investigator may also screen the medical records of patients with whom they do not have a 
treatment relationship for the limited purpose of identifying patients who would be eligible to 
enroll in the study and to record appropriate contact information in order to approach these 
patients regarding the possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process.The investigator/research staff may also review portions 
of their medical records at MSKCC in order tofurther assess eligibility. They will use the 
information provided by the patient and/or medical record toconfirm that the patient is eligible 
and to contact the patient regarding study enrollment. If the patient turns out to be ineligible 
for the research study, the research staff will destroy all information collected on the patient 
during the initial conversation and medical records review, except for any information that 
must be maintained for screening log purposes. 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team. The recruitment process outlined presents no more than minimal risk to the privacy of 
the patients who are screened and minimal PHI will be maintained as part of a screening log. 
For these reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) 
reviewing medical records to identify potential research subjects and obtain information 
relevant to the enrollment process; (2) conversing with patients regarding possible 
enrollment; (3) handling of PHI contained within those records and provided by the potential 
subjects; and (4) maintaining information in a screening log of patients approached. 
8.0 
PRETREATMENT EVALUATION 
Within 28 days prior to first dose of treatment: 
• 
Obtain informed consent 
• 
Record BRAF alteration 
• 
Verify all inclusion/exclusion criteria 
• 
Record demographic information (age) 
• 
Record current and past medical history 
• 
Document prior anticancer treatments 
• 
Record all medications/treatments that were administered/conducted within 28 days prior 
to Day 1 
Baseline evaluations 

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• 
Complete physical examination including measured height and body weight 
• 
Obtain full ophthalmic examination 
• 
Obtain full dermatologic examination (may be done by treating physician or 
dermatologist) 
• 
Assess vital signs (blood pressure, pluse, and temperature) 
• 
Assess ECOG Performance Status 
• 
Perform cardiac imaging by either ECHO or MUGA 
• 
Triplicate ECG 
• 
Collection of blood samples for the following: 
o Hematology (CBC with differential) 
o Chemistry (comprehensive chemistry panel, CK) 
o Magnesium 
o Serum pregnancy (females of childbearing potential only) 
• Complete tumor assessments with appropriate radiological scans to document all 
suspected sites of disease, measurable or non-measurable, as defined by RECIST 
9.0 
TREATMENT/INTERVENTION PLAN 
 
All patients will receive encorafenib and binimetinib. Encorafenib and binimetinib can be 
taken with or without food and can be taken together. Patients can self-administer doses at 
home on clinic days, as no PK studies are planned. Patients will receive a pill diary to record 
when they take the investigational agents. 
Patients will continue to receive treatment until disease progression by RECIST Version 1.1, 
unacceptable toxicity, or until one of the criteria in Section 13.0 is met. Clinical assessments 
to evaluate tolerability will be performed on day 15 of cycle 1 and then day 1 of each 
subsequent cycle. Observed toxicities will be graded as per NCI-CTCAE Version 5. 
Standard safety evaluations will include laboratory analysis of blood samples, ECG, ECHO 
or MUGA, and ophthalmologic and dermatologic assessments. Standard tumor evaluations 
will consist of imaging studies with CT chest/abdomen/pelvis with contrast or, in patients 
unable to tolerate contrast, with non-contrast CT chest and MRI abdomen/pelvis every 8 
weeks. Research evaluations include blood collection for cfDNA analysis every 4 weeks and 
mandatory tumor biopsy at baseline and on day 7 of treatment. 
9.1 Dose levels 
Patients will be monitored for AEs on an ongoing basis. The severity of AEs will be evaluated 
using the NCI-CTCAE, v.5. If a patient develops a toxicity, the dose may be modified as 
outlined in Table 5. The phase I portion of the study consists of two dose levels: level 1, 
binimetinib 45 mg BID plus encorafenib 450 mg QD, and level 2, binimetinib 60 mg BID 21 
days on/ 7 days off plus encorafenib 450 mg QD 21 days on/ 7 days off. Patients 
participating in the phase I portion of the study will not have their drug dose reduced in the 
DLT period of the first 28 days unless they experience a DLT. 
Table 5. Dose Levels for Dose Modifications 
For dose level 1 (encorafenib 450 mg QD continuous + binimetinib 45 mg BID 
continuous): 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
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Encorafenib (mg QD) 
Binimetinib (mg BID) 
Starting dose 
450 
45 
Dose level -1 
300 
30 
Dose level -2 
225 
15 
Dose level -3 
150 
Discontinue 
treatment 
Abbreviations: QD, once daily; BID, twice daily. 
For dose level 2 (encorafenib 450 mg QD 21 days on/ 7 days off + binimetinib 60 mg 
BID 21 days on/ 7 days off): 
 
Encorafenib (mg QD) 
Binimetinib (mg BID) 
Starting dose 
450 
60 
Dose level -1 
300 
45 
Dose level -2 
225 
30 
Dose level -3 
150 
15 
Abbreviations: QD, once daily; BID, twice daily. 
9.2 Dose modifications 
All dose modifications should be based on the worst preceding toxicity. Table 6 includes 
criteria for interruption and reduction of encorafenib and/or binimetinib. In general, doses 
should not be reduced or interrupted for Grade 1 AEs unless the AE is a specific ocular AE 
referred to in Table 6. Treatment to control symptoms should be provided as appropriate, if 
applicable. 
When the AE that resulted in a dose reduction improves to and remains stable at the 
patient’s Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose 
level at the discretion of the Investigator, provided there are no other concomitant toxicities 
that would prevent drug re-escalation. There is no limit to the number of times patients can 
have their dose reduced or re-escalated (in increments specified in Table 5); however: 
• 
No dose re-escalation of encorafenib is allowed after a dose reduction due to prolonged 
QTcF ≥ 501 msec 
• 
No dose re-escalation of binimetinib is allowed after a dose reduction due to LVEF 
dysfunction or prolonged QTcF ≥ 501 msec 
• 
No dose re-escalation of binimetinib or encorafenib is allowed after a dose reduction due 
to retinal toxicity ≥ Grade 2. 
• 
Patients may not remain on study if they have toxicity requiring discontinuation of one of 
the two drugs. 
Table 6. Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
Eye Disorders - Retinal Events (including serous detachment of the retina), Posterior 
Uveitisc 
Any visual acuity impairment at screening should be documented and should be 
considered as baseline. 
Grade 1 
Maintain dose levels of encorafenib and binimetinib and repeat ophthalmic 
monitoring including visual acuity assessment and OCT within 10 days 
• 
If patient remains asymptomatic (Grade 1), maintain dose level of 
encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol 
• 
If patient becomes symptomatic (blurred vision, photophobia, etc.) or 
visual acuity assessment shows Grade 2, follow Grade 2 dose guidelines 
below 
Grade 2 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days 
• 
If resolved to baseline or Grade ≤ 1, resume treatment at current dose 
level of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol 
• 
If not resolved to baseline or Grade ≤ 1, resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib and continue the schedule of 
visual assessments established per protocol 
• 
If posterior uveitis lasts > 6 weeks, permanently discontinue binimetinib 
and encorafenib. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days: 
• 
If posterior uveitis resolves to Baseline or Grade ≤ 1 in < 6 weeks, 
resume treatment at 1 reduced dose levelb of encorafenib and binimetinib 
and continue the schedule of visual assessments established per 
protocol 
• 
If posterior uveitis does not resolve to Baseline or Grade ≤ 1 in < 6 
weeks, permanently discontinue binimetinib and encorafenib 
• 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced dose 
levelb of encorafenib and binimetinib and continue the schedule of visual 
assessments established per protocol 
• 
If not resolved to baseline or Grade ≤ 2, continue the interruption and 
repeat the ophthalmic assessment in 10 days. 
o If resolved to baseline or Grade ≤ 2, resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib and continue the schedule 
of visual assessments established per protocol 
o If remains Grade 3, permanently discontinue encorafenib and 
binimetinib 
Grade 4 
Permanently discontinue encorafenib and binimetinib and immediate follow-up 
with ophthalmic monitoringc 
Eye Disorder - RVOc 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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New York, New York 10065 
 
 
 
Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
RVO of any 
grade 
Permanently discontinue encorafenib and binimetinib and immediately follow-up 
with ophthalmic monitoringc 
Other Eye Disorders (i.e., Non-retinal Events) 
Grade 1 – 2 
Maintain dose level of encorafenib and binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or resolution 
Grade 3 
Interrupt dosing of encorafenib and binimetinib and refer patient to 
ophthalmologist within 7 daysc: 
• 
If resolved to Grade ≤ 1 in ≤ 21 days, resume treatment at 1 reduced 
dose levelb of encorafenib and binimetinib 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue 
encorafenib and binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolutionc 
Grade 4 
Permanently discontinue encorafenib and binimetinib and immediate follow-up 
with ophthalmic monitoring until stabilization or resolutionc 
Liver-related Adverse Events 
Grade 1 
AST or ALT 
> ULN to 3 × 
ULN 
Maintain dose level of encorafenib and binimetinib 
Grade 2 
AST or ALT 
> 3 to 5.0 × 
ULN or 
3 × baseline 
valued AND 
blood bilirubing 
≤ 2.0 × ULN 
Maintain dose level of encorafenib and interrupt dosing of binimetinib until 
resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver metastasis), then: 
• 
If resolved in ≤ 14 days, maintain dose level of encorafenib and 
binimetinib 
• 
If not resolved in ≤ 14 days, interrupt dose of encorafenib (in addition to 
prior binimetinib) until resolved to Grade ≤ 1 (or Grade ≤ 2 in case of liver 
metastasis), then resume treatment at current dose level of encorafenib 
and 1 reduced dose levelb of binimetinib 
If additional occurrence: 
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 
(or Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 
reduced dose levelb of encorafenib and binimetinib 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
Investigator’s discretion, with encorafenib being resumed alone for one week 
before resuming binimetinib treatment 
AST or ALT 
> 3.0 to 5.0 × 
ULN AND 
blood bilirubing 
> 2.0 × ULN 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1, then: 
• 
If resolved in ≤ 7 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib 
• 
If not resolved in ≤ 7 days, permanently discontinue encorafenib and 
binimetinib 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
investigator’s discretion, with encorafenib being resumed alone for one week 
before resuming binimetinib treatment 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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New York, New York 10065 
 
 
 
Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
Grade 3 
AST or ALT 
> 5.0 to 8.0 × 
ULN) 
AND 
blood bilirubing 
≤ 2.0 × ULN 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 (or 
Grade ≤ 2 in case of liver metastasis), then: 
• 
If resolved in ≤ 14 days, resume treatment at current dose level of 
encorafenib and binimetinib 
• 
If not resolved in ≤ 14 days, resume treatment at 1 reduced dose levelb of 
encorafenib and binimetinib 
Treatment with encorafenib and binimetinib may be resumed sequentially at the 
investigator’s discretion, with encorafenib being resumed alone for one week 
before resuming binimetinib treatment 
If additional occurrence: 
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1 
(or Grade ≤ 2 in case of liver metastasis), then resume treatment at 1 
reduced dose levelb of encorafenib and binimetinib 
AST or ALT 
>8 × ULN 
AND blood 
bilirubing 
≤ 2.0 × ULN 
Permanently discontinue encorafenib and binimetinib 
AST or ALT 
> 5.0 × ULN 
AND 
blood bilirubing 
> 2.0 × ULN 
Permanently discontinue encorafenib and binimetinib 
Grade 4 
AST or ALT 
> 20.0 × ULN 
Permanently discontinue encorafenib and binimetinib 
Cardiac Disorders - Left Ventricular Systolic Dysfunctiona (Dose Adjustment for 
Binimetinib ONLY) 
Asymptomatic 
absolute 
decrease of > 
10% in LVEF 
compared to 
baseline and 
the LVEF is 
below the 
institution’s 
LLN (e.g., a 
decrease of 
60% to 48% is 
an absolute 
decrease of 
12%) 
Interrupt dosing of binimetinib and repeat evaluation of LVEF within 2 weeks 
• 
If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and absolute 
decrease ≤ 10% compared to baseline) ≤ 21 days, resume treatment at 1 
reduced dose levelb of binimetinib after approval of the Sponsor Principal 
Investigator. Monitor LVEF 2 weeks after resuming binimetinib, every 4 
weeks for 12 weeks and subsequently as per protocolIf the LVEF does 
not recover in ≤ 21 days, permanently discontinue binimetinib. Closely 
monitor LVEF until resolution or for up to 16 weeks 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
Grade 3 – 4 
Permanently discontinue binimetinib. Closely monitor LVEF until resolution or up 
to 16 weeks 
Note: Copies of ECHO and/or MUGA scans could be requested for patients to be 
available to the Sponsor Investigator for patients with absolute decrease 
of >10% in LVEF compared to baseline and LVEF < 50% or LLN 
CK Elevation 
Grade 1-2 
Maintain dose of encorafenib and binimetinib. Ensure patient is adequately 
hydrated. Closely monitor CK and serum creatinine 
• 
If total CK ≥ 3 × ULN, measure CK isoenzymes and myoglobin in blood or 
urine 
Grade 3 
> 5.0 - 10.0 x 
ULN without 
renal 
impairment 
(i.e., serum 
creatinine < 
1.5 × ULN or 
1.5 × baseline) 
If asymptomatic, maintain dosing of encorafenib and binimetinib. Ensure patient 
is adequately hydrated. Monitor and measure isoenzymes and myoglobin in 
blood or urine and serum creatinine 
If symptomatic (muscle pain/spasms/muscle weakness), maintain dosing of 
encorafenib and interrupt dosing of binimetinib until resolved to NCI-CTCAE 
Grade ≤ 1 and monitor closely, then: 
• 
If resolved in ≤ 21 days, maintain dose of encorafenib and resume 
treatment at 1 reduced dose levelb of binimetinib 
• 
If not resolved in ≤ 21 days, maintain dose of encorafenib and 
permanently discontinue binimetinib 
Grade 4 
without 
renal 
impairment 
(i.e., serum 
creatinine < 
1.5 × ULN or 
1.5 × baseline) 
If asymptomatic, maintain dose of encorafenib and interrupt dosing of 
binimetinib. Ensure patient is adequately hydrated. Monitor and measure 
isoenzymes and myoglobin in blood or urine and serum creatinine 
• 
If resolved in ≤ 21 days, maintain dose of encorafenib and resume 
treatment at 1 reduced dose levelb of binimetinib 
• 
If not resolved in ≤ 21 days, maintain dose of encorafenib and 
permanently discontinue binimetinib 
If symptomatic (muscle pain/spasms/muscle weakness), maintain dose of 
encorafenib and permanently discontinue binimetinib 
Grade 3 or 4 
with 
renal 
impairment 
(i.e., serum 
creatinine ≥ 
1.5 × ULN or 
1.5 × baseline) 
Interrupt dosing of encorafenib and binimetinib until resolved to NCI-CTCAE 
Grade < 1 or baseline level. Ensure patient is adequately hydrated. Monitor 
closely and measure isoenzymes and myoglobin in blood or urine and serum 
creatinine, then: 
• 
If resolved in ≤ 21 days, consider resuming treatment at 1 reduced dose 
levelb of encorafenib and binimetinib 
• 
If not resolved in ≤ 21 days, permanently discontinue encorafenib and 
binimetinib 
2nd occurrence: 
• 
Permanently discontinue encorafenib and binimetinib 
Cardiac Investigation – Prolongation of the QT interval QTcF value 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
QTcF > 500 
ms during 
treatment and 
change from 
pre-treatment 
value remains 
≤ 60 ms 
1st occurrence: 
• 
Temporarily interrupt dosing of encorafenib until QTcF < 500 ms. Then 
resume treatment at 1 reduced dose levelb of encorafenib 
2nd occurrence: 
• 
Temporarily interrupt dosing of encorafenib treatment until QTcF < 500 
ms. Then resume treatment at 1 reduced dose levelb of encorafenib 
3rd occurrence: 
• 
Permanently discontinue encorafenib and patient will have to come off 
study 
QTcF increase 
during 
treatment is 
both > 500 ms 
and > 60 ms 
change from 
pre-treatment 
values 
Permanently discontinue encorafenib and binimetinib 
Rash 
Grade 1 
Maintain dose level of encorafenib and binimetinib 
Initiate Initial Rash Treatment Regimen if it was not already started and rash 
should be closely monitored 
Grade 2 
1st occurrence: 
• 
Maintain dose level of encorafenib and binimetinib 
• 
Initiate Initial Rash Treatment Regimen if it was not already started and 
rash should be closely monitored 
• 
Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt 
dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib and binimetinib. 
For dermatitis acneiform, treatment with encorafenib may be maintained 
if, in the judgment of the investigator, the rash is considered to be 
unrelated to encorafenib. If treatment with encorafenib was maintained 
and no improvement within 8 days, interrupt dosing of encorafenib 
2nd occurrence: 
• 
Reassess within ≤ 14 days. If rash worsens or does not improve, interrupt 
dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib and 1 reduced 
dose levelb of binimetinib. For dermatitis acneiform rash, treatment with 
encorafenib may be maintained if, in the judgment of the investigator, the 
rash is considered to be unrelated to encorafenib. If treatment with 
encorafenib was maintained and no improvement within 8 days, interrupt 
dosing of encorafenib 
Grade 3 
1st occurrence: 

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Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
• 
Interrupt dosing of encorafenib and binimetinib until resolved to 
Grade ≤ 1. Reassess weekly. Then resume treatment at current dose 
level of encorafenib and binimetinib. 
• 
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation. 
2nd occurrence: 
• 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 
1. Then resume treatment at 1 reduced dose levelb of encorafenib and 
binimetinib. 
Resume treatment with encorafenib at the same dose level if, in the 
judgment of the Investigator, the rash is considered to be unrelated to 
encorafenib 
• 
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation 
Grade 4 
Permanently discontinue encorafenib and binimetinibf 
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndromee (Dose 
Adjustment for Encorafenib ONLY) 
Grade 1 
Maintain dose of encorafenib. Promptly institute supportive measures, such as 
topical therapy, for symptomatic relief. Give instruction on life-style modifications. 
Grade 2 
1st occurrence: 
• 
Maintain dose of encorafenib and HFSR should be closely monitored. 
Promptly institute supportive measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-style modifications. 
• 
If no improvement ≤ 14 days, interrupt dosing of encorafenib until 
resolved to Grade ≤ 1. Resume treatment with encorafenib at current 
dose level. Continue supportive measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-style modifications. 
Additional occurrence: 
• 
Treatment with encorafenib may be maintained or interrupted based upon 
the Investigator’s discretion. Continue supportive measures, such as 
topical therapy, for symptomatic relief. Give instruction on life-style 
modifications. 
• 
If interrupted dosing of encorafenib per investigator’s judgment, interrupt 
until resolved to Grade ≤ 1. Resume treatment with encorafenib at the 
same dose level or 1 reduced dose levelb at the Investigator’s discretion. 
Grade 3 
1st or additional occurrence: 
• 
Interrupt dosing of encorafenib until resolved to Grade ≤ 1. Promptly 
initiate supportive measures, such as topical therapy, for symptomatic 
relief. Give instruction on life-style modifications. Reassess the patient 
weekly. 
Then resume treatment at 1reduced dose levelb of encorafenib 
• 
Consider referral to dermatologist and manage HFSR per dermatologist’s 
recommendation 

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IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
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Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
> 3nd occurrence: 
• 
Interrupt dosing of encorafenib until resolved to Grade ≤ 1, decision to 
resume treatment with encorafenib at 1 reduced dose levelb or 
permanently discontinue encorafenib at the Investigator’s discretion. 
SCC, KA and any Other Suspicious Skin Lesion (Dose Adjustment for Encorafenib ONLY) 
Grade ≤ 3 
Maintain dose of encorafenib (dose interruptions or modifications are not 
required). Treatment of SCC, KA, and any other suspicious skin lesion (eg. new 
primary melanoma) should occur based upon institutional practice. 
Diarrhea 
Uncomplicated 
Grade 1-2 
Maintain dose of encorafenib. Consider temporary interruption of binimetinib until 
resolved to Grade ≤ 1. Then resume treatment at current dose level of 
binimetinib 
Complicated 
Grade 1-2 
Consider temporary interruption of encorafenib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib 
Interrupt dosing of binimetinib until resolved to Grade ≤ 1. Then resume 
treatment at 1 reduced dose levelb of binimetinib 
Grade 3-4 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at current dose level of encorafenib if, in the judgment of the 
Investigator, the toxicity is considered to be unrelated to encorafenib, or at 1 
reduced dose levelb. Resume treatment at 1 reduced dose level of binimetinib 
Nausea/Vomiting 
Grade 1-2 
Maintain dose level of encorafenib and binimetinib. Promptly institute antiemetic 
measure. 
Grade 3 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤ 1. Then 
resume treatment at 1 reduced dose levelb of encorafenib. Resume treatment 
with binimetinib at the current dose if, in the judgment of the Investigator, the 
toxicity is considered to be unrelated to binimetinib, or at 1 reduced dose levelb. 
Note: Interrupt dosing of encorafenib and binimetinib for ≥ Grade 3 vomiting or 
Grade 3 nausea only if the vomiting or nausea cannot be controlled with optimal 
antiemetics (as per local practice) 
Grade 4 
Permanently discontinue encorafenib and binimetinib.f 
Interstitial Lung Disease/Pneumonitis 
Grade 1 
Maintain dose level of encorafenib and binimetinib. 
Grade 2 
Maintain dose of encorafenib. Withhold binimetinib for up to 3 weeks. 
If improved to Grade 0 or 1, resume treatment at 1 reduced dose level of 
binimetinib. 
If not resolved within 3 weeks, permanently discontinue binimetinib. 
Grade 3-4 
Permanently discontinue binimetinib. 
All Other Adverse Events (Suspected to be Related to Encorafenib and/or Binimetinib) 
Grade 1-2 
If the event is a persistent Grade 2 AE not responsive to a specific therapy, 
consider interruption or reduction of encorafenib and binimetinib, as applicable 

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Worst toxicity 
NCI-CTCAE, 
v.5 Grade 
(unless 
otherwise 
specifieda) 
Recommended Dose Modifications for Encorafenib-related and/or 
Binimetinib-related Adverse Events 
Grade 3 
Interrupt dosing of encorafenib and binimetinib until resolved to Grade ≤1 or to 
pretreatment/baseline level. If the event resolves ≤ 21 days, then study drug may 
be resumed at 1 reduced dose levelb based upon the Investigator’s discretion. 
Grade 4 
Permanently discontinue encorafenib and binimetinib.f 
a Not according to NCI-CTCAE 
b Dose reduction below 150 mg QD for encorafenib, and below 15 mg BID for binimetinib is not 
allowed. 
c Ophthalmic monitoring mandated for retinal events, posterior uveitis, RVO: further evaluation 
with specialized retinal imaging (e.g. ocular coherence tomography, fluorescein angiography). Any 
diagnosis of retinal events must be supported by presence or absence of symptoms, visual acuity 
assessment and findings in OCT. 
d For patients enrolled with liver metastases and baseline LFT elevations. 
e Disorder characterized by redness, marked discomfort, swelling, and tingling in the palms 
of the hands or the soles of the feet. 
f A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to 
Grade ≤ 1 within 28 days of discontinuing drug and, if in the opinion of the Sponsor Investigator, 
the event is not life-threatening and the patient can be managed and monitored for recurrence of 
AE. Any patients requiring a treatment interruption of duration > 28 days must discontinue study 
drug permanently. 
g Refers to total bilirubin. 
 
9.3 Permitted contraception methods 
Female patients are either postmenopausal for at least 1 year, are surgically sterile for at 
least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from 
Screening through 30 days after the last dose of study drug/treatment. In addition, female 
participants must refrain from donating ova during the study through 30 days after the end of 
systemic exposure of study drug/treatment. 
Male participants should use a condom during treatment and through 90 days after the end 
of systemic exposure to study drug/treatment. If the male participant has a partner that is of 
child-bearing potential, the partner should also use contraception through 90 days after the 
end of systemic exposure to study drug/treatment. In addition, male participants must refrain 
from donating sperm during the study through 90 days after the end of systemic exposure of 
study drug/treatment. Males who have had a vasectomy qualify as having met the 
requirement for a highly effective birth control method. 
NOTE: There is a potential for encorafenib to induce CYP3A4, which may reduce the 
effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form of 
non-hormonal contraception is required for females of childbearing potential during 
participation in this study. 
The contraception guidelines outlined below are adapted from the recommendations related 
to contraception and pregnancy testing in clinical trials guidance document (Clinical Trials 

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Facilitation Group Guidelines 2014). Participants must agree to use highly effective methods 
of contraception if it is mandated locally or when, in the judgment of the Investigator, 
compliance with acceptable methods is likely to be suboptimal. 
The following methods have been classified as being highly effective (i.e., failure rate < 1% 
per year when used consistently and correctly) in preventing a pregnancy13: 
• 
Complete abstinence from heterosexual intercourse during the entire period of risk 
associated with the study treatments; the reliability of sexual abstinence should be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner (considered highly effective provided the vasectomized male has 
received medical assessment of surgical success and that the male is a female 
participant’s sole sexual partner) 
Acceptable birth control methods characterized as having 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 
9.4 Concomitant medications 
Appendix A lists concomitant medications to use with caution 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
The following are the planned evaluations and interventions. The schedule is summarized in 
Figure 5. There is a 3 day +/- window for all interventions, except imaging assessments and 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
the pre-treatment biopsy, which have a +/- 7-day window. Each treatment cycle is defined as 
28 days. 
• 
Clinical assessment (physical examination-including assessment of visual acuity, 
complete blood count with differential, comprehensive 
chemistry profile, CK) at baseline, day 15 of cycle 1, and then day 1 of each 
subsequent cycle 
• 
Research blood collection for cfDNA analysis at baseline and then day one of each 
subsequent cycle (two 10 mL streck tubes) 
• 
ECG, done in triplicate, at baseline and then day 1 of each subsequent cycle 
• 
ECHO/MUGA at baseline, 4 weeks (C2D1), and then every 8 weeks 
• 
Ophthalmologic evaluation at baseline, Cycle 1 Day 21, Cycle 2 Day 21 and then Day 
1 of every other Cycle (beginning with Cycle 5) and at anytime patients complains of 
visual symptoms or has decreased visual acuity. 
• 
Dermatologic evaluations – can be performed by treating physician or dermatologist – 
at baseline and then every 8 weeks. It is recommended that patients have 
dermatologic evaluations for up to 6 months followind discontinuation of encorafenib. 
• 
Imaging for tumor assessment with CT chest/abdomen/pelvis with contrast or, in 
patients unable to tolerate contrast, with CT chest and MRI abdomen/pelvis 
• 
Optional tumor biopsy at baseline and at C1D7 of an accessible site, ideally at the 
same site for both biopsies. Pre-treatment biopsy, if completed, must be collected 
before the start of encorafenib and binimetinib. 
 
An end-of-treatment evaluation will be performed between 28 and 42 days of the last dose 
(assessments/procedures for this visit outlined in Figure 5). 
 
Patients will continue to be followed for overall survival after end-of-treatment. Where 
available, medical records will be reviewed or, if not available, patients will be contacted 
every 3 months to record survival status. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
Figure 5. Study Calendar 
 
Procedure or 
Assessment 
Screening 
Cycle 1 
Subsequent Cycles 
Follow- 
up phase 
Day 
Within 28 
days prior 
to 
treatment 
1 
7 
15 
21 
1 
8 
15 
21 
End of 
Treatment 
Informed Consent 
X 
Physical exam 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
Blood test (cbc 
w/diff, 
comprehensive 
chemistry profile, 
magnesium, CK) 
X 
X 
X 
X 
X 
Research blood test 
(cfDNA) 
X 
X 
X 
Pregnancy test (if 
able to become 
pregnant) 
X 
X 
X 
X 
Triplicate ECG 
X 
X 
X 
ECHO / MUGA 
X 
X* 
X 
Eye exam 
X 
X 
X** 
X** 
X 
Dermatology exam 
X 
X*** 
X 
Tumor biopsy**** 
X 
X 
Treatment 
(encorafenib) 
QD oral medication 
Treatment 
(binimetinib) 
BID oral medication 
Tumor assessments 
X 
every 8 weeks 
Concomitant 
Medications 
X 
Adverse Events 
X 
*ECHO/MUGA at baseline, 4 weeks (C2D1), and then every 8 weeks 
**Ophthalmologic evaluation at baseline, Cycle 1 Day 21, Cycle 2 Day 21, and then Day 1 of every other cycle 
(beginning with Cycle 5) or anytime patient complains of visual symptoms or has decrease in visual acuity 
*** Dermatologic evaluations – can be performed by treating physician or dermatologist – at baseline and then 
every 8 weeks. It is recommended that patients have dermatologic evaluations up to 6 months following 
discontinuation of encorafenib. 
****Optional tumor biopsy at baseline and at C1D7. The pre-treatment biopsyhas a +/- 7 day window and the 
C1D7 biopsyhas a +/-3 day window. 
 
 
 
 
 
 
 
 
 
Correlative studies 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
Planned correlative studies will evaluate PD markers for response and potential biomarkers 
for response/resistance. Tumor biopsy specimens collected immediately prior to treatment 
and on day 7 of treatment will be used to evaluate expression of phosphorylated ERK and of 
ERK transcriptional output genes. Immunohistochemical analysis will be used to determine 
phospho-ERK levels prior to treatment and on treatment, and RT-PCR (reverse transcription- 
polymerase chain reaction) will be used to measure expression of the ERK transcriptional 
output genes DUSP6, SPRY2, and ETV1. Plasma collected every 4 weeks on trial will be 
used for serial ctDNA analysis with treatment; cfDNA will be submitted for digital droplet PCR 
analysis for fraction of mutant BRAF and to track changes with treatment. Primers will be 
developed based on tumor BRAF alteration; primers for many of the recurrent activating non- 
V600 BRAF mutants are already available and the MSK Marie-Josée and Henry R. Kravis 
Center for Molecular Oncology can generate new primers using the patient’s tumor as a 
positive control. Changes in expression level of phosphorylated ERK and the ERK output 
genes and, in cfDNA, BRAF mutant levels will be correlated with RECIST tumor 
assessments. 
Baseline and end of treatment cfDNA will be subjected to NGS using the MSK cfDNA multi- 
gene assay to explore potential mechanisms of resistance. 
Tumor genotyping by DNA analysis will be performed to identify somatic alterations in 
archived tissue from all cases, and genomic alterations will be correlated with response. All 
patients who did not undergo MSK-IMPACT genomic analysis of tumor tissue for detection of 
BRAF alterations will have pre-treatment tumor tissue sequenced with this assay to confirm 
the BRAF alteration. Patients will not be removed from the study if MSK-IMPACT analysis 
does not confirm the non-V600 activating BRAF alteration. 
Additional biomarkers may be identified and measured as appropriate. 
11.0 
TOXICITIES/SIDE EFFECTS 
The toxicity profile of encorafenib and binimetinib (alone and together) is summarized above 
in Section 5. 
Toxicity should be assessed using the NCI-CTCAE, Version 5. A DLT is defined as an AE or 
abnormal laboratory value assessed as at least possibly related to the study medication, 
unrelated to disease, disease progression, intercurrent illness, or concomitant medications or 
therapies, which occurs within 28 days following the first dose of binimetinib or encorafenib. 
The event must occur during Cycle 1 of therapy and meet any of the criteria listed in the table 
below. The inability to deliver at least 75% of planned dose intensity due to toxicity in the first 
21 days for binimetinib and in the first 28 days for encorafenib will also be considered a DLT. 
Whenever a patient experiences toxicity that fulfills the criteria for a DLT, treatment with the 
study drug will be interrupted and reduced per protocol, and the toxicity will be followed up. 
 
 
 
 
 
 
Table 6. Criteria for Dose Limiting Toxicities 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Cardiac disorders: 
• 
Absolute decrease of LVEF > 10% compared to baseline and the LVEF is below the institution’s 
LLN 
• 
Left ventricular systolic dysfunction Grade ≥ 3 
• 
Other cardiac disorders Grade ≥ 3 
Vascular disorders: 
• 
Grade 3 hypertension for > 14 consecutive days 
• 
Grade 4 hypertension 
General disordersand administration site conditions: 
• 
Fatigue Grade 3 for ≥ 1 week 
Respiratory disorders: 
• 
Interstitial lung disease/ pneumonitis Grade ≥ 2 
Skin and subcutaneous tissue disorders: 
• 
Rash, HFSR, or photosensitivity NCI-CTCAE Grade 3 for > 14 consecutive days despite 
maximal skin toxicity treatment (as per local practice) 
• 
Rash, HFSR, or photosensitivity NCI-CTCAE Grade 4 
Gastrointestinal disorders: 
• 
Diarrhea Grade 3 for ≥ 48 hours despite optimal use of antidiarrheal therapy 
• 
Diarrhea Grade 4 
• 
Nausea/vomiting Grade 3 for ≥ 48 hours despite optimal use of antiemetic therapy 
• 
Nausea/vomiting Grade 4 
Investigations: 
• 
Total bilirubin Grade ≥ 3 
• 
AST or ALT Grade ≥ 3 in conjunction with total bilirubin Grade ≥ 2 of any duration 
• 
AST or ALT Grade 3 for > 7 consecutive days 
• 
AST or ALT Grade 4 
• 
Serum creatinine Grade ≥ 3 
• 
CK elevation ≥ Grade 3 associated with an increase in creatinine ≥ 1.5 × the patient’s 
baseline screening creatinine 
• 
ANC Grade 4 for > 7 consecutive days 
• 
Platelet count Grade 3 with signs of clinically significant bleeding 
• 
Platelet count Grade 4 
• 
QTcF prolonged ≥ Grade 3 (on at least 2 separate ECGs) 
Eye disorders-Retinal: 
• 
Retinopathy or retinal detachment Grade ≥ 3, confirmed by ophthalmic examination 
• 
Retinal vascular disorder RVO, confirmed by ophthalmic examination 
Eye disorders–Visual disturbances without ocular (retinal) changes: 
• 
Blurred vision, flashing lights, floaters: Grade ≥ 3 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Eye disorders – (other specify): 
• 
Grade ≥ 3 for > 21 consecutive days 
• 
Grade 4 confirmed by ophthalmic examination 
Other hematologic and nonhematologic toxicities: 
• 
Thrombocytopenia Grade 4 > 7 days 
• 
Neutropenic fever 
• 
Electrolyte abnormality Grade 3+ that lasts >72 hours, unless the patient has clinical symptoms, 
in which case all grade 3+ electrolyte abnormality regardless of duration should count as a DLT. 
• 
Any other Grade ≥ 3 AE except: 
• 
Lymphocyte count decreased (lymphopenia) Grade ≥ 3 unless clinically significant 
• 
Isolated laboratory changes (e.g. alkaline phosphatase, cholesterol, lipase, serum 
amylase) or those due to sampling or laboratory errors without associated clinical 
signs or symptoms may be determined to not be DLTs upon discretion of the 
Investigator 
• 
 Grade 3+ amylase or lipase elevation not associated with symptoms or clinical 
manifestations of pancreatitis does not need to be counted as a DLT. 
 
Abbreviations: LVEF, left ventricular ejection fracture; LLN, lower limit of normal; HFSR, Hand- 
Foot Skin Reaction; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CK, 
creatinine kinase; ANC, absolute neutrophil count; ECG, electrocardiogram; QTcF, corrected 
QT interval by Fredericia; RVO, retinal vein occlusion; AE, adverse event; DLT, dose-limiting 
toxicity. 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Radiologic tumor assessments will be performed in accordance with the Schedule of 
Procedures. CT and/or MRI will be used as appropriate for baseline tumor assessment 
which must be performed within 28 days prior to C1D1. Radiologic tumor assessments will 
be performed every 8 weeks +/- 7-day window. All target and non-target sites of active 
disease identified at screening must be followed for the duration of the study. Their presence 
and absence should be noted throughout follow-up. The same method of measurement (e.g. 
CT, MRI) and the same technique of assessment should be used to characterize each 
identified and reported lesion at baseline through to the final visit. Overall objective response 
for each patient is based on the combined results for target and non-target lesions. Tumor- 
based efficacy endpoints (i.e., PFS and ORR) will be based on tumor assessments 
performed by the radiologist and assessed by the Principal Investigator. Response and 
progression of disease will be evaluated using RECIST Version 1.1. Tumor assessments will 
be performed until the occurrence of documented disease progression or patient withdrawal 
from the study (e.g., progressive disease, lost to follow-up, withdrawal of consent, or death), 
whichever comes first. Additional tumor evaluations will be performed as clinically indicated. 
Missed tumor assessments must be performed as soon as possible. 
The longest diameters (LDs) for all target lesions will be recorded (short axis for target 
pathological lymph nodes). The LD for all target lesions will be added and reported as the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
baseline sum LD (SLD). Per RECIST Version 1.1, for determining complete response (CR) 
or partial response (PR), all post-baseline tumor measurements will be compared with the 
baseline SLD; for determining progressive disease (PD), the post-baseline measurement is 
compared with the smallest SLD recorded since initiation of treatment, including baseline. 
Patients who discontinue study treatment and do not have PD will be asked to remain on 
study for tumor evaluation per protocol and for determination of PFS. 
All patients will be evaluable for toxicity from the time of their first treatment with encorafenib 
and binimetinib. Any patient who has received a dose of therapy with encorafenib and 
binimetinib will have their disease evaluated for radiographic response. Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
If at any time the patient develops progressive disease or unacceptable toxicity, he/she will 
be taken off study. 
In addition, a subject should be withdrawn from the trial treatment, if, in the opinion of the 
investigator, it is medically necessary, or if it is the wish of the subject. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document subject outcome, if possible. 
Patients should be removed from therapy if any of the following occur: 
• 
Tumor progression. This should be based on radiographic progression or a clinical 
deterioration thought by the clinical investigator to be secondary to tumor burden. 
• 
The occurrence of other unacceptable toxicity indicating the need for cessation of 
treatment. 
• 
The physician feels it is in the best interest of the patient to stop treatment. 
• 
Patient refusal to continue with therapy. 
• 
Non-compliance by the patient with protocol requirements. 
• 
Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort 
should be made to re-establish contact. In any circumstance, every effort should be made 
to document subject outcome, if possible. 
• 
Patient becomes pregnant. 
• 
Termination of the study by investigator or Array BioPharma. 
 
If the reason for withdrawal from the trial is the death of the patient, the two options for 
categorizing withdrawal are either progressive disease or an AE. More than one AE may be 
documented as a reason for withdrawal. Note that death is an outcome and not an AE. 
 
Patients can continue treatment beyond progression if they are receiving clinical benefit from 
treatment. 
 
14.0 
BIOSTATISTICS 
 
Phase I 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
Between 3 and 12 patients will be enrolled in the phase I portion of this study. We will first 
treat 3-6 patients at dose level 1, the approved dose of encorafenib 450 mg oral QD and 
binimetinib 45 mg PO BID, to evaluate the safety of this dose level in this population. If this 
dose level is found to be safe, up to 6 patients will be treated with dose level 2, encorafenib 
450 mg oral QD continuous and binimetinib 60 mg oral BID 21 days on/7 days off. If one or 
fewer patients experience DLTs in the first 28 day treatment cycle, then we will declare that 
this dose can be safely given in this population and phase II portion will proceed with this 
regimen. In this case the six patients treated at dose level 2 in the Phase I portion will be 
included in the Phase II portion. If however 2 or more patients experience DLTs in the first 
28 days, then the phase II portion will enroll patients at the dose 1 level of encorafenib 450 
mg oral QD and binimetinib 45 mg oral BID. All patients will then be included in the efficacy 
endpoint. Patients who receive less than 75% of planned therapy in the first 28 days for 
reasons not related to adverse events will not be evaluated for DLTs and will be replaced. 
Phase II 
The primary endpoint of the phase II portion is the best objective response rate of the 
combination. Primary statistical analysis will be performed on data from the population 
comprising all patients receiving any dose of the investigational agents 
(encorafenib/binimetinib). Any patient who drops out prior to the 8 week assessment will be 
deemed a non-responder. 
We infer a historical response rate (RR) of about 15% based on experience with ERK 
inhibitors in this population9 and the activity of binimetinib in NRAS mutant melanoma11. 
These trials provide the only genomically annotated efficacy data for ERK pathway inhibitors 
in similar populations. With a total number of 32 patients, using a Simon’s minimax 2 stage 
design, we can show a difference in RR from 15% to 35% with type I and II error rates of 0.1 
each. We will enroll 17 patients in the first stage and if 3 or more responses are observed 
then an additional 15 patients will be enrolled for a total of 32 patients. Otherwise, if 2 or less 
responses are observed, the study will be terminated. Enrollment will pause after the first 17 
patients enter the study to evaluate RR. If 3 or more patients already achieved a response, 
then the study will proceed to the second stage. If fewer than 3 RECIST responses are 
seen, then there will be a pause of up to 16 weeks from the start of treatment of the last 
enrolling patient to allow monitoring of treatment efficacy. Responses in the first stage do not 
need to be confirmed with repeat CT scan for the study to proceed to the second stage. At 
the end of the study, if 8 or more responses are observed then we would consider the study 
promising. 
Secondary objectives: PFS will be calculated from the start of treatment until progression or 
death whichever occurs first. OS is defined as the interval between the time of initiation of 
therapy and the date of death from any cause. Patients who are alive at the time of study 
completion will be censored at the time the patient was last known to be alive. PFS and OS 
will be estimated using the Kaplan-Meier method. 
Safety and tolerability will be summarized using descriptive statistics. All patients receiving 
any dose of the investigational agents (encorafenib/binimetinib) will be included in the 
analysis. We will also evaluate long-term tolerability as defined by percent of patients that 
require dose interruption, reduction, or discontinuation due to AEs. Please note three novel 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
dosing schedules were used in this protocol. The initial level 2 dose was encorafenib 450 
mg QD continuous + binimetinib 60 mg BID 21 days on/ 7 days off. This dose was amended 
for intermittent dosing of both agents to limit unopposed RAF inhibitor treatment. The 
expansion dose was then amended to continuous treatment with both drugs after several 
patients reported good tolerance of continuous dosing during the first three weeks and 
symptomatic improvement but recrudescence of symptoms during the week off drug. 
Exploratory objectives: Changes in RNA expression (continuous variables) between pre- 
treatment and day 7 of the ERK transcriptional output genes DUSP6, SPRY2, and ETV1 will 
be associated with response using Wilcoxon rank sum test while associations between 
response and immunohistochemical analysis of phosphorylated ERK expression 
(categorical) measured at pre-treament and day 7 post-treatment will be assessed using 
generalized estimating equations (GEE). The BRAF variant allelic fraction in cfDNA will be 
evaluated in plasma by droplet digital PCR to give a quantitative assessment. Associations 
between objective response rate and the changes in the proportion of detectable BRAF 
alterations between pre-treatment and week 4 will be assessed using the Wilcoxon rank sum 
test. Proportions of mutations identified by the next-generation sequencing assay will be 
estimated using binomial proportions along with exact 95% confidence intervals and 
associations between mutation status and objective response rate will be assessed using 
Fisher’s exact test controlling the false discovery rate using Benjamini-Hochberg method to 
account for the multiple testing. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
15.2 
Randomization 
Not applicable. 
16.0 
DATA MANAGEMENT ISSUES 
A Clinical Research Coordinator(CRC) will be assigned to the study. The responsibilities of 
the CRC include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the study team. Medidata will be used for data collection. The data will be reported to the 
institution (MSK IRB) and the drug manufacturer (Array BioPharma) as appropriate. Tumor 
slides will be stored in the MSK Diagnostic Molecular Pathology Laboratory. Results from 
laboratory studies will include photomicrographs of immunohistochemistry (IHC) studies, 
computer files of sequencing data, and computer files from cfDNA analysis. These files will 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
be stores on the MSK Department of Medicine server. Documentation linking patient 
identifiers with patient samples and results will be securely maintained in the Medidata with 
access limited to study investigators. 
16.1 
Quality Assurance 
Routine registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality 
and protocol compliance audits will be conducted by the study team, at a minimum of two 
times per year, and more frequently if indicated. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at MSK were approved by the National Cancer 
Institute (NCI) in September 2001. The plans address the new policies set forth by the NCI 
in the document entitled “Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSK were 
established and are monitored by the MSK Office of Clinical Research. The MSK DSM 
Plans can be found on the MSKCC Intranet at: http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, safety, 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research quality assurance) and departmental procedures for quality 
control. Additionally, there are two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs. The committees: the Data and Safety 
Monitoring Committee (DSMC) for phase I and II clinical trials, and the Data and Safety 
Monitoring Board (DSMB) for phase III clinical trials, report to MSK’s Research Council and 
IRB. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonisation (ICH) to the extent required by the FDA, and 
MSK policies. Participation in this trial is voluntary. All patients will be required to sign a 
statement of informed consent, which must conform to MSK IRB guidelines. The study will 
protect the rights of all human subjects and the informed consent will clearly define the risks, 
benefits, toxicities, and side effects of treatment. We will also thoroughly explain the 
alternative options for treatment. The patients will be aware of the potential financial costs 
and burdens of enrolling on a clinical trial. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
17.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB/PB. 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified researchers. 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
The report should contain the following information: 
• 
The date the adverse event occurred 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office 
17.2.1 Array SAE Reporting 
 
All SAEs occurring in patients from the first dose of Array study drug until 30 days after the 
last dose of Array study drug must be reported to Array BioPharma Inc. within 24 hours of 
the Investigator’s knowledge by faxing a completed SAE form to Array BioPharma Inc. at the 
number provided on the SAE form or fax cover sheet. SAEs occurring greater than 30 days 
after the last dose of Array study drug should be reported to Array BioPharma Inc. only if 
considered related to the Array product. 
If new information becomes available for a previously reported SAE, a follow-up SAE report 
should be sent within 24 hours. The follow-up information should describe whether the event 
has resolved or continues, if and how it was treated, and whether the patient continued or 
withdrew from study participation. 
Investigators must follow patients with SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, the patient is lost to follow up, or death OR until 30 days 
after the last dose of Array study drug, whichever occurs first. Ongoing treatment-related 
SAEs may be followed beyond this time period if clinically indicated. 
 
If a patient becomes pregnant during the study, administration of study drug is to be 
discontinued immediately. 
Pregnancies (both those of female patients and female partners of male patients) must be 
reported to Array BioPharma Inc. within 24 hours of the Investigator’s knowledge. All 
pregnancies should be followed through to outcome and the outcome must be reported to 
Array BioPharma Inc. 
Pregnancies themselves are not considered AEs or SAEs. However, any AEs or SAEs 
occurring during pregnancy are to be reported following AE and SAE reporting guidelines. 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the IRB/PB of this Center. The consent form will include 
the following: 
1. The nature and objectives, potential risks, and benefits of the intended study 
2. The length of study and the likely follow-up required 
3. Alternatives to the proposed study (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research-specific information. In 
addition to signing the IRB informed consent form, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
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Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 18-547 A(13) 
Approval date: 24-Nov-2020 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
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20.0 
APPENDICES 
 
Appendix A. Concomitant medications to use with caution. 
Appendix B. CT Biopsy Dose Analysis