Conditions: High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma
Keywords: BRAF V600E/K High Grade Primary Brain Tumor High Grade Glioma Glioblastoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
The goal of this study is to estimate the efficacy of encorafenib and binimetinib as measured by radiographic response in recurrent high-grade primary brain tumors.

Detailed description:
Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs).

Secondary Objectives

1. Estimate efficacy as measured by progression-free survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug.
2. Evaluate duration of response in subjects who have a partial or complete response.
3. Quantify the time-to-response among subjects who have a radiologic response.
4. Estimate efficacy as measured by overall survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug.
5. Characterize the toxicity profile of the combination of encorafenib and binimetinib in this patient population.

There are two arms: medical and surgical. Subjects on the surgical arm must have a high-grade glioma or a known BRAF-mutated low-grade glioma with high clinical suspicion for progression to high-grade.

Medical: Following enrollment, patients will receive encorafenib and binimetinib at the FDA-approved dose of 450 mg of encorafenib once daily and the FDA-approved dose of 45 mg of binimetinib twice daily separated by 12 hours, continuously in 28-day cycles until progression or unacceptable toxicity. Patients will be followed by routine blood work, and general and neurological examination. A brain MRI will be performed prior to every odd-numbered cycle (every 8 weeks). Response will be assessed by RANO criteria. Patients may remain on study and receive treatment until progression or other reason.

Surgical: These subjects will take encorafenib and binimetinib in combination at their FDA-approved doses for 10-14 days prior to surgery. The last dose of both drugs will be administered two hours prior to surgery. Specimens will be collected during surgery. After surgery, the subjects will not take further encorafenib or binimetinib until a study visit to assess their neurological exam, physical exam, and performance status, at 2-6 weeks post-operatively. At time of restarting combination treatment, subjects will follow the schedule for the medical cohort, and will continue treatment until progression.

Arms:
arm 1: Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

Research Bloods arm 2: Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

Research Bloods arm 3: Pre-op -14 days: Encorafenib 450mg QD and Binimetinib 45mg BID last dose of both drugs 2hrs prior to surgery

Tumor; research blood; CSF samples

post surgery: Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle arm 4: Encorafenib 450mg QD Binimetinib 45mg BID 28 day cycle

Research Bloods

Interventions: intervention 1: Encorafenib intervention 2: Binimetinib intervention 3: Research Bloods intervention 4: Tumor Tissue
Intervention descriptions: intervention 1: 450mg QD 28 day cycle intervention 2: 45mg BID 28 day cycle intervention 3: Baseline; pre-cycle 3; Pre-cycle 7; off Treatment intervention 4: at time of surgery contrast enhancing and non enhancing tumor; 20 unstained slides

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
Version 05/24/2021 
 
 
 
 
 
 
 
 
                                            
 
ABTC #: 1802 
 
 
 
 
 
 
 
 
 
 
NCI #: ABTC-1802 
  
 
 
 
 
 
 
 
 
             
 
  
Version Date – 05/24/2021 
Previous Versions – 06/27/19, 12/3/19, 01/21/20, 02/28/20, 11/30/20 
 
 
A Phase II Study of Binimetinib in Combination with Encorafenib in Adults 
with Recurrent BRAF V600-Mutated High-Grade Astrocytoma or other 
Primary Brain Tumor 
A Protocol of the Adult Brain Tumor Consortium (ABTC)  
 
Coordinating Center: ABTC Central Operations Office, 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins  
 
Study Chair 
Karisa Schreck, MD, PhD 
Sidney Kimmel Comprehensive Cancer Center 
201 North Broadway 
Viragh 9th Floor, Box 3 
Baltimore, MD 21231 
Phone: 410-614-9916    
Fax: 410-614-9335 
Email: ksolt1@jhmi.edu 
 
 
Study Co-Chair 
Stuart Grossman, MD 
Sidney Kimmel Comprehensive Cancer Center 
201 North Broadway201 North Broadway 
Viragh 9th Floor, Box 3 
Baltimore, MD 21231 
Phone: 410-955-8837    
Fax: 410-614-9335 
Email: grossman@jhmi.edu 
 
 
Imaging Chair 
Benjamin M. Ellingson, PhD 
University of California Los Angeles 
924 Westwood Blvd, Suite 615 
Los Angeles, CA 90024 
Phone: 310-481-7572 
Email: bellingson@mednet.ucla.edu  
 
Biostatistician 
Xiaobu Ye, MD, MS 
Johns Hopkins University 
600 N. Wolfe Street/ Meyer 8-181D 
Baltimore, MD 21287 
Phone: 410-614-6261 
Email: xye3@jhmi.edu 
 
Investigational Agents: Encorafenib, Binimetinib 
NSC #: 807064 (encorafenib), 788187 (binimetinib) 
IND #: Exempted  
IND Sponsor: ABTC 
 
 
 
 
 


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PARTICIPATING INVESTIGATORS:  
Adult Brain Tumor Consortium participating members 
 
 
 
 
ABTC Manager 
Joy Fisher 
Johns Hopkins University 
Phone: 410-955-3657 
Email: jfisher@jhmi.edu 
ABTC Project Manager 
Serena Desideri 
Johns Hopkins University 
Phone: 410-614-4400 
Email: sdeside1@jhmi.edu 
 
 
Protocol Development Coordinator 
Eleni Kostalas-Lentis 
Johns Hopkins University 
Phone: 410-502-5973  
Email: ekostal1@jh.edu 
 
 
ABTC Programmer Analyst  
Neeraja Danda 
Johns Hopkins University 
Phone: 410-502-5929 
Email: ndanda1@jhmi.edu 
 
 
 
Nursing Contact  
Michaella Iacoboni, RN 
 
Johns Hopkins University 
 
Phone: 410-955-4009 
Fax: 410-614-9335 
 
 
 
Email:  msheeh13@jhmi.edu 
 
 
Pharmacy Contact 
Anne Delisa, PharmD, BCOP 
Sidney Kimmel Comprehensive Cancer 
Center at Johns Hopkins 
Phone: 410- 502-1036 
Email: adelisa@jhmi.edu 


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TABLE OF CONTENTS 
SECTION .................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
CHANGE..................................................................................................... ERROR! BOOKMARK NOT DEFINED. 
TABLE OF CONTENTS ............................................................................................................................................ 3 
1.0 
OBJECTIVES .................................................................................................................................................. 5 
2.0 
BACKGROUND AND RATIONALE ........................................................................................................... 6 
2.1 
BRAF MUTATIONS IN GLIOMAS .................................................................................................................... 6 
2.2  
ENCORAFENIB ................................................................................................................................................ 7 
2.3 
BINIMETINIB ................................................................................................................................................... 7 
2.4 
COMBINATION THERAPY ................................................................................................................................ 8 
2.5 
RATIONALE IN BRAIN TUMORS ...................................................................................................................... 9 
2.6 
CORRELATIVE STUDIES BACKGROUND ........................................................................................................ 11 
3.0 
PATIENT ELIGIBILITY CRITERIA ........................................................................................................ 12 
3.1 
PATIENT SAMPLE ......................................................................................................................................... 12 
3.2 
INCLUSION CRITERIA.................................................................................................................................... 13 
3.3 
EXCLUSION CRITERIA .................................................................................................................................. 14 
3.4 
ADDITIONAL INCLUSION CRITERIA FOR SURGICAL ARM .............................................................................. 16 
4.0 
TREATMENT PLAN .................................................................................................................................... 16 
4.1 
TREATMENT SCHEMA ................................................................................................................................... 17 
4.2 
TREATMENT REQUIREMENTS FOR SUBSEQUENT CYCLES .............................................................................. 19 
4.3 
ENCORAFENIB AND BINIMETINIB ADMINISTRATION..................................................................................... 19 
4.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............................................. 20 
4.4.1 Permitted Concomitant Therapy Requiring Caution and/or Action ........................................................... 20 
4.4.2 Prohibited Concomitant Medications During Study ................................................................................... 21 
4.4.3 Corticosteroids ........................................................................................................................................... 22 
4.4.4 Herbal and Non-Traditional Medications .................................................................................................. 22 
4.5  
LIFESTYLE CONSIDERATIONS ....................................................................................................................... 22 
4.5.1 Contraception ............................................................................................................................................. 22 
4.5.2 Contraception Guidance: ........................................................................................................................... 23 
4.5.3 Meals and Dietary Restriction .................................................................................................................... 24 
4.5.4 Activity ........................................................................................................................................................ 24 
5.0 
DOSING DELAYS/DOSE MODIFICATION FOR TOXICITY .............................................................. 24 
5.1 
DOSE MODIFICATION FOR ENCORAFENIB AND BINIMETINIB ........................................................................ 24 
5.2 
ENCORAFENIB AND BINIMETINIB DOSE RE-ESCALATION GUIDELINES ........................................................ 32 
5.3 
MAJOR EVENTS ............................................................................................................................................ 32 
5.4 
USE OF HEMATOLOGIC GROWTH FACTORS .................................................................................................. 32 
5.5 
TOXICITY CRITERIA ..................................................................................................................................... 32 
6.0 
PHARMACEUTICAL INFORMATION .................................................................................................... 33 
6.1 
ENCORAFENIB .............................................................................................................................................. 33 
6.2 
BINIMETINIB ................................................................................................................................................. 33 
6.3 
AGENT ORDERING ........................................................................................................................................ 34 
6.4  
AGENT ACCOUNTABILITY ............................................................................................................................ 34 
6.5 
USEFUL LINKS AND CONTACTS .................................................................................................................... 34 
7.0 
PROCEDURES FOR PATIENT ENTRY ON STUDY ............................................................................. 34 
7.1 
CTEP REGISTRATION PROCEDURES ............................................................................................................. 34 
7.2 
SITE REGISTRATION REQUIREMENTS – INSTITUTIONAL REVIEW BOARD APPROVAL ................................... 35 
7.3 
PATIENT REGISTRATION ............................................................................................................................... 37 


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8.0 
RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE ................................................ 38 
8.1 
CRITERIA FOR RESPONSE ASSESSMENT ........................................................................................................ 38 
8.2 
ASSESSMENT OF RESPONSE .......................................................................................................................... 40 
8.3 
SAFETY ASSESSMENTS ................................................................................................................................. 40 
8.4 
QUALITY ASSURANCE .................................................................................................................................. 40 
9.0 
MONITORING OF PATIENTS .................................................................................................................. 42 
9.1 
TABLE OF REQUIRED OBSERVATIONS - MEDICAL ARM AND SURGICAL ARM .............................................. 42 
9.2  
TABLE OF ADDITIONAL REQUIRED OBSERVATIONS - SURGICAL ARM ......................................................... 45 
9.3 
ADVERSE EVENTS: LISTS AND REPORTING REQUIREMENTS ......................................................................... 46 
9.3.1 
Lists of AEs for encorafenib and binimetinib, alone and in combination ............................................ 46 
9.3.2 
Adverse Event Characteristics ............................................................................................................. 52 
9.4 
SERIOUS ADVERSE EVENTS AND EXPEDITED ADVERSE EVENT REPORTING ................................................ 53 
9.4.1 
Definition – Serious Adverse Event (SAE) ........................................................................................... 53 
9.4.2 
Expedited Adverse Event Reporting ..................................................................................................... 53 
9.4.3 
Other SAE Reporting ........................................................................................................................... 54 
9.5 
ROUTINE ADVERSE EVENT REPORTING ........................................................................................................ 55 
9.6 
CORRELATIVE STUDIES ................................................................................................................................ 56 
9.6.1 
Pharmacokinetic Assessment (All Surgical Patients): Exploratory ..................................................... 56 
9.6.2 
Resistance Mechanisms (All Patients): Exploratory ............................................................................ 56 
9.6.3 
Pharmacodynamic studies (All Surgical Patients): Exploratory ......................................................... 57 
9.6.4 
Circulating Tumor DNA (All Patients): Exploratory ........................................................................... 57 
9.6.5 
Overview of Biospecimen Collection on Surgical Arm ........................................................................ 58 
9.6.6 
Archival Tumor Tissue: Exploratory ................................................................................................... 59 
10.0    OFF TREATMENT/OFF STUDY CRITERIA .......................................................................................... 60 
10.1 
OFF TREATMENT CRITERIA .......................................................................................................................... 60 
10.2 
OFF STUDY CRITERIA ................................................................................................................................... 61 
11.0   STATISTICAL CONSIDERATIONS ......................................................................................................... 61 
11.1  
STUDY DESIGN/ ENDPOINTS: ........................................................................................................................ 61 
11.2  
SAMPLE SIZE JUSTIFICATION ........................................................................................................................ 61 
11.3 
ANALYSIS OF SECONDARY END POINTS: ...................................................................................................... 62 
11.4 
ANALYSIS OF EXPLORATORY ENDPOINTS: ................................................................................................... 63 
12.0   STUDY ADMINISTRATION ...................................................................................................................... 64 
12.1 
INVESTIGATOR’S STUDY FILE ...................................................................................................................... 64 
12.2 
SOURCE DATA/DOCUMENTS ........................................................................................................................ 64 
12.3 
DOCUMENT RETENTION AND ARCHIVING .................................................................................................... 64 
12.4  
DATA COLLECTION/REPORTING ................................................................................................................... 65 
12.5 
STUDY MONITORING .................................................................................................................................... 65 
12.6 
AUDITS AND INSPECTIONS ............................................................................................................................ 66 
13.0  REFERENCES .............................................................................................................................................. 67 
14.0  ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................... 71 
APPENDIX I – PATIENT MEDICATION DIARY - BINIMETINIB ................................................................. 72 
APPENDIX II – PATIENT MEDICATION DIARY - ENCORAFENIB ............................................................ 73 
APPENDIX III – PRE-SURGICAL TREATMENT MEDICATION DIARY .................................................... 74 
APPENDIX IV – PATIENT CLINICAL TRIAL WALLET CARD .................................................................... 75 
 
 
 
 


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1.0 
OBJECTIVES  
 
Primary Objective 
Estimate the efficacy of combination treatment with encorafenib and binimetinib, as 
measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-
mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs).  
Secondary Objectives 
1. Estimate efficacy as measured by progression-free survival in subjects with 
recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K 
mutation who receive drug.  
2. Evaluate duration of response in subjects who have a partial or complete response. 
3. Quantify the time-to-response among subjects who have a radiologic response. 
4. Estimate efficacy as measured by overall survival in subjects with recurrent 
malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who 
receive drug. 
5. Characterize the toxicity profile of the combination of encorafenib and binimetinib 
in this patient population. 
 Exploratory Objectives 
1. Estimate efficacy as measured by response rate, progression free survival, and 
overall survival in study participants with tumors other than MG and anaplastic 
PXA (cohort 3).  
2. Estimate encorafenib and binimetinib concentrations in enhancing brain tissue and 
cerebrospinal fluid from a surgical cohort. 
3. Explore putative mechanisms of resistance to encorafenib and binimetinib in 
BRAF-V600E/K mutated gliomas from an upfront surgical cohort and in patients 
who progress on study and undergo a clinically-indicated surgery. 
4. Analyze the functional inhibition of the ERK signaling pathway in tumor tissue 
from a surgical cohort of patients treated with encorafenib and binimetinib, and 
correlate serum concentrations with changes in pathway activity.  
5. Measure BRAF-V600 DNA mutant fraction in CSF and plasma over time while 
participants are receiving treatment. 
 
 
 


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2.0 
BACKGROUND AND RATIONALE 
 
2.1 
BRAF Mutations in Gliomas 
 
BRAF is one of 3 RAF-kinase isoforms (the others are ARAF and CRAF). All three are 
activated by dimerization, and induce MEK1 and MEK2 (MEK1/2) phosphorylation, 
which then activates ERK1 and ERK2 (ERK1/2). ERK1/2 translocates into the nucleus and 
regulates targets associated with proliferation, differentiation, and survival.(1) BRAF can 
be constitutively activated by point mutations removing the need for dimerization or by 
fusions with other kinases (KIAA1549-BRAF).(2) The BRAF V600 point mutation in 
particular is located within the kinase domain and allows constitutive activation of the 
kinase by removing inhibitory domain and prerequisite of dimerization for activity. This 
results in increased activation of the ERK signaling pathway and leads to cell proliferation 
and survival.(2) 
 
While BRAF fusions are relatively common in pediatric gliomas, BRAF V600 mutations 
are also present in some adult gliomas. BRAF V600 mutations have been described in a 
variety of adult and pediatric gliomas including pleomorphic xanthoastrocytomas (PXA) 
(60-80%), gangliogliomas (20-70%), pilocytic astrocytomas (9-10%), low grade gliomas 
(5-15%) and glioblastomas (GBM) (1-5%).(3-5) While mutation is less common in adult 
GBM, it is relatively enriched for in the epitheliod subtype of GBM,(5, 6) and possibly in 
low grade astrocytomas as well (5-15%).(7) Despite a relatively low incidence in adults, 
the potential for targeted therapy makes BRAF V600 mutations in recurrent gliomas 
significant, as prognosis is poor and treatment options are very limited.  
 
Current treatment for high-grade gliomas in adults is maximal safe surgical resection, 
followed by radiation with concurrent temozolomide, then adjuvant temozolomide. (8)  
Low-grade gliomas may be treated with an alternative chemotherapy regiment or radiation 
alone. Despite this, the average life expectancy for patients with glioblastoma is less than 
18 months even with standard therapy, which was approved by the FDA thirteen years ago. 
While there is a significant amount of research underway for novel treatments, overall these 
have been disappointing to date. Recent advances in molecular diagnostics have revealed 
different glioblastoma subtypes that may have different driver mutations. (9) 
 
The overall effect of BRAF mutations on the natural history of gliomas is unclear.  A 
retrospective study of young adults (age 18-35) with GBM found BRAF mutations are 
associated with improved prognosis as compared to BRAF-WT tumors.(10) A similar 
result was found in a recent meta-analysis, which found BRAF-V600 mutations correlated 
with improved overall survival for young adults and low grade gliomas, but have no effect 
on prognosis in GBM in adults >35 years old, though the sample size was quite small.(11) 
In PXAs, BRAF mutations are associated with a longer overall survival in one analysis,(12) 
though not in another.(13) 
 
 
 


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2.2  
Encorafenib 
 
Encorafenib [methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3(methanesulfonamido) phenyl] 
-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate] is a 
potent BRAF kinase inhibitor that is orally bioavailable and FDA approved in combination 
with binimetinib for the treatment of unresectable or metastatic melanoma with BRAF 
V600E or K mutations. It inhibits all RAF isoforms, but is most potent against the BRAF 
V600E mutations (IC50 = 0.35 nM), but also against wild-type (wt) BRAF and CRAF (IC50 
0.47 nM and 0.3 nM, respectively) in in vitro cell-free assays. (14)  
 
Clinical Pharmacokinetics (PK) and Drug-drug Interactions of Encorafenib  
 
The pharmacokinetics (PK) of encorafenib were studied in healthy subjects and patients with 
solid tumors, including advanced and unresectable or metastatic cutaneous melanoma 
harboring a BRAF V600E or K mutation. After repeat once-daily dosing, steady-state 
conditions were reached within 15 days, exposure being approximately 50% lower compared 
to Day 1, with a median half-life ~4 hours, and moderate intersubject variability (percent 
coefficient of variation [%CV]) of area under the curve (AUC; 12.3% to 68.9% over a range 
of doses). The PK of encorafenib has been shown to be approximately dose proportional after 
multiple doses, with any deviation from dose proportionality likely due to auto-induction of 
CYP3A4.  
 
The human ADME study in healthy subjects showed that encorafenib is at least 86% absorbed 
and has a preferential distribution to plasma as compared to blood. Encorafenib was mainly 
eliminated via metabolism, with low levels of unchanged encorafenib detected in urine and 
feces. The dose was equally recovered in urine and feces (47.2% in each matrix) and the renal 
clearance was estimated to be 1.8%. 
 
Results from a food-effect clinical study in healthy subjects have indicated that the influence 
of food on the PK of encorafenib is mild and not clinically relevant; therefore, encorafenib can 
be taken without regard to food. In combination studies, when administered with binimetinib, 
PK parameters of encorafenib were similar to those observed in the single-agent study. 
 
2.3 
Binimetinib 
 
Binimetinib is an adenosine triphosphate (ATP)-uncompetitive inhibitor of MEK1 and MEK2. 
In cell-free systems, binimetinib inhibits MEK1 and MEK2 with half maximal inhibitory 
concentration (IC50) values of 12 nM and 46 nM, respectively, on purified enzymes. The IC50 
value of the active metabolite of binimetinib, AR00426032, was 7.1 nM. It is approved by the 
FDA in combination with encorafenib for the treatment of unresectable or metastatic 
melanoma with BRAF V600E or K mutations. (15) 
 
Clinical Pharmacokinetics (PK) and Drug-Drug Interactions of Binimetinib 
 
The PK of binimetinib are characterized by moderate to high variability, accumulation of 
approximately 1.5-fold, and steady state concentrations reached within 15 days. Binimetinib 
has been shown to be approximately dose proportional (Clinical Study Pfizer -162-111). The 
human ADME study indicated that approximately 50% of binimetinib dose was absorbed. The 


8 
 
 
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primary metabolic pathways include glucuronication (up to 61.2% via UGT1A1), N-
dealkylation (up to 17.8% via CYP1A2 and CYP2C19) and amide hydrolysis. The excretion 
route was 31.7% of unchanged binimetinib in feces and 18.4% in urine. Estimated renal 
clearance of unchanged binimetinib was 6.3% of total dose. The impact of UGT1A1 inhibitors 
or inducers has not been clinically assessed.  
 
Food-effect clinical studies have indicated that the influence of food on the PK of binimetinib 
is mild and not clinically relevant; therefore, binimetinib can be taken with food. 
 
2.4 
Combination Therapy 
 
Mathematical models support the fact that resistance to two different drugs, given serially, 
emerges faster than to the two drugs given simultaneously. (16) Unfortunately, resistance 
to BRAF inhibitors emerges in an average of 5-7 months in patients with melanoma. (17, 
18) This occurs by a variety of different mechanisms including secondary mutations in 
BRAF, truncations, upregulation of other RAS/RAF family members, PI3K activation, 
PTEN loss, or RTK upregulation. (19-23) There have been attempts to avoid resistance by 
blocking MEK1/2, which is immediately downstream of BRAF, thereby making it more 
difficult for tumors to escape inhibition. Early studies showed that if a BRAF inhibitor is 
followed by a MEK inhibitor at the time of tumor progression, there is only a marginal 
improvement in survival (1.8mo). (24) More recently, the upfront combination of BRAF 
and MEK inhibitors has resulted in improved progression free survival as compared to 
monotherapy, and three different combinations of BRAF and MEK inhibitors are approved 
by the FDA for advanced-stage melanoma, including encorafenib and binimetinib (Table 
1). (25-27) Encorafenib and binimetinib are approved by the FDA for combination therapy 
in patients with advanced or metastatic melanoma with an E or K mutation. (14, 15) The 
phase 3 COLUMBUS trial in advanced / metastatic melanoma with BRAF V600E or K 
mutations compared encorafenib plus binimetinib against vemurafenib alone and showed 
a progression free survival rate of 14.9 versus 7.3 months. (27) Overall survival was also 
favorable in the combination group, with median survival of 33.6 months with combination 
treatment and 16.9 months with vemurafenib alone. (28) 
 
Study 
Population 
Therapy 
CMEK162X2110, 
Phase 1b/2 (n=189) 
BRAF V600E/K mutated 
advanced solid tumor 
Encorafenib plus binimetinib 
CLGX818X2109, 
Phase 2 (n=158) 
Advanced melanoma with 
BRAF V600 mutation 
Encorafenib plus binimetinib 
CMEK162B2301, 
Phase 3 (n=921) 
Advanced melanoma with 
BRAF V600 mutation 
Encorafenib plus binimetinib vs. 
vemurafenib or encorafenib 
 
Table 1: Compilation of clinical trials assessing encorafenib and binimetinib in patients 
with advanced cancer.  
 
 
 
 
 


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Clinical Pharmacokinetics (PK) of Combination Therapy 
 
Administration of 45 mg binimetinib twice daily with escalating doses of daily encorafenib 
showed no distinct trend towards change in Cmax or AUC of binimetinib or encorafenib 
(compared to single-agent PK studies), per investigator brochure.  
 
Blood Brain Barrier Penetration of Encorafenib and Binimetinib 
 
Encorafenib is a P-glycoprotein (P-gp) substrate and an inhibitor of breast cancer resistance 
protein (BCRP), while binimetinib is a P-gp and BCRP substrate. Due to the function of 
the blood-brain barrier, the penetration of a drug into the brain depends on its intrinsic 
membrane permeability and its susceptibility to active efflux.(29) Although encorafenib 
and binimetinib have high intrinsic membrane permeability, efflux transporters may result 
in reduced brain concentrations for both.  
 
Animal models have limited utility in predicting the effect of efflux transporter proteins on 
human brain concentrations. (29, 30) For example, dabrafenib and trametinib are efflux 
transporter substrates thought to have limited brain penetration based on nonclinical data, 
yet the combination had clinical activity in patients with melanoma brain metastasis in the 
COMBI-MB study. (31-33) 
 
2.5 
Rationale in Brain Tumors 
 
BRAF Inhibitor Monotherapy in Brain Tumors 
 
In pediatric brain tumors, BRAF inhibitor PLX4720 was able to inhibit MEK and ERK 
phosphorylation, as well as downstream AKT phosphorylation, in BRAF-V600E mutated 
astrocytoma cell lines, but not wild type tumor cell lines. It also prolonged survival of mice 
with xenografts from BRAF mutant brain tumors but not wild type tumors. (34) 
 
BRAF inhibitors are being evaluated in gliomas with encouraging results. There have been 
several case reports of targeted treatment with BRAF inhibitors in adults with BRAF-V600 
mutated primary brain tumors (Table 2). A recent basket study of vemurafenib 
monotherapy included adults with primary brain tumors and demonstrated positive 
responses to monotherapy in malignant gliomas (MG; 1/11 PR, 3/11 SD ≥ 6mo) and 
pleomorphic xanthoastrocytomas (PXAs; 4/7 radiographic responses PR or greater). (35) 
This is noteworthy, as response rates in recurrent glioblastoma trials are typically 3-8% for 
treatments that are non-efficacious (Table 1). Unfortunately, the average time to 
progression on BRAFi monotherapy was 5.3-5.7 months, similar to the results in 
melanoma. These results suggest that BRAF-V600 mutant brain tumors are sensitive to 
BRAFi, but develop resistance over time.   
 
 
 
 
 


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Age/  
Sex 
Histology 
Prior Rx 
BRAF  Rx 
Time on 
Txt 
Best 
Outcome 
Reference 
34/F 
PXA 
RT, TMZ, PCV 
Vemurafenib 
4 mo 
Stable 
disease 
Chamberlain 
(36) 
47/F 
PXA 
RT, TMZ, PCV 
Vemurafenib 
10 mo 
PR 
Chamberlain 
53/M 
PXA 
RT+TMZ, PCV 
Vemurafenib 
10 mo 
PR 
Chamberlain 
43/M 
Anaplastic 
PXA 
RT+TMZ, PCV 
Vemurafenib 
6 mo 
Progression 
Chamberlain 
26/M 
Epithelioid 
GBM 
None 
Vemurafenib 
1 week 
PR 
Leaver (37) 
39/M 
Anaplastic 
PXA 
RT 
Vemurafenib 
2 mo 
CR 
Leaver 
41/M 
Anaplastic 
PXA 
TMZ, RT + 
TMZ 
Vemurafenib 
3 mo 
PR 
Lee (38) 
35/F 
PXA 
None 
Dabrafenib 
3 mo 
PR 
Usubalieva 
(39) 
25/M 
HGG from 
ganglioglioma 
RT+TMZ, 
adjuvant TMZ 
Dabrafenib + 
TTFields 
24+ mo 
CR 
Meletath (40) 
21/F 
Anaplastic 
PXA 
RT, 
Vemurafenib 
Dabrafenib 
16+ mo 
CR 
Brown (41) 
Table 2: Published reports of BRAF-directed therapy in adults. Legend: PXA = pleomorphic 
xanthoastrocytoma; GBM = glioblastoma; HGG = high grade glioma; RT = radiation therapy; TMZ = 
temozolomide; PCV = procarbazine, lomustine and vincristine; CR = complete response; PR = partial 
response. 
 
 


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BRAF / MEK Inhibitor Combination Therapy in Brain Tumors 
 
Anecdotal clinical experience in the form of case reports suggests that combined BRAF 
and MEK inhibition (BRAFi/MEKi) can lead to sustained clinical and radiographic 
responses in some patients with recurrent BRAF V600-mutated recurrent high grade 
gliomas (HGG) in whom multiple previous therapies had failed (Table 3). (42-45)  
 
Age/Sex 
Histology 
Prior Rx 
BRAF/MEK 
Time on 
Txt 
Best 
Outcome 
31/M 
Anaplastic 
PXA 
XRT+ TMZ, XRT, 
Dabrafenib/ 
trametinib 
14 mo 
PR 
35/F 
Epitheliod 
GBM 
XRT+TMZ, gliadel 
Dabrafenib/ 
trametinib 
30 mo 
PR 
28/F 
Epitheliod 
GBM 
None 
Dabrafenib/ 
trametinib 
11 mo 
PR 
32/F 
Anaplastic 
PXA 
XRT, vem+bev, 
Bev+CCNU 
Dabrafenib/ 
trametinib 
8 mo 
PR 
21/F 
Anaplastic 
PXA 
XRT, Vem, Dab 
Dabrafenib/ 
trametinib 
3 mo 
PR 
48/F 
Anaplastic 
PXA 
XRT, PCV, TMZ, 
Carboplatin 
Dabrafenib/ 
trametinib 
11 mo 
PR 
24/M 
Anaplastic 
PXA 
XRT+TMZ, Bev 
Dabrafenib/ 
trametinib 
3 mo 
PR 
Table 3: Published reports of BRAF/MEK inhibitor combined therapy in adults with high grade glioma. 
Legend: PXA = pleomorphic xanthoastrocytoma; GBM = glioblastoma; RT = radiation therapy; TMZ = 
temozolomide; PCV = procarbazine, lomustine and vincristine; Bev = bevacizumab; Vem = vemurafenib, 
Dab = dabrafenib; CCNU = lomustine; PR = partial response. 
 
2.6 
Correlative Studies Background 
  
BRAF-V600 DNA Mutant Fraction in CSF and Plasma 
 
Circulating tumor DNA (ctDNA) detected in 
plasma is becoming a powerful tool for 
detecting 
remission 
or 
progression 
in 
systemic cancers. (46-50) However, ctDNA is 
a generally insensitive tool for brain tumors. 
Our collaborators have demonstrated that 
cerebrospinal fluid (CSF) may be a more 
sensitive means of detecting circulating DNA 
(CSF-tDNA) than blood (Figure 2). (47) We 
intend to determine how sensitively and 
reliably ctDNA mutations can be detected in 
patients undergoing a uniform treatment 
regimen. ctDNA will be quantified from both 
CSF and plasma, and analyzed over time in 
patients who contribute multiple samples. 
Figure 2: Detection of CSF-tDNA from 
primary brain tumors as derived from 
ventricular or lumbar CSF. Detected in 
18/19 HGG and 8/15 LGG 
0
10
20
30
40
50
60
70
80
90
100
HGG
LGG
% of patients with + CSF-
tDNA (matching tumor)
18/19 
7/15 


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3.0 
PATIENT ELIGIBILITY CRITERIA 
 
 
3.1 
Patient Sample 
 
Sample Size:  
 
 
 
Minimum: 28 patients / Maximum: 62 patients 
 
 
Accrual Rate: 
 
1 patient per month  
 
 
 
Gender: 
 
Male and female 
 
Age: 
 
Patients must be at least 18 years of age.  
 
Race: 
 
Minorities will be actively recruited.  No exclusion to this study will be based on race or 
ethnicity.  
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
5 
0 
0 
7 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
5 
0 
0 
9 
White 
14 
21 
3 
8 
46 
More Than One Race 
0 
0 
0 
0 
0 
Total 
20 
31 
3 
7 
62 
 


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3.2 
Inclusion Criteria 
Patients eligible for inclusion in this study must meet all the following criteria within 30 days 
unless otherwise specified: 
1. Subjects must have histologically confirmed high-grade glioma at diagnosis or 
recurrence (including but not limited to glioblastoma (GBM), anaplastic astrocytoma 
(AA), and gliosarcoma), or other high-grade primary brain tumor [including but not 
limited 
to 
anaplastic 
pleomorphic 
xanthoastrocytoma 
(aPXA), 
anaplastic 
ependymoma, and anaplastic ganglioglioma (AG)], that is recurrent after irradiation.  
2. Patients must have a previously documented BRAF-V600 E or K mutation as 
performed by PCR or next generation sequencing in a CLIA-approved laboratory 
(including but not limited to Caris and FoundationOne). 
3. Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing 
disease by MRI imaging within 30 days of starting treatment.  
4. The following intervals from previous treatments are required to be eligible: 
• 12 weeks from the completion of radiation.  
• 16 weeks from an anti-VEGF therapy 
• 4 weeks from a nitrosourea chemotherapy 
• 3 weeks from a non-nitrosourea chemotherapy 
• 2 weeks or 5 half-lives from any investigational (not FDA-approved) 
agents  
• 2 weeks from administration of a non-cytotoxic, FDA-approved agent 
(e.g., erlotinib, hydroxychloroquine, etc.) 
 
5. Patients must be 18 years of age or older.  
6. Patients must have a Karnofsky Performance (KPS) Status  60%. 
7. Patients must have the following organ and marrow function within 30 days of starting 
treatment:  
Absolute neutrophil count 
>1,000/mcL 
Platelets 
>100,000/mcL 
Hemoglobin 
> 9 g/dL 
Total bilirubin                           1.5 x institutional upper limit of normal (ULN) 
OR total bilirubin >1.5 × ULN with direct bilirubin 
< 1.5 × ULN; 
AST (SGOT)/ALT (SGPT) 
 3 x institutional ULN 
Creatinine  
 
≤ 1.5 x institutional ULN 
 
                    OR 
Creatinine clearance   
 
> 50 ml/min/1.73m2 for patients with creatinine 
levels above institutional normal 
APTT or PTT 
 
≤ 
1.5 
x 
institutional 
ULN; 
subjects 
on 
anticoagulation may be permitted to participate 
LVEF   
 
 
> 50% as determined by MUGA or ECHO 
QTc Interval  
 
 480 ms per triplicate averaged baseline ECG. 
 


14 
 
 
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8. Patients must be able to provide written informed consent. 
9. Women of childbearing potential must have a negative serum pregnancy test prior to 
study start. Women of childbearing potential must agree to use adequate contraception 
(intrauterine device, barrier, or other non-hormonal method of birth control; or 
abstinence) and not to donate ova from screening through 30 days after the last dose of 
study drug. Male participants must also agree to use adequate contraception and not to 
donate sperm from screening until 90 days after the last dose of study drug.   
10. Patients must be maintained on a stable or decreasing dose of systemic corticosteroid 
regimen (no increase for 5 days) prior to baseline MRI. Topical and inhaled steroid 
treatment is allowed. 
11. Patients must have no concurrent malignancy except curatively treated basal or 
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or 
bladder.  Patients with other malignancies must be disease-free for  2  years. 
12. Patients must be able to swallow tablets and capsules.  
13. Patients must have a tumor tissue form completed and signed by a pathologist; sites 
must agree to provide this form within 14 days after treatment start (see Section 9.6.4). 
The tumor tissue form must indicate availability of archived tissue. The archived 
tissue should be from the most recent tumor resection, demonstrating active tumor 
when sufficient tissue is available.  If sufficient tissue is not available from the most 
recent surgery, then tissue from an earlier surgery is acceptable, if available, including 
from the initial resection at diagnosis.  
3.3 
Exclusion Criteria 
Patients meeting any of the following criteria are excluded from the study: 
1. 
Patients receiving any other standard or investigational agents are ineligible. 
2. 
Patients with history or current evidence of the following conditions are excluded: 
neuromuscular disorder with associated elevated CK (e.g. inflammatory myopathies, 
muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy), 
pancreatitis, retinal vein occlusion, uncontrolled HIV, or Hepatitis B/C. An exception 
will be made for (HIV)-infected patients on effective anti-retroviral therapy with 
undetectable viral load within 6 months and for subjects with cleared HBV and HCV 
infections, who may enroll in the study. 
3. 
Known hypersensitivity or contraindication to any component of binimetinib or 
encorafenib or their excipients  
4. 
Current use of a prohibited medication (including herbal medications, supplements, 
or foods), as described in Section 4.4, or use of a prohibited medication ≤ 7 days prior 
to the start of study treatment. 
5. 
Patient has not recovered to ≤ Grade 1 non-hematologic toxic effects of prior therapy 
before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are 
not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related 
endocrinopathies) are exceptions and may enroll. 


15 
 
 
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6. 
Impaired cardiovascular function or clinically significant cardiovascular disease 
including, but not limited to, any of the following:  
• 
History of acute coronary syndromes (including myocardial infarction, 
unstable angina, coronary artery bypass grafting, coronary angioplasty or 
stenting) ≤ 180 days prior to start date; 
• 
Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥ 2);  
• 
Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA 
or ECHO;  
• 
Uncontrolled hypertension defined as persistent systolic blood pressure 
≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current 
therapy; 
• 
History or presence of clinically significant cardiac arrhythmias (including 
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled 
paroxysmal supraventricular tachycardia); 
• 
Triplicate average baseline QTc interval ≥ 480 ms. 
7. 
Impairment of gastrointestinal function or disease which may significantly alter the 
absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or 
diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal 
absorption), or recent (≤ 90 days) history of a partial or complete bowel obstruction, 
or other conditions that will interfere significantly with the absorption of oral drugs. 
8. 
History of recent (≤ 90 days) thromboembolic or cerebrovascular event such as 
transient ischemic attack, cerebrovascular accident, or hemodynamically significant 
(massive or sub-massive) deep vein thrombosis or pulmonary emboli (DVT/PE). 
Note: Patients with DVT/PE that does not result in hemodynamic instability may 
enroll as long as they are anticoagulated for at least 4 weeks. Note: Patients with 
DVT/PE related to indwelling catheters or other procedures may enroll. 
9. 
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection or psychiatric illness/social situations that would limit compliance 
with study requirements, are ineligible.  
10. Pregnant women are excluded from this study because the effects of encorafenib 
and/or binimetinib on a fetus are unknown.  Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treatment of the mother with 
encorafenib or binimetinib, breastfeeding should be discontinued if the mother is 
treated with encorafenib and/or binimetinib.  
11. Patients who previously received BRAF or MEK inhibitors are excluded (including 
but not limited to dabrafenib, vemurafenib, encorafenib, sorafenib, trametinib, 
binimetinib, cobimetinib, or selumetinib). 
12. Patients will be excluded if their tumor harbors a known RAS activating mutation. 
This does not need to be specifically tested for eligibility.  
 


16 
 
 
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3.4 
Additional Inclusion Criteria for Surgical Arm 
 
Patients must meet the above inclusion / exclusion criteria for consideration with one 
exception. Patients with a BRAF-V600 E or K mutated low-grade glioma for whom there 
is a strong clinical suspicion of progression to high-grade would also be eligible for this 
arm. Additionally: 
 
1. Patients must have a clinical indication for a tumor surgery. 
 
2. No a priori contraindication to biospecimen collection (blood, tumor, CSF). 
 
 
4.0 
TREATMENT PLAN 
 
This is a Phase II, open-label, multicenter efficacy study of encorafenib in combination 
with binimetinib in adult patients with recurrent BRAF-V600E/K mutated high-grade 
primary brain tumors. The goal of this study is to estimate the efficacy of encorafenib and 
binimetinib as measured by radiographic response in recurrent high-grade primary brain 
tumors.  
 
There are two arms: medical and surgical. All subjects on the medical arm must have 
histologically confirmed high-grade glioma (including but not limited to glioblastoma 
(GBM), anaplastic astrocytoma (AA), and gliosarcoma), anaplastic pleomorphic 
xanthoastrocytoma (aPXA) or other high-grade primary brain tumor (including but not 
limited to anaplastic ganglioglioma (AG), and anaplastic ependymoma) that is recurrent 
after first-line treatment. Subjects on the surgical arm must have a high-grade glioma or a 
known BRAF-mutated low-grade glioma with high clinical suspicion for progression to 
high-grade. 
 
 
 


17 
 
 
Version 05/24/2021 
 
4.1 
Treatment Schema  
 
Medical Arm Treatment Schema 
 
Following enrollment, patients will receive encorafenib and binimetinib at the FDA-
approved dose of 450 mg of encorafenib once daily and the FDA-approved dose of 45 mg 
of binimetinib twice daily separated by 12 hours, continuously in 28-day cycles until 
progression or unacceptable toxicity. Patients will be followed by routine blood work, and 
general and neurological examination. A brain MRI will be performed prior to every odd-
numbered cycle (every 8 weeks). Response will be assessed by RANO criteria (Section 
8.1). Patients may remain on study and receive treatment until progression or as otherwise 
determined in Section 10.1.  
 
 
 
 
 


18 
 
 
Version 05/24/2021 
 
Surgical Arm Treatment Schema 
Subjects in the surgical cohort must be candidates for a clinically-indicated surgery and must have 
a BRAF V600E/K-mutated high-grade glioma or a low-grade glioma with high clinical suspicion 
for progression to high-grade. These subjects will take encorafenib and binimetinib in combination 
at their FDA-approved doses (see Section 4.3 for administration details) for 10-14 days prior to 
surgery, with a preference for 14 days, though a minimum of 10 days is acceptable.  The last dose 
of both drugs will be administered two hours prior to surgery. Specimens will be collected as 
described in Section 9.6 and processed as described in the Laboratory Manual. 
After surgery, the subjects will not take further encorafenib or binimetinib until a study visit to 
assess their neurological exam, physical exam (or telemedicine physical evaluation), and 
performance status, at 2-6 weeks post-operatively. At time of restarting combination treatment, 
subjects will follow the schedule listed above for the medical cohort, and will continue treatment 
as defined in Section 10.1. 
Patients with histopathology inconsistent with high-grade glioma (either treatment effect or low 
grade glioma) will be replaced. Overall survival will be assessed from the first day that patient 
receives drug to death from any cause. 
 
 
 


19 
 
 
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Required Ophthalmology Exam for the Medical and Surgical Arms  
 
A full ophthalmic examination will be performed by an ophthalmologist at Screening, and 
include best corrected visual acuity, slit lamp examination, intraocular pressure, dilated 
fundoscopy and Ocular Coherence Tomography (OCT). Examination of the retina is 
required, especially to identify findings associated with serous retinopathy and RVO. On 
study, patients receiving binimetinib should be assessed at every physical examination for 
decreased visual acuity using a gross perimetry test (as opposed to automated visual field 
testing) in person or by telemedicine evaluation.  Symptomatic patients should be referred 
for a full ophthalmic consultation.  
• For patients with clinical suspicion of retinal abnormalities of any grade 
(e.g., serous retinopathy, RVO, photopsia, metamorphopsia, impairment of 
visual acuity), these additional assessments should be mandatory:  
Non-vascular abnormalities: spectral domain OCT recommended Vascular abnormalities: 
fluorescein angiography of the central 30 degrees. 
 
4.2 
Treatment Requirements for subsequent cycles 
  
If patients do not meet stopping criteria for encorafenib or binimetinib, and their study 
drugs are not being held based on their adverse events (per CTCAE version 5.0 defined 
in Section 5.1), they will proceed with the next cycle. 
 
4.3 
Encorafenib and Binimetinib Administration 
 
Encorafenib will be administered in combination with binimetinib using the FDA approved 
doses. The dose of encorafenib is 450 mg orally once daily, taken with binimetinib. The 
dose of binimetinib is 45 mg orally twice daily, taken approximately 12 hours apart.  It is 
recommended that both study drugs be taken in the morning rather than the evening. The 
study drugs may be taken with or without a meal.  
 
Medical Arm patients: Encorafenib and binimetinib are taken every day for each 28 day 
cycle. 
 
Surgical Arm patients: Encorafenib and binimetinib are taken for 10-14 days prior to 
surgery (preferably 14 days, though a minimum of 10 days is acceptable).  The last dose 
of both drugs will be taken two hours prior to surgery. Following recovery from surgical 
resection (2-6 weeks), encorafenib and binimetinib are taken every day for each 28 day 
cycle.  
 
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled.  
 
If a subject misses a dose of binimetinib, the subject may take the dose immediately if the 
next dose is scheduled for at least 6 hours later. If the next scheduled dose of binimetinib 


20 
 
 
Version 05/24/2021 
 
is due in less than 6 hours, the subject should skip the dose and resume binimetinib dosing 
at the next scheduled dose.  
 
If a subject misses a dose of encorafenib, the subject may take the dose immediately if the 
next dose is scheduled for at least 12 hours later. If the next scheduled dose of encorafenib 
is due in less than 12 hours, the subject should skip the dose and resume encorafenib dosing 
at the next scheduled dose. 
 
Treatment will generally be administered on an outpatient basis. Patients will be provided 
with medication diaries (Appendix I-IV) and instructed in their use. Patients will be 
instructed to bring all unused medication and their diaries to each study visit for assessment 
of compliance. 
 
Because study treatment is intended for self-administration, if coming to the clinic 
presents a safety risk, it is permitted to ship the study drug and the appropriate medication 
diaries to the patient’s residence before the scheduled cycle Day 1.  The study drug 
should be shipped by a secure delivery method with package tracking and a delivery 
confirmation. The regulatory requirements for maintaining investigational product remain 
and should be addressed and documented. 
 
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the patient's malignancy.  
 
4.4 
General Concomitant Medication and Supportive Care Guidelines 
 
 
4.4.1 Permitted Concomitant Therapy Requiring Caution and/or Action 
 
Encorafenib has been identified in vitro to be metabolized by CYP3A4 and to a lesser 
extent by CYP2C19. Concomitant use of moderate CYP3A4 inhibitors while on study 
should be avoided. If use of moderate CYP3A4 inhibitors is unavoidable and no 
alternatives are available, short-term use (≤ 30 days) is permitted with accompanying dose 
reduction to one-half of the encorafenib dose prior to use of moderate CYP3A4 inhibitors 
(or as close as can be achieved without exceeding the target dose). The encorafenib dose 
that was taken prior to initiating the CYP3A4 inhibitor may be resumed after the inhibitor 
has been discontinued for 3 to 5 elimination half-lives. Strong inhibitors of CYP2C19 
should be used with caution when co-administered with encorafenib.   
 
Encorafenib is a reversible inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP3A4 
and UGT1A1. It is also a time-dependent inhibitor of CYP3A4, and induced CYP2B6, 
CYP2C9 and CYP3A4 in human primary hepatocytes. Permitted medications to be used 
with caution in this study include those that are sensitive substrates of CYP1A2, CYP2B6, 
CYP2C9, CYP2C9, CYP3A4, and UGT1A1 or those substrates that have a narrow 
therapeutic index. 
 
There is a potential for encorafenib to induce CYP3A4, which may reduce the effectiveness 
of hormonal contraception methods. Therefore, the use of at least 1 form of non-hormonal 


21 
 
 
Version 05/24/2021 
 
contraception is required for females of childbearing potential during participation in this 
study. Caution should be used in participants receiving concomitant treatment with other 
drugs that are substrates of CYP3A4 as the efficacy of these drugs could be reduced when 
administered with encorafenib.  
 
In vitro data showed that encorafenib is a substrate of the transporter P-gp. Thus, drugs that 
are known to inhibit or induce P-gp should be used with caution. Encorafenib is also a 
potent inhibitor of the renal transporters, OAT1, OAT3 and OCT2, and the hepatic 
transporters OATP1B1 and OATP1B3. The co-administration of drugs that are known to 
be sensitive or narrow therapeutic index substrates of OAT1, OAT3, OCT2, OATP1B1 or 
OATP1B3 should be used with caution. 
 
In vitro, binimetinib has been identified to be primarily metabolized by glucuronidation 
through UGT1A1. Binimetinib has also been shown to be a substrate of P-gp and BCRP. 
It is advised that inhibitors and inducers of UGT1A1, P-gp or BCRP transporters should 
be taken with caution when co-administered with binimetinib.  
 
For a listing of examples of substrates, inhibitors and inducers to be used with caution, 
please consult with the FDA website: Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers.  Note that this list is not exhaustive. 
 
Investigators should use caution when administering encorafenib or binimetinib with 
concomitant medications with a known, conditional or possible risk to prolong the QT 
interval and/or induce TdP. Subjects receiving such medications must be carefully 
monitored for potentiation of toxicity due to any individual concomitant medication, and 
may require dose titration of the concomitant medication. See the CredibleMeds® website 
for examples: Combined List of Drugs That Prolong QT and/or cause Torsades de Pointes 
(TDP). Note that this list is not exhaustive. 
 
4.4.2 Prohibited Concomitant Medications During Study 
 
   
Patients may receive other medications that the investigator deems to be medically 
necessary, with the specific exception of non-protocol specified chemotherapy, 
radiotherapy, anti-neoplastic biological therapy or other investigational agents.  Patients 
who require the use of any of the aforementioned treatments for clinical management 
should be removed from the study. 
 
Per FDA labeling, administration of encorafenib along with a strong or moderate CYP3A4 
inhibitor increases encorafenib plasma concentrations and may increase adverse reactions. 
The use of strong inhibitors of CYP3A4 is prohibited. Concomitant administration of 
encorafenib with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma 
concentrations and decrease encorafenib efficacy. Use of moderate and strong inducers of 
CYP3A4 is prohibited. Similarly, concomitant administration of encorafenib with sensitive 
CYP3A4 substrates my result in increased toxicity or decreased efficacy. Specifically, co-
administration of encorafenib with hormonal contraceptives (CYP3A4 substrates) can 
result in decreased concentrations and loss of hormonal contraceptive efficacy. Avoid 


22 
 
 
Version 05/24/2021 
 
hormonal contraceptives.    
 
The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential for drug interactions. The study team should check a frequently-
updated medical reference for a list of drugs to avoid or minimize use thereof.    
 
 
 
4.4.3 Corticosteroids 
The lowest required corticosteroid dose should be maintained throughout the duration of 
the study in order to eliminate steroid effects as a confounding variable in the interpretation 
of serial brain imaging studies. Corticosteroid doses can be tapered as clinically indicated 
if the patient appears to be responding to therapy as judged by serial scans. Alternatively, 
corticosteroid dose may be increased in the event of clinical deterioration or at the 
discretion of the attending physician. In the event of suspected clinical deterioration, repeat 
brain imaging is recommended. 
4.4.4 Herbal and Non-Traditional Medications 
 
 
 
No data exist regarding the interaction of encorafenib and binimetinib with commonly used 
herbal or non-traditional medications. Patients should be instructed not to use such 
medications while receiving encorafenib and binimetinib therapy. 
4.5  
Lifestyle Considerations 
4.5.1 Contraception  
Female participants of childbearing potential 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. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). If fertility is unclear (e.g., amenorrhea in 
adolescents or athletes) and a menstrual cycle cannot be confirmed before first dose of 
study treatment, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 


23 
 
 
Version 05/24/2021 
 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), Investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required.  
• Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 
4.5.2 Contraception Guidance: 
 
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 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 pregnancy: 
• 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) 


24 
 
 
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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 
 
4.5.3 Meals and Dietary Restriction  
 
Participants must avoid consumption of grapefruit, pomegranates, star fruits, Seville 
oranges or products containing the juice of each during the entire study and preferably 7 
days before the first dose of study drugs, due to potential CYP3A4 interaction with 
encorafenib. Orange juice is allowed. 
 
4.5.4 Activity  
 
Strenuous physical activities, such as competitive sports, can result in significant increases 
in CK levels while on binimetinib treatment. Participants should be cautioned not to start 
a new strenuous exercise regimen after first dose of study treatment. 
 
 
  
5.0 
DOSING DELAYS/DOSE MODIFICATION FOR TOXICITY 
 
Clinically significant adverse events or abnormal laboratory values assessed as unrelated 
to disease progression, intercurrent illness, or concomitant medications may require dose 
delay and/or dose modification. Such toxicities must have an attribution of possible, 
probable, or definite to encorafenib and/or binimetinib (see Section 9.3). If multiple 
toxicities occur, dose modification decisions should be based on the most severe toxicity. 
If there is any question or clarification required concerning a toxicity, the treating site 
should contact the ABTC Central Office to determine patient’s toxicity status.  The ABTC 
Central Office, with the Study Chair (who may consult with Pfizer) will make the final 
decision. 
 
5.1 
Dose Modification for Encorafenib and Binimetinib 
 
The dose levels and the general approach to encorafenib and/or binimetinib dose 
modification on this trial are shown below. Adverse events (AEs) should be treated with 
the appropriate maximum supportive care, and dose reductions should be clearly recorded 
on the case report form. 
 
Dose modifications are required for any clinically significant toxicity and are defined 
below.  
• In general, if toxicity occurs that is attributed to only one of the agents, 
only that agent should be dose-reduced/modified.  
• If administration of binimetinib is interrupted, administration of 
encorafenib may be continued, but at a maximal dose of 300 mg per day.  


25 
 
 
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• If administration of encorafenib is interrupted, administration of 
binimetinib may be continued at the same dose 
• If either binimetinib or encorafenib are permanently discontinued, the 
other drug should also be discontinued and the patient removed from the 
study. 
 
If there is any question, Serena Desideri (sdeside1@jhmi.edu) or Neeraja Danda 
(ndanda1@jhmi.edu) at the  ABTC Central Office and the Study Chair should be contacted. 
 
Dose Reduction Schedule for Encorafenib 
 
 
 
 
 
 
 
Dose Reduction Schedule for Binimetinib 
Dose Level 
Binimetinib Dose/Schedule 
0 
45 mg twice daily 
-1 
30 mg twice daily 
-2 
15 mg twice daily 
 
Recommended Encorafenib Dose Modifications * 
*For adverse events that may be related to both encorafenib and binimetinib, guidance is 
provided for the other agent also.  
 
For patients with pre-existing disorder resulting in AE >1, the new event must resolve to at 
least the pre-existing baseline to resume treatment following the prescribed rules as outlined 
in the Modification Table.  
 
Severity of Adverse Event 
Dose Modifications 
New Primary Malignancies 
Non-cutaneous RAS mutation-
positive malignancies 
Permanently discontinue. 
Uveitis 
Grade 1-3 
If Grade 1 or 2 does not respond to specific ocular 
therapy, or for Grade 3 uveitis, withhold encorafenib 
and binimetinib for up to 6 weeks. 
• If improved, resume encorafenib and 
binimetinib at same or one reduced dose. 
• If not improved, permanently discontinue 
encorafenib and binimetinib. 
Grade 4  
Permanently discontinue encorafenib and binimetinib. 
Other Eye Disorders (i.e., non-Uveitis Events 
Dose Level 
Encorafenib Dose/Schedule 
0 
450 mg daily 
-1 
300 mg daily 
-2 
225 mg daily 
-3 
150 mg daily 


26 
 
 
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Severity of Adverse Event 
Dose Modifications 
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 days. 
 
• If resolved to Grade ≤ 1 in ≤ 21 days, resume 
treatment at one reduced dose level 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 
resolution. 
Grade 4 
Permanently discontinue encorafenib and binimetinib 
and immediate follow-up with ophthalmic monitoring 
(refer to footnote 18 of Table 9-1) until stabilization or 
resolution. 
QTc Prolongation 
QTc > 500 ms and ≤ 60 ms 
increase from baseline 
1st - 2nd occurrence:  
• Temporarily interrupt dosing of encorafenib 
until QTc < 500 ms. Then resume treatment at 1 
reduced dose level of encorafenib. 
3rd occurrence:  
• Permanently discontinue encorafenib. 
QTc > 500 ms and > 60 ms 
increase from baseline 
Permanently discontinue. 


27 
 
 
Version 05/24/2021 
 
Severity of Adverse Event 
Dose Modifications 
Hepatotoxicity 
Grade 2 AST or ALT  
Maintain encorafenib dose. 
• If no improvement within 2 weeks, withhold 
encorafenib until improved to Grade 0-1 or to 
pretreatment/baseline levels and then resume at 
the same dose. 
Grade 3 or 4 AST or ALT 
increased 
See Other Adverse Reactions 
Dermatologic (Except Hand-foot Skin Reactions) 
Grade 2 
Initiate supportive measures: 
• Avoid unnecessary sunlight, apply broad-
spectrum sunscreen at least twice daily.  
• Use mild-strength topical steroid 
(hydrocortisone 1% cream) or topical antibiotic 
(e.g., clindamycin) OR oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg 
BID)  
If no improvement within 2 weeks, withhold 
encorafenib until Grade 0-1. Resume at same dose if 
first occurrence  or reduce one dose level if recurrent. 
Grade 3 
Initiate supportive measures above. Withhold 
encorafenib until Grade 0-1. Resume at same dose if 
first occurrence  or reduce one dose level if recurrent. 
Grade 4 
Permanently discontinue encorafenib. 
Hand-foot Skin Reaction (HFSR)/Palmar-plantar Erythrodysesthesia Syndrome (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:  


28 
 
 
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Severity of Adverse Event 
Dose Modifications 
• 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 one reduced dose level based upon the 
Investigator’s discretion. 
Grade 3 
1st or additional occurrence:  
Interrupt dosing of encorafenib until resolved to 
Grade ≤ 1. Promptly initiate supportive 
measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-
style modifications. Reassess the patient 
weekly. Then resume treatment at one reduced 
dose level of encorafenib. 
• Consider referral to dermatologist and manage 
HFSR per dermatologist’s recommendation. 
> 3nd occurrence: 
Interrupt dosing of encorafenib until resolved to 
Grade ≤ 1, decision to resume treatment with 
encorafenib at one reduced dose level or permanently 
discontinue encorafenib should be based upon the 
Investigator’s discretion. 
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 one reduced dose level 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 one reduced dose level. 
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. 
Other Adverse Reactions (including renal, hemorrhage).  
Recurrent Grade 2 or  
First occurrence of any 
Grade 3 
Withhold encorafenib for up to 4 weeks. 
• If improves to Grade 0-1 or to pretreatment/baseline 
levels, resume at one reduced dose level. 
• If no improvement, permanently discontinue. 
First occurrence of any 
Grade 4 
Permanently discontinue encorafenib or withhold for up to 4 
weeks. 


29 
 
 
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Severity of Adverse Event 
Dose Modifications 
• If improves to Grade 0-1 or to pretreatment/baseline 
levels, then resume at one reduced dose level.  
• If no improvement, permanently discontinue. 
Recurrent Grade 3 
Consider permanently discontinuing. 
Recurrent Grade 4 
Permanently discontinue. 
 
Recommended Binimetinib Dose Modifications * 
*For adverse events that may be related to both encorafenib and binimetinib, guidance is 
provided for the other agent also. 
 
For patients with pre-existing disorder resulting in AE >1, the new event must resolve to at 
least the pre-existing baseline to resume treatment following the prescribed rules as outlined 
in the Modification Table.  
 
Severity of Adverse Event 
Dose Modifications 
Cardiomyopathy 
Asymptomatic, absolute 
decrease in LVEF of > 10% 
from baseline that is also 
below the LLN 
Withhold binimetinib for up to 4 weeks, evaluate LVEF every 
2 weeks. 
Resume binimetinib at one reduced dose level if the following 
are present: 
• LVEF is at or above the LLN and 
• Absolute decrease from baseline is 10% or less and  
• Patient is asymptomatic. 
If LVEF does not recover within 4 weeks permanently 
discontinue binimetinib. 
Grade 3-4 (Symptomatic 
congestive heart failure or 
absolute decrease in LVEF 
of > 20% from baseline that 
is also below LLN) 
Permanently discontinue binimetinib. Closely monitor LVEF 
until resolution or up to 16 weeks. 
Venous Thromboembolism 
Uncomplicated DVT or PE 
Withhold binimetinib. 
• If improves to Grade 0-1, resume at one reduced dose 
level. 
• If no improvement, permanently discontinue 
binimetinib. 
Life threatening PE 
Permanently discontinue binimetinib. 
Serous Retinopathy 
Symptomatic serous 
retinopathy/ Retinal 
pigment epithelial 
detachments 
Withhold binimetinib for up to 10 days. 
• If improves and becomes asymptomatic, resume at the 
same dose. 
• If not improved, resume at one reduced dose level or 
permanently discontinue binimetinib. 
Retinal Vein Occlusion (RVO) 


30 
 
 
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Severity of Adverse Event 
Dose Modifications 
Any Grade 
Permanently discontinue binimetinib. 
Uveitis 
Grade 1-3 
If Grade 1 or 2 does not respond to specific ocular therapy, or 
for Grade 3 uveitis, withhold binimetinib and encorafenib for 
up to 6 weeks. 
• If improved, resume at same or one reduced dose level. 
• If not improved, permanently discontinue binimetinib 
and encorafenib. 
Grade 4  
Permanently discontinue binimetinib and encorafenib. 
Other Eye Disorders (i.e., Non-retinal Events, non-Uveitis 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 days. 
• If resolved to Grade ≤ 1 in ≤ 21 days, resume treatment 
at one reduced dose level 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 resolution.  
Grade 4 
Permanently discontinue encorafenib and binimetinib and 
immediate follow-up with ophthalmic monitoring until 
stabilization or resolution. 
Interstitial Lung Disease 
Grade 2 
Withhold binimetinib for up to 4 weeks. 
• If improved to Grade 0-1, resume at one reduced dose 
level. 
• If not resolved within 4 weeks, permanently 
discontinue. 
Grade 3 or Grade 4 
Permanently discontinue. 
Hepatotoxicity 
Grade 2 AST or ALT 
increased 
Maintain binimetinib dose.  
• If no improvement within 2 weeks, withhold 
binimetinib until improved to Grade 0-1 or to 
pretreatment/baseline levels and then resume at the 
same dose. 
Grade 3 or 4 AST or ALT 
increased 
See Other Adverse Reactions 
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations 
Grade 4 asymptomatic CPK 
elevation or 
Any Grade CPK elevation 
with symptoms or with 
Withhold binimetinib dose for up to 4 weeks. 
• If improved to Grade 0-1 resume at one reduced dose 
level. 


31 
 
 
Version 05/24/2021 
 
Severity of Adverse Event 
Dose Modifications 
renal impairment 
• If not resolved within 4 weeks, permanently 
discontinue binimetinib. 
Dermatologic  
Grade 2 
Implement supportive measures as above under encorafenib, 
dermatologic. If no improvement within 2 weeks, withhold 
until Grade 0-1. Resume at same dose if first occurrence or at 
one reduced dose level if recurrent. 
Grade 3 
Withhold until Grade 0-1. Resume at same dose if first 
occurrence or reduce one dose level if recurrent. 
Grade 4 
Permanently discontinue. 
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 one reduced dose level 
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 one reduced 
dose level. 
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. 
Other Adverse Reactions 
(including hemorrhage) 
 
Recurrent Grade 2 or  
First occurrence of any 
Grade 3 
Withhold for up to 4 weeks. 
• If improves to Grade 0-1 or to pretreatment/baseline 
levels, resume at one reduced dose level. 
• If no improvement, permanently discontinue. 
First occurrence of any 
Grade 4 
Permanently discontinue or withhold for up to 4 weeks. 
• If improves to Grade 0-1 or to pretreatment/baseline 
levels, then resume at one reduced dose level.  
• If no improvement, permanently discontinue. 
Recurrent Grade 3 
Consider permanently discontinuing. 
Recurrent Grade 4 
Permanently discontinue. 
 
 
 


32 
 
 
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5.2 
Encorafenib and Binimetinib Dose Re-Escalation Guidelines 
 
The lowest recommended dose level of encorafenib is 150 mg QD and the lowest 
recommended dose level of binimetinib is 15 mg BID. When the AE that resulted in a dose 
reduction improves to and remains stable at the patient’s baseline level for a minimum of 
14 days, the dose can be re-escalated to the next dose level at the discretion of the 
Investigator, provided there are no other concomitant toxicities that would prevent drug re-
escalation. There is no limit to the number of times the patient can have their dose reduced 
or re-escalated, however: 
• No dose re-escalation of encorafenib is allowed after a dose reduction due to 
prolonged QTc ≥ 501 msec  
• No dose re-escalation of binimetinib is allowed after a dose reduction due to LVEF 
dysfunction  
• No dose re-escalation of binimetinib or encorafenib is allowed after a dose 
reduction due to retinal toxicity ≥ Grade 2. 
Please refer to Dose Modification Table for recommended dose modifications for 
encorafenib and/or binimetinib, if applicable, based on the occurrence of treatment-related 
AEs. If a patient is re-escalated on a drug, please note this clearly on the case report forms 
and notify the ABTC Central Office that re-escalation is taking place.  
5.3 
Major Events 
Major Events are non-treatment-related grade 3 and 4 hematologic and non-hematologic 
toxicities. Treatment should be delayed for major events if encorafenib and binimetinib may 
further complicate the non-treatment-related event.  If a major event requires a delay of 
treatment, treatment must be delayed until toxicity is resolved (≤ grade 1 [or tolerable grade 
2 for non-hematologic toxicity] or ≤ baseline). If toxicity is not resolved in  6 weeks, the 
patient may be removed from treatment, pending discussion with the ABTC Central Office. 
The ABTC Central Office should be consulted if you are not clear on whether to continue 
or delay treatment. 
5.4 
Use of Hematologic Growth Factors 
During the first 28 days of treatment, granulocyte colony stimulating factor (G-CSF) should 
be administered only for severe or prolonged neutropenia or for neutropenic sepsis.  There 
will be no constraint on the use of growth factors during subsequent treatment; however, 
prophylactic use is discouraged and adherence to the American Society of Clinical 
Oncology (ASCO) guidelines is recommended (JCO, 12, 1994: pp 2471-2508).  Patients 
should receive all necessary supportive care, including blood products, transfusions, 
antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies 
(insulin, thyroid hormones, estrogen/progesterone). 
5.5 
Toxicity Criteria 
All toxicities will be described and graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/ 
electronic_applications/ctc.htm). See also Section 9.3, Recording of Adverse Events. 


33 
 
 
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6.0 PHARMACEUTICAL INFORMATION 
 
6.1  
Encorafenib  
Other Names:  Braftovi, LGX818 
Information: Encorafenib is manufactured by Pfizer and is supplied as hard gelatin 
capsules in a dosage strength of 75 mg. Encorafenib capsules consist of encorafenib drug 
substance, 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 and yellow, ferrosoferric oxide, and monogramming ink.  The capsule has a beige 
cap with a stylized “A” and a white body on which is written “LGX 75mg”. 
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 polypropylene, child-resistant screw cap. Each bottle 
contains 90 capsules of Encorafenib. Encorafenib bottles will be labeled, 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 Pfizer and should 
not be repackaged at the site or pharmacy. 
Stability: Refer to documentation enclosed with each shipment for expiration date. This is 
not included on the label for this product but will be provided with each shipment. 
Route of Administration:  Oral administration. Take encorafenib by mouth once daily with 
or without food. If a dose is missed, the dose can be taken if it is more than 12 hours until the 
next dose, otherwise it should be skipped. 
6.2  
Binimetinib 
Other Names:  Mektovi, MEK162 
Information: Binimetinib is manufactured by Pfizer 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 with a stylized “A” on one side and “15” on the 
other side.  
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 polypropylene, child-resistant screw cap. Each bottle 
contains 180 tablets of Binimetinib. Binimetinib bottles will be labeled, 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 Pfizer and should 
not be repackaged at the site or pharmacy. 
Stability:  Refer to documentation enclosed with each shipment for expiration date. This is 
not included on the label for this product but will be provided with each shipment. 


34 
 
 
Version 05/24/2021 
 
Route of Administration:  Oral administration. Take binimetinib by mouth twice daily with 
or without food approximately 12 hours apart. If a dose is missed, the dose can be taken if it 
is more than 6 hours until the next dose, otherwise it should be skipped. 
6.3  
Agent Ordering  
The investigator or those named as sub-investigators on the Statement of Investigator Form 
1572 agree to supply study drugs only to those subjects enrolled in the study.  The 
investigator or designee will keep a current and accurate inventory of all clinical drug 
supplies provided by Pfizer.  The study site will maintain a dispensing log.  
Once a site has submitted all required regulatory documents to ABTC (Forms 
1572, curriculum vitae (CV), licenses, Institutional Review Board (IRB) protocol 
approval) an initial supply of drug can be ordered. An ABTC drug order form, which can 
be found on the ABTC website (ABTConsortium.org), should be emailed to the ABTC 
Central Office to initiate sending drug.    The ABTC Central Office will forward the drug 
order form to Pfizer.  Please allow 7 days from the receipt of the drug order at Pfizer for 
drug shipment. 
6.4  
Agent Accountability 
Each institutional investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all drugs received from Pfizer, 
using the NCI Oral Drug Accountability Record Form (Oral DARF).  
Upon termination of the study the investigator or designee must complete a final inventory 
of supplies. Unused study drug should be disposed of per institutional pharmacy policy and 
noted in the record. 
6.5 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov 
 
7.0 
PROCEDURES FOR PATIENT ENTRY ON STUDY 
This study is supported by the NCI Cancer Trials Support Unit (CTSU) Regulatory Office 
and uses the Oncology Patient Enrollment Network (OPEN). 
7.1 
CTEP Registration Procedures 
 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical 
trial to register and renew their registration annually.  To register, all individuals must 
obtain 
a 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to Oncology Patient Enrollment Network (OPEN) 


35 
 
 
Version 05/24/2021 
 
or Rave or acting as a primary site contact) must complete their annual registration using 
CTEP’s 
web-based 
Registration 
and 
Credential 
Repository 
(RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are 
outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, 
training, 
employment, 
license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact 
the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites 
on the FDA Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
7.2 
Site Registration Requirements – Institutional Review Board Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but not 
limited to the following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 


36 
 
 
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• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and applied 
to the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their intent 
to open the study locally.  The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab → 
Regulatory Submission  
 
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
 
1818 Market Street, Suite 3000 
 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website.   
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ Click on the Regulatory tab  
▪ Click on the Site Registration tab 
▪ Enter your NCI # and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 


37 
 
 
Version 05/24/2021 
 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
7.3 
Patient Registration 
Patient enrollment will be facilitated using OPEN. All site staff will use OPEN. OPEN is a 
web-based registration system available for ABTC studies from 9 a.m. to 4:30 p.m. Eastern 
Time.  To access OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam ) and a 'Registrar' role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or 
NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or investigator 
receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. 
Since this study includes a Phase I component, patient enrollment for this study will be 
facilitated using the Slot-Reservation System in conjunction with the registration system on 
OPEN. Prior to discussing protocol entry with the patient, all site staff must use the CTSU 
OPEN Slot Reservation System to ensure that a slot on the protocol is available to the 
patient. Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll patients to this study.  
Prior to accessing OPEN, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the group web site as a tool to 
verify eligibility. 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
Access requirements for OPEN:  
• Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for 
credentialing in the CTSU members' web site.  
• To perform registrations, the site user must have been assigned the 'Registrar' role 
(or equivalent) on the relevant Group or CTSU roster.  
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Upon completion of the registration process in OPEN, sites must 
contact the ABTC Central Office to obtain confirmation of the patient’s registration and 
dose assignment.  
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL (https://open.ctsu.org). For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 


38 
 
 
Version 05/24/2021 
 
 
8.0 
RESPONSE ASSESSMENT / SAFETY AND QUALITY ASSURANCE 
 
8.1 
Criteria for Response Assessment 
 
Patients with measurable enhancing disease will be assessed by the high grade glioma 
(HGG) RANO (radiographic assessment in neuro-oncology) criteria54, while patients with 
no measurable enhancing mass and only T2/FLAIR abnormalities will be assessed using 
the low grade glioma (LGG) RANO criteria55.  For the purposes of this study, subjects 
should be re-evaluated at the end of every 2 cycles (approximately every 8 weeks) with a 
contrast-enhanced cranial MRI scan. The response will be determined as outlined in the 
RANO criteria below. 
 
Measurable Disease on HGG RANO. Bi-dimensionally, contrast-enhancing, measurable 
lesions with clearly defined margins by MRI scan, with a minimal size of 1 cm x 1 cm, and 
visible on 2 axial slices which are at least 5 mm apart with 0 mm skip. If there are >2 
lesions (multifocal) at baseline, the investigator must choose the largest two to be followed 
before a participant is entered on study. The remaining lesions will be considered non-
measurable for the purpose of objective response determination. Unless progression is 
observed, objective response can only be determined when all measurable and non-
measurable lesions are assessed.  
 
 
 
 


39 
 
 
Version 05/24/2021 
 
Complete Response – CR (requires all of the following): 
a) Complete disappearance of all enhancing measurable and non-measurable disease, 
including T2 or FLAIR hyperintense lesions, sustained for at least 4 weeks. In the 
absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease. 
b) No new lesions. 
c) All measurable and non-measurable lesions, including T2/FLAIR hyperintense 
lesions, must be assessed using the same techniques as baseline. 
d) Subjects must be off corticosteroids (or on physiologic replacement doses only). 
e) Stable or improved non-enhancing (T2/FLAIR) lesions. 
f) Stable or improved clinically. 
 
Note: Subjects with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
Partial Response – PR (requires all of the following): 
a) Greater than or equal to 50% decrease compared to baseline in the sum of products 
of perpendicular diameters of all measurable enhancing lesions (HGG RANO) or T2 
hyperintense lesions (LGG RANO), sustained for at least 4 weeks. In the absence of a 
confirming scan 4 weeks later, this scan will be considered only stable disease. 
b) No progression of non-measurable disease if HGG RANO is used. 
c) No new enhancing or non-enhancing lesions. 
d) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
e) The corticosteroid dose at the time of the scan evaluation should be no greater than 
the dose at time of baseline scan. 
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan if using HGG RANO. 
g) Stable or improved clinically. 
 
Note: Subjects with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
 
Stable Disease – SD (requires all of the following): 
a) Does not qualify for CR, PR, or progressive disease (PD). 
b) The designation of stable disease requires a minimum of 4-week duration. 
c) All measurable and non-measurable sites must be assessed using the same 
techniques as baseline. 
d) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose was increased for 
new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered to 
show stable disease will be the scan obtained when the corticosteroid dose was 
equivalent to the baseline dose. 
e) Stable clinically. 


40 
 
 
Version 05/24/2021 
 
Progressive Disease – PD (defined by any of the following): 
 
a) For HGG RANO: ≥25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared to the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids.*  
b) Any new enhancing or non-enhancing lesion. 
c) Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, etc.) or changes in corticosteroid dose. The definition of clinical 
deterioration is left to the discretion of the treating physician, but it is recommended 
that a decrease in 20% of KPS or from any baseline to 50% or less be considered, unless 
attributable to comorbid events. 
d) Failure to return for evaluation due to death or deteriorating condition. 
e) Clear progression of non-measurable disease. 
 
* Stable doses of corticosteroids include patients not on corticosteroids. 
 
8.2 
Assessment of Response 
 
Assessment of response will begin with the MRI performed just prior to every odd-
numbered treatment cycle. If during any scheduled MRI, the subject has a Complete 
Response or Partial Response, the MRI should be repeated prior to the next cycle.  All 
scans are to be compared to the smallest measurement scan to date.  The subject will then 
return to the every odd-numbered cycle schedule. This is required to confirm the duration 
of response.  Subjects will be classified as responders if they have a minimum duration of 
response for 4 weeks at any time after the first cycle of encorafenib and binimetinib. MRI 
scans of subjects showing tumor response (PR or CR) as determined locally will be 
centrally reviewed by a neuroradiologist who will independently assess tumor size, 
compute percent tumor regression, and provide the final determination of tumor response. 
 
8.3 
Safety Assessments 
 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology and blood chemistry, pregnancy 
testing (in women of childbearing potential), regular measurement of vital signs, and the 
performance of physical/neurological, ophthalmic, and dermatologic examinations; ECGs 
and other cardiac monitoring may be performed as necessary. 
 
 
8.4 
Quality Assurance 
 
Adherence to protocol therapy:  Screening/baseline source documentation will be 
submitted/uploaded into CTEP’s iMedidata Rave system and will be reviewed by the 
ABTC Central Office. As a quality assurance measure for the treatment delivered on this 
protocol, primary patient records may be reviewed. The records to be examined will be 
selected retrospectively and at random; complete records must therefore be maintained on 


41 
 
 
Version 05/24/2021 
 
each patient treated on the protocol.  These records should include primary documentation 
(e.g., laboratory report slips, X-ray reports, scan reports, pathology reports, physician 
notes, etc.), which confirm that: 
 
•  
The patient met each eligibility criterion. 
•  
Signed informed consent was obtained prior to treatment. 
• 
Treatment was given according to protocol (dated notes about doses given; any 
reasons for any dose modifications). 
•  
Toxicity was assessed according to protocol (laboratory report slips,  etc.). 
• 
Response was assessed according to protocol (MRI scan, lab reports, dated notes on 
measurements and clinical assessment, as appropriate). 
• 
 
NCI Drug Accountability Records were maintained for this protocol. 
 


42 
 
 
Version 05/24/2021 
 
9.0 
MONITORING OF PATIENTS 
9.1 
Table of Required Observations - Medical Arm and Surgical Arm 
Table 9.1 Required Observations – Medical and Surgical Arms. Encorafenib and 
Binimetinib (28-Day Cycles) 
 
 
1 – All baseline measurements must be done within minus 30 calendar days of  treatment 
administration unless otherwise specified 
2 – Including blood pressure, respiratory rate, heart rate, temperature, weight, height: height is 
required at baseline only; weight is required at each clinical evaluation.  
 
Base 
line 
Pre-
Surgery 
 
(surgical 
arm only) 
Day of 
Surgery 
 
(surgical 
arm only) 
Post-
Surgery 
 
(surgical 
arm only) 
Pre-Cycle 
1 
 
 (surgical 
arm only) 
Days 
1-28 of 
every 
cycle 
Pre 
Cycle 
2 
Pre 
Cycle 
3 
Pre 
Cycle 
4 
Pre 
Cycle 
5 
 
Pre 
Cycle 
6 
Pre- 
Cycle 
7 
Pre 
Even 
Cycles 
after 
Cycle 7 
Pre- 
Odd 
Cycles 
after 
Cycle 7 
Off  
Treat-
ment 
30 
Days 
Post-
final 
Dose 
Encorafenib 
 
6 
6 
 
 
6 
 
 
 
 
 
 
 
 
 
 
Binimetinib 
 
7 
7 
 
 
7 
 
 
 
 
 
 
 
 
 
 
Glucocorticoids 
Dose Evaluation 
1 
 
 
24 
5 
 
5 
5 
5 
5 
 
5 
5 
5 
5 
8 
10 
AE Evaluation 
1 
 
21 
24 
5 
 
5 
5 
5 
5 
5 
5 
5 
5 
8,10 9, 10 
MRI 
1,13 
 
 
24 
5, 25 
 
 
5, 13 
 
5,13 
 
5,13 
 
5, 13 
8 
 
H&P/Neuro 
Exam 
1 
 
 
 
5 
 
5 
5 
5 
5 
5 
5 
 
5 
8 
 
Ophthalmology 
Exam 
18 
 
 
 
 
 
5,18 5,18 5,18 5,18 5,18 5,18 
 
5,18 
 
 
Dermatology 
Exam 
1,19 
 
 
 
 
 
 
5,19 
 
5,19 
 
5,19 
 
5,19 
19 10,19 
KPS 
1 
 
 
 
5 
 
5 
5 
5 
5 
5 
5 
 
5 
8 
 
Vital Signs 
1,2 
 
 
 
2, 5 
 
2, 5 
2, 5 2, 5 2, 5 2,5 2, 5 
 
2, 5 
2,8 
 
Triplicate ECG 1,16,2
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or 
MUGA 
1 
 
 
 
 
 
17 
 
 
17 
 
 
 
 
 
 
CBC, Diff, 
Platelets 
1 
 
 
 
5 
 
5 
5 
5 
5 
5 
5 
5 
5 
8 
 
Serum 
Chemistry, CK, 
Troponin 
1,3 
 
 
 
3,5 
 
3, 5 
3, 5 3, 5 3, 5 3,5 
3, 5 
3, 5 
3, 5 
3,8 
 
APTT or PTT 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
Pregnancy Test 
1,4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research CSF 
5,15 
 
5,15 
 
 
 
 
5,15 
 
 
 
5,15 
 
 
5,15 
 
Research Blood 5,11 
 
5,22 
 
 
 
 
5,11 
 
 
 
5,11 
 
 
5,11 
 
Archived Tumor 
Tissue 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Tissue 
from Protocol 
Surgery  
 
 
23 
 
 
 
 
 
 
 
 
 
 
 
20 
 


43 
 
 
Version 05/24/2021 
 
3 – Including albumin, alkaline phosphatase, total bilirubin, bicarbonate, calcium, creatinine, 
creatinine kinase, glucose, potassium, total protein, troponin, SGOT, SGPT, sodium. 
4 – For women of child-bearing potential.   
5 – Within minus 7 calendar days of cycle start. 
6 – Surgical Arm: Pre-surgery, Encorafenib is administered once daily for 10-14 days prior to 
scheduled surgery, including the day of surgery (see Section 4.3). Patients are required to keep 
a medication diary (Appendix III). 
 
Medical Arm and Surgical Arm (Post-Surgery): Encorafenib is administered orally once daily 
on Days 1-28 of each 28-day cycle (see Section 4.3). Patients are required to keep a medication 
diary (Appendix II). 
7 – Surgical Arm: Pre-surgery, Binimetinib is administered orally twice daily for 10-14 days prior 
to scheduled surgery, including the day of surgery (see Section 4.3). Patients are required to 
keep a medication diary (Appendix III). 
 
Medical Arm and Surgical Arm (Post-Surgery): Binimetinib is administered orally twice daily 
on Days 1-28 of each 28-day cycle (see Section 4.3). Patients are required to keep a medication 
diary (Appendix I). 
8 – Evaluations done within +7 days of off treatment date unless indicated: do not repeat: if MRI 
within minus 14 days of off-treatment date; if  H&P/neuro, KPS, labs within minus 5 days of 
off-treatment date.  
9  – Adverse Events must be followed for at least 30 days from last dose of encorafenib and 
binimetinib. 
10 – Perform within +14 days of the 30-day post-last dose date. 
11 – Research blood for circulating tumor DNA (20 mL whole blood per time point) is to be 
collected at baseline, pre-Cycle 3, pre-Cycle 7, and at time of progression or off treatment. See 
Section 9.6.4. 
12 – NA  
13 – MRI with tumor measurements should be repeated every 8 weeks. See Section 4.1. 
14 – Archived tumor tissue from the most recent tumor resection will be collected from patients 
when sufficient tissue is available. See Section 9.6.6. 
15 – Surgical Arm: CSF will be collected during surgical procedure (required), prior to tumor 
disturbance. See Table 9.2.1  below and Section 9.6.4. 
 
CSF donation at the following time points is optional in Medical Arm and Surgical Arm 
patients and requires additional, specific consent on consent form. In patients who consent, it 
should be collected at baseline, prior to cycle 3, prior to cycle 7, and at progression (6 mL per 
time point) or off treatment. It can be collected via Ommaya reservoir or lumbar puncture. See 
Section 9.6.4. 
16 – ECG should be done prior to study enrollment, then as indicated clinically. 
17 – Echocardiogram or MUGA scan should be performed prior to study enrollment, prior to Cycle 
2, then every 3 cycles (i.e. cycle 5, 8, 11 etc..) thereafter unless indicated more frequently  
18 – A full ophthalmic examination will be performed by an ophthalmologist at Screening, and 
include best corrected visual acuity, slit lamp examination, intraocular pressure, dilated 
fundoscopy and Ocular Coherence Tomography (OCT). Examination of the retina is required, 
especially to identify findings associated with serous retinopathy and RVO. On study, patients 
receiving binimetinib should be assessed at every physical examination for decreased visual 
acuity using a gross perimetry test (as opposed to automated visual field testing) in person or 


44 
 
 
Version 05/24/2021 
 
by telemedicine evaluation.  Symptomatic patients should be referred for a full ophthalmic 
consultation.  
 
 * For patients with clinical suspicion of retinal abnormalities of any grade (e.g., 
serous retinopathy, RVO, photopsia, metamorphopsia, impairment of visual 
acuity), these additional assessments should be mandatory:  
• Non-vascular abnormalities: spectral domain OCT recommended  
• Vascular abnormalities: fluorescein angiography of the central 30 degrees. 
19 – Dermatology evaluation should be performed by a study team member at baseline and every 
8 weeks on trial, and for up to 6 months following discontinuation of encorafenib treatment. 
20 – Flash-frozen tissue and 20 unstained FFPE slides following guidelines in Section 9.6.5 should 
be obtained from all patients who progress and have a clinically-indicated surgical resection 
at time of progression. 
21 – Surgical Arm: patients should be seen on the day of surgery (prior to surgery) to evaluate for 
AEs. 
22 – Surgical Arm (and Medical Arm patients undergoing a clinically-indicated surgery for their 
brain tumor while on study): See “Blood” in the Table of Additional Required Observations 
below (Table 9.2.1) for details and also Section 9.6.5. 
23 – Surgical Arm (and Medical Arm patients undergoing a clinically-indicated surgery for their 
brain tumor while on study): See “Tumor Tissue” in the Table of Additional Required 
Observations below (Table 9.2.1) for details and also Section 9.6.5. 
24 – Within 3 days post-surgery. 
25 – Surgical Arm: Pre-Cycle 1 MRI does not need to be repeated if post-surgical MRI is within 
21 days of Cycle 1 start. 
26 – The ECG replicates should be extracted from the recordings at the predefined time points (5 
minutes apart (+ 5min) 
 
 
IMPORTANT: The guidance below is subject to applicable local Institutional Policy on telemedicine. In the event 
that local Institutional Policy regarding telemedicine differs from this guidance, then please follow local 
Institutional Policy. 
  
Telemedicine visits may be substituted for in person clinical trial visits or portions of clinical trial visits where 
determined to be appropriate and where determined by the investigator not to increase the participants risks. 
Required physical exams may be performed as a telemedicine physical evaluation, during telemedicine visits. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit 
entails and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine 
acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the 
event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will 
be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
  
Additionally, informed consent should be obtained in person, but if deemed necessary, via telemedicine. 
 
 


45 
 
 
Version 05/24/2021 
 
9.2  
Table of Additional Required Observations - Surgical Arm  
Patients on the surgical arm will be required to undergo all baseline observations as detailed for 
the medical arm in Section 9.1 prior to surgical resection with the exception of research CSF 
collection. Upon resumption of encorafenib and binimetinib after surgery (as detailed in Section 
4.1), the Cycle 1-12 observations and off-treatment observations as detailed in the medical arm 
will also be observed.  Observations listed below are additional on day of surgery. 
Patients on the Medical Arm undergoing a clinically-indicated surgery for their brain tumor while 
on study should also adhere to specimen collection guidelines for Surgical Arm patients (below). 
Table 9.2 Required Observations on Day of Surgery – surgical arm patients 
 
1 – Encorafenib and Binimetinib should both be administered orally with a small quantity of water 
as necessary 2 hours before the patient’s surgical time. 
2 – Exact time for all drug administration and sample removal should be charted on case report 
forms (CRFs). 
3 – The blood and CSF samples should be collected as close in time to the resection as possible. 
In the event that a specific blood tube is not available, a reasonable substitution (in volume 
only) may be made; however, the blood collected should not exceed that as outlined in the 
consent document.  The same tube-type should be collected in all instances (e.g., two 6mL 
lavender top / EDTA tubes may be substituted for a 10mL tube). 
4 – Three surgical specimens should be removed and flash-frozen. See Section 9.6.5. 
5 - 20 unstained FFPE slides should be requested after tissue specimen is processed and final 
pathology report is complete. See Section 9.6.5. This is in addition to archival tumor tissue 
obtained for all study patients.  
 
Means of Collection 
2 hours prior 
to surgery 
Just prior to 
surgery (after 
induction of 
anesthesia 
Prior to 
tumor 
disturbance 
During 
surgical 
resection 
After 
closure 
Encorafenib 
 
1, 2 
 
 
 
 
Binimetinib 
 
1, 2 
 
 
 
 
Blood 
PD/Reistance/Circulating 
Tumor DNA: 
10mL x 1 
 
2,3 
 
 
 
cTDNA:EDTA Lavender 
top 
10mL x 2 
 
2,3 
 
 
 
PK: EDTA Lavender top 
10mL x 1 
 
2,3 
 
 
2,3 
Cerebrospinal 
Fluid 
sterile container, 6mL 
 
 
2,3 
 
 
Tumor Tissue 
0.05-0.10 cm3 contrast 
enhancing tumor 
 
 
 
2,4 
 
0.05-0.10 cm3 non-
enhancing tumor 
 
 
 
2,4 
 
0.5 cm3 contrast 
enhancing tumor tissue 
 
 
 
2,4 
 
 
20 unstained slides 
 
 
 
 
5 
Documentation 
On CRFs 
2 
2 
2 
2 
2 


46 
 
 
Version 05/24/2021 
 
9.3 
Adverse Events: Lists and Reporting Requirements  
 
Patients will be evaluated for toxicity if they have received at least one dose of encorafenib 
and binimetinib.  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 9.3.1) and the characteristics of an observed AE (Section 
9.3.2) will determine whether the event requires expedited reporting via the CTEP Adverse 
Event Reporting System (CTEP-AERS) in addition to routine reporting. 
    
Adverse Events will be collected for at least 30 days following the last dose of study drug.  
 
All adverse events must be reported to the ABTC Central Office and the NCI in the manner 
described and per the requirements of the investigative site’s Institutional Review Board.  
 
Adverse events will be entered into CTEP’s iMedidata Rave database by the investigative 
site in a timely manner.  See Section 12.0 – Records to be Kept. 
 
9.3.1 Lists of AEs for encorafenib and binimetinib, alone and in combination 
 
Table 9-3 
Identified risks of single-agent encorafenib 
MedDRA System Organ 
Class 
Adverse Drug Reaction 
Frequency 
Category 
 
Blood and Lymphatic System 
Disorders 
Anemia 
Common 
 
Ear and labyrinth disorders 
Vertigo 
Common 
 
Eye disorders 
Iridocyclitis 
Uncommon 
 
Gastrointestinal Disorders 
Abdominal Pain 
Common 
 
Abdominal pain upper 
Common 
 
Constipation 
Common 
 
 
 
 
Pancreatitis 
Uncommon 
 
Pancreatitis Acute 
Uncommon 
 
General disorders and 
administration site conditions 
Xerosis 
Common 
 
Immune System Disorders 
Hypersensitivity 
Common 
 
Investigations 
Alanine aminotransferase 
increased 
Common 
 
Aspartate aminotransferase 
increased 
Common 
 
Blood alkaline phosphatase 
increased 
Common 
 
Blood creatinine increased 
Common 
 
Gamma-glutamyltransferase 
increased 
Common 
 
Metabolism and nutrition 
Decreased appetite 
Very common 
 


47 
 
 
Version 05/24/2021 
 
disorders 
Musculoskeletal and connective 
tissue disorders 
Muscle spasms 
Common 
 
 
Muscular weakness 
Common  
 
Neoplasms benign, malignant 
and unspecified (incl. cysts and 
polyps) 
Acanthoma 
Uncommon 
 
Basal cell carcinoma 
Uncommon 
 
Keratoacanthoma 
Common 
 
Melanocytic nevus 
Common 
 
Skin papilloma 
Common 
 
Squamous cell carcinoma 
Common 
Nervous system disorders 
Aguesia 
Common 
 
 
 
 
Dysguesia 
Common 
 
Dysaesthesia 
Common 
Hyperaesthesia 
Common 
Hypoaesthesia 
Uncommon 
Neuralgia 
Common  
Peripheral neuropathy 
Very common 
 
Psychiatric disorders 
Insomnia 
Very common 
 
Skin and subcutaneous tissue 
disorders 
Hair loss 
Very common 
 
Drug eruption 
Uncommon 
Dry skin 
Very common 
 
Hyperkeratosis 
Very common 
 
Itching 
Very common 
 
Palmar-plantar 
erythrodysaesthesia 
Very common 
 
Palmoplantar keratoderma 
Very common 
 
Rash follicular 
Common 
 
Rash generalized 
Common 
 
Rash macular 
Common 
 
Rash maculo-papular 
Common 
 
Rash papular 
Common 
 
Rash pruritic 
Common 
 
Skin redness 
Very common 
 
Urticaria 
Uncommon 
 
 
 


48 
 
 
Version 05/24/2021 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
for 
Binimetinib (NSC 788187) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1374 patients. Below is the CAEPR for 
Binimetinib. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Table 9-4 Identified risks of single-agent binimetinib 
Version 2.1, September 11, 20191 
 
 Adverse Events with Possible  
 Relationship to Binimetinib 
 (CTCAE 5.0 Term) 
[n= 1374] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(bradycardia) 
  
 
 
Heart failure 
  
EYE DISORDERS 
  
 
Blurred vision 
 
 Blurred vision (Gr 2) 
 
 
Eye disorders - Other (ocular 
hypertension) 
  
 
 
Eye disorders - Other (retinal 
vascular occlusion) 
  
Eye disorders - Other 
(visual disorder)2 
 
 
 Eye disorders - Other (visual disorder)2 
Gr 2) 
 
 
Periorbital edema 
  
 
Retinopathy3 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 


49 
 
 
Version 05/24/2021 
 
 
 Adverse Events with Possible  
 Relationship to Binimetinib 
 (CTCAE 5.0 Term) 
[n= 1374] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face 
 
  
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
CPK increased4 
 
 CPK increased4 (Gr 2) 
 
Ejection fraction decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Generalized muscle 
weakness 
 
 Generalized muscle weakness (Gr 2) 
 
Musculoskeletal and 
connective tissue disorder - 
Other (myopathy) 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis  
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash acneiform 
 
 
 Rash acneiform (Gr 2) 
Rash5 
 
 
 Rash5 (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (nail 
disorders) 
 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (severe 
cutaneous reaction)6 
  


50 
 
 
Version 05/24/2021 
 
 
 Adverse Events with Possible  
 Relationship to Binimetinib 
 (CTCAE 5.0 Term) 
[n= 1374] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Skin and subcutaneous tissue 
disorders - Other (skin 
fissures) 
 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 2) 
 
Thromboembolic event 
 
  
 
Vascular disorders - Other 
(hemorrhage)7 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2Visual disorders may include visual disturbance, blurred vision, visual acuity reduced, flashing 
light, and floaters.  
3Retinopathy may include chorioretinopathy, chorioretinitis, and retinal detachment. 
4CPK increased may be associated with muscle pain and muscle weakness. 
5Rash may include rash maculo-papular and erythematous rash. 
6Severe cutaneous reactions may include bullous dermatitis, exfoliative dermatitis, erythema 
multiforme, and toxic skin eruptions. 
7The majority of hemorrhage events were mild, although serious bleeding events in the eyes, GI 
tracts or lungs have rarely been reported. 
Adverse events reported on binimetinib trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that binimetinib caused the adverse event: 
 
Blood and lymphatic system disorders - Febrile neutropenia 
Cardiac disorders - Atrial fibrillation; Atrial flutter; Atrioventricular block complete; Cardiac 
arrest; Cardiac disorders - Other (atrioventricular block); Cardiac disorders - Other (irregular 
heart rate); Cardiac disorders - Other (tachyarrhythmia); Cardiac disorders - Other (tachycardia); 
Myocardial infarction; Palpitations; Supraventricular tachycardia  
Endocrine disorders - Hypothyroidism 
Eye disorders - Dry eye; Eye disorders - Other (eye edema); Eye disorders - Other (visual field 
defect); Glaucoma 
Gastrointestinal disorders - Abdominal distension; Ascites; Cheilitis; Colitis; Colonic 
obstruction; Dry mouth; Duodenal perforation; Dyspepsia; Dysphagia; Esophagitis; Flatulence; 
Gastritis; Gastrointestinal disorders - Other (anorectal discomfort); Gastrointestinal disorders - 
Other (gastroenteritis); Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal 
disorders - Other (pneumatosis intestinalis); Hemorrhoids; Ileus; Pancreatitis; Small intestinal 
obstruction; Small intestinal perforation 
General disorders and administration site conditions - Chills; Death NOS; Edema trunk; Flu 
like symptoms; General disorders and administration site conditions - Other (axillary pain); 


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General disorders and administration site conditions - Other (ulcer hemorrhage); Malaise; Multi-
organ failure 
Hepatobiliary disorders - Hepatobiliary disorders - Other (biliary colic); Hepatobiliary 
disorders - Other (cholestasis); Hepatobiliary disorders - Other (hepatic function abnormal)  
Infections and infestations - Bacteremia; Bronchial infection; Kidney infection; Lung infection; 
Paronychia; Peritoneal infection; Sepsis; Shingles; Soft tissue infection; Upper respiratory 
infection; Urinary tract infection; Viremia 
Injury, poisoning and procedural complications - Bruising 
Investigations - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine 
increased; Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased; 
Investigations - Other (C-reactive protein increased); Investigations - Other (electrocardiogram 
change); Investigations - Other (haptoglobin increased); Lipase increased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Serum amylase increased; 
Weight gain; Weight loss 
Metabolism and nutrition disorders - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (diabetes mellitus); Metabolism and nutrition disorders - Other 
(hypoproteinemia); Tumor lysis syndrome 
Musculoskeletal and connective tissue disorders - Arthritis; Flank pain; Muscle cramp; Neck 
pain; Pain in extremity 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Treatment related 
secondary malignancy; Tumor pain 
Nervous system disorders - Akathisia; Dysgeusia; Headache; Nervous system disorders - Other 
(dropped head syndrome); Nervous system disorders - Other (myasthenic syndrome); 
Paresthesia; Presyncope; Somnolence; Spinal cord compression; Syncope; Transient ischemic 
attacks 
Psychiatric disorders - Confusion; Hallucinations; Insomnia; Psychiatric disorders - Other 
(abnormal behavior); Suicide attempt 
Renal and urinary disorders - Acute kidney injury; Hematuria; Proteinuria 
Respiratory, thoracic and mediastinal disorders - Aspiration; Atelectasis; Cough; Hypoxia; 
Oropharyngeal pain; Pharyngolaryngeal pain; Pleural effusion; Pneumothorax; Pulmonary 
hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(asthma); Wheezing 
Skin and subcutaneous tissue disorders - Eczema; Erythroderma; Hyperhidrosis; Palmar-
plantar erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous tissue disorders - 
Other (excoriation); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin and 
subcutaneous tissue disorders - Other (rosacea); Skin and subcutaneous tissue disorders - Other 
(skin burning sensation); Urticaria 
Vascular disorders - Hypotension; Lymphedema; Superficial thrombophlebitis; Vascular 
disorders - Other (aortic dilatation) 
 
Note: Binimetinib in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 


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Table 9-5 Identified risks of encorafenib in combination with binimetinib 
MedDRA System Organ 
Class 
Adverse Drug Reaction 
Frequency 
Category 
 
Cardiac disorder 
Diastolic dysfunction 
Uncommon 
 
Left ventricular dysfunction 
Uncommon 
 
Eye disorders 
Chorioretinopathy 
Common 
 
Detachment of retinal 
pigment epithelium 
Very common 
 
Iritis 
Uncommon 
 
Visual impairment 
Very common 
 
Gastrointestinal disorders 
Colitis 
Uncommon 
 
Gastrointestinal hemorrhage 
Uncommon 
 
Rectal haemorrhage 
Uncommon 
Investigations 
Ejection fraction decreased 
Common 
 
Vascular disorders 
Hypertension 
Common 
 
 
9.3.2 Adverse Event Characteristics 
 
Definition - Adverse Event (AE) 
 
Adverse event is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite). 
 
Recording of Adverse Events - ABTC AE Form  
 
• The investigator will monitor each patient closely for the development of adverse 
events and record all such events on the ABTC AE Case Report Form.  Each single 
sign or symptom must be reported separately.  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocol 
Development/electronic_applications/ctc.htm). You must use one of the CTCAE 
criteria to define your event. 
 
Adverse events not included in the CTCAE should be reported under “Other” within 
the appropriate category and graded 1 to 5 according to the general grade definitions - 
mild, moderate, severe, life-threatening, fatal or disabling - as provided in the CTCAE 
or the CTCAE Manual.  New adverse events may be submitted to the CTEP Help Desk 
at ncictcaehelp@mail.nih.gov for annual evaluation by the CTCAE Change 
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• Attribution of the AE: The investigator will be asked to document his/her opinion of 
the relationship of the event to study medication as follows: 
 
 
- Unrelated – The AE is clearly not related to the investigational agent(s). 
- Unlikely – The AE is doubtfully related to the investigational agent(s). 
- Possible – The AE may be related to the investigational agent(s). 
- Probable – The AE is most likely related to the investigational agent(s). 
- Definite – The AE is clearly related to the investigational agent(s). 
 
• All adverse events should be followed up in accordance with good medical practice.  
Abnormalities of laboratory events which, in the opinion of the investigator, constitute 
adverse events (even if not serious) should be followed. 
 
9.4 
Serious Adverse Events and Expedited Adverse Event Reporting 
 
9.4.1 Definition – Serious Adverse Event (SAE) 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect 
6) 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 subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
9.4.2 Expedited Adverse Event Reporting 
 
➢ 
Use CTEP-AERS Web Application and Document on ABTC AE Form  
 
• All SAEs must be documented on both the ABTC AE form and using the CTEP-
AERS Web Application within 24 hours of learning of the event. 
 
• Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers). In the rare occurrence when Internet connectivity is lost, 
a 24-hour notification is to be made to the ABTC Central Office by telephone at 
410-614-4400 or 410-955-3657 or 410-599-4610.  Once Internet connectivity is 
restored, the 24-hour notification must be entered electronically into CTEP-AERS 
by the original submitter at the site. 


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• When a serious adverse event (SAE) is reported through CTEP-AERS, the 
pharmaceutical company, Pfizer, will be notified by ABTC. This reporting must 
occur within twenty-four (24) hours of awareness of an SAE, or immediately upon 
awareness if the SAE is fatal or life-threatening. ABTC will utilize the secure SAE 
reporting email provided by Pfizer to submit this report.  All SAEs will be 
documented and tracked by Pfizer as well as through the ABTC Central Office.  
Queries and follow up required for completing all SAEs will be conducted through 
Pfizer and the ABTC Central Office in a timely fashion.  When an expedited report 
is required (15 days), a speedy resolution of queries will be expected in order to 
allow for on-time reporting to the FDA. ABTC is responsible for reporting all SAEs 
to the FDA. 
• All SAEs (related or unknown relationship to study drug) will be followed until 
satisfactory resolution or until the investigator deems the event to be chronic or the 
subject to be stable. Withdrawal from the study and all therapeutic measures will 
be at the discretion of the investigator. 
• CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) of 
the Adult Brain Tumor Consortium (ABTC), the local treating physician, and the 
Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail 
recipients. 
Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions”.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
9.4.3 Other SAE Reporting 
Any Serious Adverse Event, as described in Section 9.4.1, including death due to any 
cause, which occurs during this study must be reported immediately (within 24 hours) 
to the ABTC Central Office.   
 
 A phone call must be made to: 
SERENA DESIDERI 
ABTC DATA COORDINATOR 
OFFICE: 410-614-4400 
FAX: 410-614-9335 
OR JOY FISHER, ABTC MANAGER: 410-955-3657 / 410-599-4610 
 
  
 


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These events also must be reported by the investigator to the appropriate Institutional 
Review Board (IRB). 
 
Patients who are removed from study due to adverse events should be followed until the 
adverse event has resolved or stabilized.  Copies of relevant documentation, such as 
laboratory reports, should be kept with the patient's study records. 
 
Pregnancy or Drug Exposure during Pregnancy 
 
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 Pfizer within 24 hours of the Investigator’s knowledge. All pregnancies should 
be followed through to outcome and the outcome must be reported to Pfizer.  
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. 
Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
Any secondary malignancies that occur following treatment with encorafenib and 
binimetinib should be reported via CTEP-AERS. Three options are available to describe 
the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in Section 12.0. 
 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
9.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions (Section 12.4).  
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 


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will enroll in future studies using similar agents.  AEs are reported in a routine manner at 
scheduled times during the trial using Medidata Rave.  For this trial the Adverse Event 
CRF is used for routine AE reporting in Rave. 
9.6 
Correlative Studies  
 
9.6.1 Pharmacokinetic Assessment (All Surgical Patients): Exploratory 
 
 
This correlative study is mandatory for all patients in the surgical arm. It is also optional 
for patients on the medical arm who progress while on treatment and undergo a clinically 
indicated resection while on study drugs. 
 
Blood, cerebrospinal fluid, and tissue samples will be collected on the day of surgery at 
time points specified in Section 9.2. Details for the collection, processing, storage, and 
shipment of samples are provided in the Laboratory Manual. 
 
We hypothesize tumor drug concentration will directly correlate with functional ERK 
inhibition, and may correlate with extent and duration of response in individual patients. 
Levels of total (protein-bound and unbound) encorafenib and binimetinib, as well as the 
active metabolite of each parent compound, will be measured as continuous variables using 
validated LC/MS methods in order to calculate the tumor-to-plasma ratio as an estimate of 
tumor permeability. (51) We will compare drug concentrations between enhancing and 
non-enhancing brain, and CSF. This assay will be performed by the ABTC-associated 
Applied Pharmacology Core at Johns Hopkins led by Dr. Michelle Rudek-Renaut. 
 
9.6.2 Resistance Mechanisms (All Patients): Exploratory 
 
There are two parts to this correlative study. Archival tumor tissue for genomic analysis 
will be obtained from all patients in the study (medical and surgical cohorts) as outlined in 
Section 9.1.  
 
In the second component, FFPE post-treatment surgical tissue will be obtained from all 
patients in the surgical cohort (as described in the Laboratory Manual), and from patients 
who progress while on treatment and undergo an additional surgery. These slides will be 
obtained using the same procedure as described for archival tumor tissue. 
 
A significant proportion of patients with melanoma or glioma treated with BRAF/MEK 
inhibitors develop therapeutic resistance over time as defined by relative insensitivity to 
targeted therapy leading to progressive disease. Thus, determination of resistance 
mechanisms is critical for future drug development. Putative mechanisms of resistance are 
defined as genomic or expression level changes that are likely to confer resistance, either 
because they have already been defined as such in other cancers, or because they are 
predicted to have a protein-level effect decreasing sensitivity to BRAF/MEK inhibitors. 
There are many known examples in other tumor types including mutations in BRAF, RAS, 
overexpression of COT, BRAF, CRAF, or YAP1, activation of receptor tyrosine kinases, 
or loss of NF1, PTEN, or STAG2/3. 
 


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Whole exome sequencing (WES) and RNA sequencing (RNAseq) will be performed to 
compare mutations in pre- and post-treatment samples (Illumina HiSeq 2500). WES & 
RNAseq will also be performed on unpaired baseline specimens from patients on the 
medical arm who do not respond to treatment with the assumption that a de novo 
mechanism of resistance exists in these tumors. We will use whole blood for comparison 
to filter out germline SNPs in all patients. Germline mutations will not be identified or 
reported. Results will have variant calling through standard procedures associated with the 
Computational Biology Core at Johns Hopkins. We will manually examine remaining 
variants to exclude sequencing errors and ensure sufficient coverage depth of at least 20x. 
We will compare candidate mutations against published genomic alterations conferring 
resistance, such as second-site mutations in BRAF, RAS mutations, and loss of PTEN 
and/or NF1. (20-23) For RNAseq results, we will use pathway analysis of the differentially 
expressed genes to identify potential alterations responsible for acquired resistance within 
individual patients and across the entire cohort. This assay will be performed by the 
laboratory of Drs. Schreck and Pratilas at Johns Hopkins.  
 
9.6.3 Pharmacodynamic studies (All Surgical Patients): Exploratory 
 
This correlative study is mandatory for all patients in the surgical arm. It is also optional 
for patients on the medical arm who progress while on treatment and undergo a clinically 
indicated resection while on study drugs. 
 
Blood and tissue samples will be collected on the day of surgery at time points specified in 
Section 9.2.1. Details for the collection, processing, storage, and shipment of samples are 
provided in the Laboratory Manual. 
 
Functional inhibition of ERK signaling will be measured by relative expression levels of 
phospho-ERK and p90 Ribosomal S6K (RSK) as quantified on immunoblot using standard 
procedures for quantification in the software ImageJ (https://imagej.nih.gov/ij/index.html). 
The ratios of phospho-ERK to total ERK and RSK to total ERK will be quantified as 
continuous variables. ERK inhibition will be measured as the fold-change in functional 
ERK activity (pERK/tERK and RSK/tERK, separately) between baseline (derived from 
archival tissue) and the surgical specimen.  Functional inhibition will be correlated with 
peak serum concentrations separately for pERK and RSK to determine whether there is 
any correlation. This assay will be performed by the laboratory of Drs. Schreck and Pratilas 
at Johns Hopkins. 
 
9.6.4 Circulating Tumor DNA (All Patients): Exploratory 
 
This correlative study is mandatory for all patients, but there are two stages.  
 
All patients on the medical and surgical arms will have a blood specimen (20 mL whole 
blood per time point) collected at pre-specified time points (see below). The blood samples 
will be collected, processed, stored, and shipped as described in the Laboratory Manual. 
 


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Cerebrospinal fluid donation is optional (other than the CSF collected during surgery for 
surgical arm patients, which is required) and requires additional, specific consent on 
consent form from patients on the medical and surgical arms. In patients who consent, it 
should be collected at the pre-specified time points below, same as for blood. It can be 
collected via Ommaya reservoir or lumbar puncture at the discretion of the treating 
physician (6 mL per time point). A patient does not need to consent to all these time points, 
but may elect to donate CSF for only one of these time points.  Cerebrospinal fluid will be 
collected, processed, stored, and shipped as described in the Laboratory Manual. 
 
Time Points: 
• Baseline 
• Pre-Cycle 3 
• Pre-Cycle 7 
• Off Treatment  
 
Tumor-specific circulating DNA distinguishes from normal DNA by the occurrence of 
point mutations in tumor derived DNA. Tumor-specific circulating DNA can be detected 
in CSF as well as blood. (46) We will use Safe-SeqS, a next-generation sequencing assay 
that enables the detection of tumor specific DNA in a high background of normal DNA 
with high sensitivity and specify. (52)  In this study, the BRAF V600E or K mutation is 
used to identify and monitor the fraction of tumor DNA. Tumor-specific circulating DNA 
as measured by the Safe-SeqS assay will be a continuous variable and shall be represented 
as a ratio between the mutant and wild-type allele evaluated (mutant fraction). The 
development of techniques to analyze genetic alterations in blood and CSF of patients is a 
rapidly changing field. The methods used to adequately detect mutated DNA and to 
differentiate it from wild type DNA will be adjusted and modified as appropriate on an 
ongoing basis. This assay will be performed by the laboratory of Dr. Chetan Bettegowda 
at Johns Hopkins. 
 
9.6.5 Overview of Biospecimen Collection on Surgical Arm 
 
Patients with a history of BRAF-V600E/K mutated glioma who are planning to undergo 
surgical tumor resection and are eligible to participate in this study (based on 
inclusion/exclusion criteria in Sections 3.2 and 3.3) may participate in the surgical arm. 
Patients on the medical arm who experience likely progression and require a clinically 
indicated surgery are also eligible if they continue drug until the day of surgery. All patients 
in this cohort should take their last dose of binimetinib and encorafenib two hours prior to 
surgery. At the time of this clinically indicated surgery, biospecimens will be collected, 
after the induction of general anesthesia, in the following order: 
 
1) Prior to tumor manipulation: Whole blood (total of 40 mL) and cerebrospinal fluid (6 mL). 
 
a. Blood will typically be obtained from an arterial line and/or venous line placed as 
part of standard of care, placed immediately on wet ice, and processed as described 
in the Laboratory Manual.   
 


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b. CSF will be obtained in one of three ways per discretion of the neurosurgeon ± 
principal investigator, placed immediately on wet ice, and processed as described 
in the Laboratory Manual. Determination as to the method of CSF extraction 
(specifically, whether or not a lumbar puncture is indicated) will be determined 
prior to surgery and patient will confirm on consent form. 
i. By Ommaya reservoir access prior to the surgical procedure. 
ii. By lumbar puncture after the induction of anesthesia so as to induce no 
additional discomfort to the patient. 
iii. During surgery, from cisternal aspiration, if the cistern were to be opened 
as part of the planned surgical procedure. 
iv. During surgery, from ventricular aspiration, if the ventricle were to be 
encountered as part of the planned surgical procedure. 
 
2) At tumor manipulation: Enhancing and non-enhancing brain tumor tissue. 
 
a. After frozen section confirmation of glioma and confirmation with the pathologist 
that sufficient material has been obtained for clinical diagnostic processing 
(grading, sub classification, and the relevant genetic testing), additional tumor 
specimens will be obtained for this study and processed as described in the 
Laboratory Manual. 
b. The specimen locations will be determined by the neurosurgeon based on MRI and 
tissue appearance with one intended to be in enhancing and the other in non-
enhancing brain per MRI-contrast pre-operative image.  The sample location will 
be noted with MRI wand and correlated with pre-operative MRI scan. 
 
3) At closure: Whole blood (10 mL), obtained as above. 
 
4) After tissue is processed: 20 unstained FFPE slides from current resection.  
 
20 unstained slides from the repeat resection should be requested and processed as outlined 
in the Laboratory Manual and shipped, along with a copy of the associated pathology 
report. 
 
9.6.6 Archival Tumor Tissue: Exploratory  
 
Archived tumor tissue from the most tumor recent resection demonstrating active tumor 
will be collected from all patients, when sufficient tissue is available. If sufficient tissue is 
not available from the most recent surgery, then tissue from an earlier surgery is acceptable, 
if available, including from the initial resection at diagnosis. 
 
At the time of registration, prior to beginning treatment, a tumor tissue form indicating 
availability must be completed and signed by a pathologist for each study participant.  This 
form provides written documentation of the availability of tissue for this study and the 
pathologist’s agreement to send it as described below. 
 


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20 unstained slides, preferentially from the most recent tumor resection, will be requested.  
The associated pathology report from the institution of collection should be shipped with 
the slides.  
 
Details for the collection and shipment of tissue samples are provided in the Laboratory 
Manual. 
 
10.0    OFF TREATMENT/OFF STUDY CRITERIA 
 
Each subject has the right to withdraw from the study at any time without prejudice.  The 
investigator may discontinue any subject’s participation for any reason, including adverse 
event or failure to comply with the protocol (as judged by the investigator such as 
compliance below 80%, failure to maintain appointments, etc.). 
Should a subject withdraw from the study, the reason must be stated on the case report 
form, and a final evaluation of the subject should be performed.  
 
Patients who go off treatment must be followed for adverse events (AEs) for at least 30 
days from the last dose of encorafenib and binimetinib. 
 
 
10.1 
Off Treatment Criteria 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
 
• 
Disease progression on MRI as determined by the local site 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
The drug manufacturer can no longer provide the study agent 
 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and 
 
the corresponding dates must be documented in the Case Report Form (CRF). 
 
 


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10.2 
Off Study Criteria 
 
Patients will only be off study at the time of death. All patients will be followed for survival 
every 2 months for the first two years from the off-treatment date; after 2 years, patients 
will be followed every 6 months until death. Survival status may be obtained by phone call, 
clinic visit, or medical records (e.g. physician notes/laboratory results of clinic or hospital 
visit). Please note that additional survival status reports will be required twice yearly for 
ABTC Central Office reporting. 
 
 
11.0   STATISTICAL CONSIDERATIONS 
 
11.1  Study Design/ Endpoints: 
           
This is a non-randomized, open-label, multicenter study of evaluating treatment efficacy 
and safety of encorafenib in combination with binimetinib in adult patients with recurrent 
BRAF-V600 mutated high-grade primary brain tumors. The study includes a total of four 
study cohorts.  The Cohort 1 includes patients with high-grade glioma (including but not 
limited to glioblastoma (GBM), anaplastic astrocytoma (AA), and gliosarcoma.  The 
Cohort 2 includes patients with anaplastic PXA that is recurrent after first-line treatment.  
The cohort 3 includes patients with recurrent high-grade brain tumor that is not included 
in the cohort 1 and 2, and the cohort 4 is a surgical cohort. All subjects must have 
histologically confirmed high-grade primary brain tumors.  
 
The three treatment cohorts are independent subtypes of the high-grade primary brain 
tumors. No randomization is required for patient allocation on to each cohort.    
 
The primary objective of the study is to evaluate efficacy of encorafenib in combination 
with binimetinib to treat patients with recurrent BRAF V600E/K-mutated malignant 
glioma (MG) and anaplastic pleomorphic xanothastrocytoma (PXAs).  
 
The primary endpoint is tumor radiographic response per RANO criteria (Section 8.1) for 
the three treatment cohorts.    
 
11.2  Sample Size Justification 
 
Sample size consideration for cohort 1 malignant gliomas (MG) and cohort 2 anaplastic 
PXAs: 
Based on the information from prior clinical trials (Scientific rational), the investigators 
consider the primary cohorts 1 (patients with AA or GBM) and 2 (Anaplastic PXAs) to 
share a similar null hypothesis of tumor response rate at 10% to be considered not clinically 
meaningful treatment effect and an alternative of 30% tumor response rate to be clinically 
desired treatment effect. A total of 23 patients is required per individual primary cohort 1 
and cohort 2.  
Cohort sample size estimation was based on a 2-stage design (minimax) with a futility 
analysis at end of first stage. Fourteen patients will be enrolled onto first stage. If no more 
than 1 response (7%) was observed among the initial 14 patients in a cohort, the cohort 


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would be terminated early and declared negative. Otherwise, nine more patients will be 
enrolled. If at least 5 responses (at least 22%) were observed among the 23 evaluable 
patients, the regimen would be considered worthy of further testing in this disease and the 
patient population.  This design yields at least 85% power to detect a true response rate of 
at least 30% at a false positive rate of 10%.  It yields at least 0.9 probability of a negative 
result if the true response rate is no more than 10%, with at least 0.58 probability of early 
negative stopping. The 2 primary cohorts will be evaluated independently.  
 
The maximum total sample size for the two primary cohorts is 46 patients (23+23). 
 
The sample size for the cohort 3 is 6 to 10 patients (other types of high-grade brain tumor 
that are not included in the primary cohort 1 or 2). This sample size is not based on 
statistical rationale but due to clinical feasibility. Patient enrollment will be considered 
completed at the time of completion of the enrollment in the cohort 1 and the cohort 2.   
   
In the correlative studies, there is a surgical cohort of 6 patients who are clinically surgical 
indicated for tissue PK study after initial treatment prior to surgery. There is no clinical or 
trial decision will be made based on outcome of the surgical cohort. Currently, prior 
information on mount of drug concentration in tumor tissue are lacking, especially with 
this combination treatment. However, 6 patients will have 90% power to detect an 80% 
true probability of BBB penetration, with .93 likelihood of rejecting a 30% true probability 
of BBB penetration. 
   
Data analysis will be performed for each cohort independently. Tumor response rate will 
be estimated as proportion of number of tumor responders over number of patients in a 
cohort, as a binomial distribution (exact method) with 80% and 90% confidence intervals.  
 
Accrual Rate: The expected accrual rate is one patient per month among 11 ABTC 
institutions.  
 
Slow Accrual Plan: 
The study will be monitored for accrual starting quarter 6. If study accrual is ≤ 50% on 
the MG arm at the end of quarter 6 (9 patients) or every 2 quarters afterwards, we will 
add additional study centers by offering this study to a larger NCTN consortium such as 
Alliance or NRG Oncology in order increase accrual. 
 
Stratification Factors: NA 
 
11.3 
Analysis of Secondary End Points: 
             
Data analysis will be conducted for each cohort independently. 
 
1. Progression-free survival: progression-free survival time is defined as the time from 
a date of treatment start to a date of the initial scan deemed tumor progression while 
patient is alive or death if there is no more than two missing imaging scans prior to 
death. The data will be censored if progressive disease was not observed at the time 


63 
 
 
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of data cut-off for analysis. Probability of progression-free survival and median 
time of progression-free survival will be estimated using Kaplan-Meier method 
along with 95% confidence intervals.  
 
2. Overall survival: survival time is defined as the time from a date of treatment started 
to a date of death. The data will be censored if patient was alive at the time of data 
cut-off for analysis. Overall survival (OS) and median OS will be estimated using 
Kaplan-Meier method along with 95% confidence interval.   
 
3. Duration of response: duration of response is defined as the time from date of tumor 
response/per imaging to date of progression. The duration of the response will be 
summarized using descriptive statistics.  
 
4. Time-to-response: time to response is defined as the time from date of treatment 
started to date of response per imaging among subjects who have a radiologic 
response. The duration of the time to response will be summarized using descriptive 
statistics. 
  
5. Toxicity:  NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be used for scoring toxicity and adverse events. The severity and 
frequency of toxicity will be tabulated using descriptive statistics. The proportions 
of subjects who experienced grade 3 or above toxicities will be estimated, along 
with 95% confidence intervals by each type of toxicity. 
 
11.4 
Analysis of Exploratory Endpoints:  
       
1. Clinical outcomes such as tumor response rate, progression-free survival, and 
overall survival for cohort 3 (recurrent BRAF-V600 mutated high-grade primary 
brain tumors not included in the cohort 1 and cohort 2). The standard definitions of 
these outcomes will be used as described above. The outcomes will be summarized 
and presented descriptively.     
2. Encorafenib and binimetinib concentrations in enhancing brain tissue and 
cerebrospinal fluid (surgical cohort): descriptive summary on mean and standard 
deviation of drug will be reported. Additional analyses are summarized in Section 
9.6.1.  
3. Putative mechanisms of drug resistance are defined as identified genomic or 
functional alterations in post-treatment tissue that are not present, or are present in 
a much smaller variant allele frequency (VAF), in pre-treatment tissue, and that 
could contribute to decreased drug sensitivity. Candidate mutations will be 
measured using the methods described in Section 9.6.2. These results will be 
manually curated and confirmed against known gene lists.  
4. Functional inhibition of the ERK signaling pathway:  the functional inhibition of 
the ERK signaling pathway is defined by the measurements of phospho-ERK and 
RSK protein, quantitated relative to total ERK. Due to the exploratory nature, the 
pathway changes after drug exposure will be reported using descriptive summary.   


64 
 
 
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5. BRAF-V600 DNA mutant fraction: the mutant fraction is measured as the number 
of BRAF V600E or –K transcripts relative to BRAF wild-type transcripts, corrected 
for differences in sequencing efficiency and the quantity of starting material. The 
mutant fraction in CSF and plasma will be collected over multiple time points 
during the study. The fraction change overtime will be presented as a liner or non-
linear trend after data checking. Descriptive summary at each individual time point 
and multiple time points will be presented graphically. 
 
A more detailed description of exploratory correlatives are provided in Section 9.6.   
 
 
12.0   STUDY ADMINISTRATION 
  
 
 
 
  
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 
12.1 
Investigator’s Study File 
The Investigator’s Study File must contain all essential documents as required by ICH E6, 
including IRB and governmental approvals with correspondence, informed consent forms, 
patient enrollment and identification logs, drug accountability records, staff curriculum 
vitae, authorization forms and other appropriate documents/correspondence etc. 
12.2 
Source Data/Documents 
Patient source documents used to record key efficacy/safety parameters, independent of the 
CRFs, may include for example, patient hospital/clinic records, original laboratory reports, 
ECG read-outs, MRI reports, pathology and special assessment reports, etc. 
Source documents are part of the study documents and must be maintained, and direct 
access to source documents made available upon request, for monitoring visits, IRB review, 
audits or inspections.  All source documents used to verify answers on CRFs will be 
uploaded to RAVE, including all documentation to prove eligibility criteria was meet. 
12.3 
Document Retention and Archiving 
The Investigator must keep all study documents on file for at least 5 years after completion 
or discontinuation of the study. Subsequently, the Sponsor will inform the Investigator when 
the study documents can be destroyed, subject to local regulations.  
These files must be made available for inspection, upon reasonable request, to authorized 
representatives of Sponsor or regulatory authorities.  
Should the Investigator wish to assign the study records to another party, or move them to 
another location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the investigational site for 
any or all of the documents, arrangements must be made between the Investigator and the 
Sponsor for appropriate storage. 


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12.4  Data Collection/Reporting 
Data collection for this study will be done exclusively through CTEP’s Medidata 
Rave.   
Access to the trial in Rave is granted through the iMedidata application to all persons with 
the appropriate roles in the Regulatory Support System (RSS).  To access iMedidata/Rave 
the 
site 
user 
must 
have 
an 
active 
CTEP 
IAM 
account 
(https://eapps-
ctep.nci.nih.gov/iam).  In addition, site users that are a member of the ABTC must have 
the Rave CRA role in RSS at the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.   Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be listed in 
the upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave accounts will also receive an 
invitation from iMedidata to activate their account.  If you have any questions, please contact 
the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
• All data are due within 14 days of evaluation time point.  Please see Section 9.1 
for evaluation time points. Note:  Source documentation to verify each CRF must 
be uploaded into Rave. 
• Serious Adverse Events, PHONE IMMEDIATELY, SEE SECTION 9.3 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, July 
31, and October 31. The ABTC Central Office is responsible for compiling and submitting 
CDUS data to CTEP for all participants and for providing the data to the Principal 
Investigator for review. 
12.5 
Study Monitoring  
The ABTC Study Monitor (Sponsor) will remotely monitor the Investigator and study team 
on a regular basis throughout the study to verify the adherence to Good Clinical Practice 
(GCP), the protocol and the completeness, consistency and accuracy of the data being 
entered into the CRFs. The Study Monitor will also ensure that the study drug is being 
stored, dispensed, and accounted for according to specifications.   
The Study Monitor will only conduct target on-site monitoring (See ABTC Monitoring plan 
for details).   If on-site monitoring is necessary, the Investigator shall ensure that the study 
monitor has direct access to all required study data (source documents) during the visits. 
This includes all patient records needed to verify the entries in the CRFs, regulatory 
documents, pharmacy records or any other documents of concern. 
The Investigator agrees to cooperate with the Study Monitor and ABTC to ensure that any 
deviations or issues detected in the course of monitoring visits are resolved. 


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12.6 
Audits and Inspections 
The study may be audited at any time, with appropriate notification, by qualified personnel 
from the Sponsor or its designees, to assess compliance with the protocol, GCP and 
regulatory requirements. These audits may also be conducted for quality assurance to ensure 
that complete and accurate data are submitted and that adverse events, complications and/or 
adverse reactions are being identified and reported. 
The study may also be inspected by health authority inspectors, after appropriate 
notification. In the event of an audit or an inspection, the Investigator must ensure that direct 
access to all study documentation, including source documents, is granted to the auditors or 
inspectors. 


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4.Dahiya S, Emnett RJ, Haydon DH, et al., BRAF-V600E mutation in pediatric and adult 
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5.Behling F, Barrantes-Freer A, Skardelly M, et al., Frequency of BRAF V600E mutations in 969 
central nervous system neoplasms. Diagn.Pathol. 2016;11:55-016-0506-2. 
6.Kleinschmidt-DeMasters BK, Aisner DLandForeman NK, BRAF VE1 immunoreactivity 
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7.Chi AS, Batchelor TT, Yang D, et al., BRAF V600E mutation identifies a subset of low-grade 
diffusely infiltrating gliomas in adults. J.Clin.Oncol. 2013;31:e233-6. 
8.Stupp R, Mason WP, van den Bent MJ, et al., European organization for research and treatment 
of cancer brain tumor and radiotherapy groups: National cancer institute of canada clinical trials 
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9.Brennan CW, Verhaak RG, McKenna A, et al., The somatic genomic landscape of glioblastoma. 
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10.Zhang RQ, Shi Z, Chen H, et al., Biomarker-based prognostic stratification of young adult 
glioblastoma. Oncotarget. 2016;7:5030-5041. 
11.Vuong HG, Altibi AMA, Duong UNP, et al., BRAF mutation is associated with an improved 
survival in glioma-a systematic review and meta-analysis. Mol.Neurobiol. 2017; 
12.Ida CM, Rodriguez FJ, Burger PC, et al., Pleomorphic xanthoastrocytoma: Natural history and 
long-term follow-up. Brain Pathol. 2015;25:575-586. 
13.Tabouret E, Bequet C, Denicolai E, et al., BRAF mutation and anaplasia may be predictive 
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14.Anonymous Braftovi (encorafenib) [package insert]. morrisville, NC: Array BioPharma; june 
2018.  
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2018.  
16.Sosman JA, Kim KB, Schuchter L, et al., Survival in BRAF V600-mutant advanced melanoma 
treated with vemurafenib. N.Engl.J.Med. 2012;366:707-714. 
17.Hauschild A, Grob JJ, Demidov LV, et al., Dabrafenib in BRAF-mutated metastatic melanoma: 
A multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365. 
18.Chapman PB, Hauschild A, Robert C, et al., Improved survival with vemurafenib in melanoma 
with BRAF V600E mutation. N.Engl.J.Med. 2011;364:2507-2516. 
19.Poulikakos PI, Persaud Y, Janakiraman M, et al., RAF inhibitor resistance is mediated by 
dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387-390. 
20.Wang J, Yao Z, Jonsson P, et al., A secondary mutation in BRAF confers resistance to RAF 
inhibition in a BRAF V600E-mutant brain tumor. Cancer.Discov. 2018;pii. 
21.Nazarian R, Shi H, Wang Q, et al., Melanomas acquire resistance to B-RAF(V600E) inhibition 
by RTK or N-RAS upregulation. Nature. 2010;468:973-977. 
22.Paraiso KH, Xiang Y, Rebecca VW, et al., PTEN loss confers BRAF inhibitor resistance to 
melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71:2750-2760. 
23.Whittaker SR, Theurillat JP, Van Allen E, et al., A genome-scale RNA interference screen 
implicates NF1 loss in resistance to RAF inhibition. Cancer.Discov. 2013;3:350-362. 
24.Kim KB, Kefford R, Pavlick AC, et al., Phase II study of the MEK1/MEK2 inhibitor trametinib 
in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without 
a BRAF inhibitor. J.Clin.Oncol. 2013;31:482-489. 
25.Long GV, Stroyakovskiy D, Gogas H, et al., Dabrafenib and trametinib versus dabrafenib and 
placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised 
controlled trial. Lancet. 2015;386:444-451. 
26.Larkin J, Ascierto PA, Dreno B, et al., Combined vemurafenib and cobimetinib in BRAF-
mutated melanoma. N.Engl.J.Med. 2014;371:1867-1876. 
27.Dummer R, Ascierto PA, Gogas HJ, et al., Encorafenib plus binimetinib versus vemurafenib or 
encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, 
randomised phase 3 trial. Lancet Oncol. 2018;19:603-615. 


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28.Dummer R, Ascierto PA, Gogas HJ, et al., Overall survival in patients with BRAF-mutant 
melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib 
(COLUMBUS): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 
2018;19:1315-1327. 
29.Di L, Umland JP, Chang G, et al., Species independence in brain tissue binding using brain 
homogenates. Drug Metab.Dispos. 2011;39:1270-1277. 
30.Syvanen S, Lindhe O, Palner M, et al., Species differences in blood-brain barrier transport of 
three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug 
Metab.Dispos. 2009;37:635-643. 
31.Mittapalli RK, Vaidhyanathan S, Dudek AZandElmquist WF, Mechanisms limiting 
distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: 
Implications for the treatment of melanoma brain metastases. J.Pharmacol.Exp.Ther. 
2013;344:655-664. 
32.Vaidhyanathan S, Mittapalli RK, Sarkaria JNandElmquist WF, Factors influencing the CNS 
distribution of a novel MEK-1/2 inhibitor: Implications for combination therapy for melanoma 
brain metastases. Drug Metab.Dispos. 2014;42:1292-1300. 
33.Davies MA, Saiag P, Robert C, et al., Dabrafenib plus trametinib in patients with BRAFV600-
mutant melanoma brain metastases (COMBI-MB): A multicentre, multicohort, open-label, phase 
2 trial. Lancet Oncol. 2017;18:863-873. 
34.Nicolaides TP, Li H, Solomon DA, et al., Targeted therapy for BRAFV600E malignant 
astrocytoma. Clin.Cancer Res. 2011;17:7595-7604. 
35.Kaley T, Touat M, Subbiah V, et al., BRAF inhibition in BRAF(V600)-mutant gliomas: Results 
from the VE-BASKET study. J.Clin.Oncol. 2018;JCO2018789990. 
36.Chamberlain MC, Salvage therapy with BRAF inhibitors for recurrent pleomorphic 
xanthoastrocytoma: A retrospective case series. J.Neurooncol. 2013;114:237-240. 
37.Leaver KM, Zhang N, Ziskin JL, Vogel H, Recht LandThomas RP, Response of metastatic 
glioma to vemurafenib. Neurooncol Pract. 2016;3:268-271. 
38.Lee EQ, Ruland S, LeBoeuf NR, Wen PYandSantagata S, Successful treatment of a progressive 
BRAF 
V600E-mutated 
anaplastic 
pleomorphic 
xanthoastrocytoma 
with 
vemurafenib 
monotherapy. J.Clin.Oncol. 2016;34:e87-9. 
39.Usubalieva A, Pierson CR, Kavran CA, et al., Primary meningeal pleomorphic 
xanthoastrocytoma with anaplastic features: A report of 2 cases, one with BRAF(V600E) mutation 
and clinical response to the BRAF inhibitor dabrafenib. J.Neuropathol.Exp.Neurol. 2015;74:960-
969. 


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40.Meletath SK, Pavlick D, Brennan T, et al., Personalized treatment for a patient with a BRAF 
V600E mutation using dabrafenib and a tumor treatment fields device in a high-grade glioma 
arising from ganglioglioma. J.Natl.Compr.Canc Netw. 2016;14:1345-1350. 
41.Brown NF, Carter TandMulholland P, Dabrafenib in BRAFV600-mutated anaplastic 
pleomorphic xanthoastrocytoma. CNS Oncol. 2016;6: 
42.Schreck KC, Guajardo A, Lin DDM, Eberhart CGandGrossman SA, Concurrent BRAF/MEK 
inhibitors in BRAF V600-mutant high-grade primary brain tumors. J.Natl.Compr.Canc Netw. 
2018;16:343-347. 
43.Johanns TM, Ferguson CJ, Grierson PM, Dahiya SandAnsstas G, Rapid clinical and 
radiographic response with combined dabrafenib and trametinib in adults with BRAF-mutated 
high-grade glioma. J.Natl.Compr.Canc Netw. 2018;16:4-10. 
44.Brown NF, Carter T, Kitchen NandMulholland P, Dabrafenib and trametinib in BRAFV600E 
mutated glioma. CNS Oncol. 2017;6:291-296. 
45.Migliorini D, Aguiar D, Vargas MI, Lobrinus AandDietrich PY, BRAF/MEK double blockade 
in refractory anaplastic pleomorphic xanthoastrocytoma. Neurology. 2017;88:1291-1293. 
46.Bettegowda C, Sausen M, Leary RJ, et al., Detection of circulating tumor DNA in early- and 
late-stage human malignancies. Sci.Transl.Med. 2014;6:224ra24. 
47.Wang Y, Springer S, Zhang M, et al., Detection of tumor-derived DNA in cerebrospinal fluid 
of patients with primary tumors of the brain and spinal cord. Proc.Natl.Acad.Sci.U.S.A. 
2015;112:9704-9709. 
48.De Mattos-Arruda L, Mayor R, Ng CK, et al., Cerebrospinal fluid-derived circulating tumour 
DNA better represents the genomic alterations of brain tumours than plasma. Nat.Commun. 
2015;6:8839. 
49.Li Y, Pan W, Connolly ID, et al., Tumor DNA in cerebral spinal fluid reflects clinical course 
in a patient with melanoma leptomeningeal brain metastases. J.Neurooncol. 2016;128:93-100. 
50.Momtaz P, Pentsova E, Abdel-Wahab O, et al., Quantification of tumor-derived cell free 
DNA(cfDNA) by digital PCR (DigPCR) in cerebrospinal fluid of patients with BRAFV600 
mutated malignancies. Oncotarget. 2016;7:85430-85436. 
51.Nijenhuis CM, Haverkate H, Rosing H, Schellens JHandBeijnen JH, Simultaneous 
quantification of dabrafenib and trametinib in human plasma using high-performance liquid 
chromatography-tandem mass spectrometry. J.Pharm.Biomed.Anal. 2016;125:270-279. 
52.Kinde I, Wu J, Papadopoulos N, Kinzler KWandVogelstein B, Detection and quantification of 
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9535. 


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14.0  ETHICAL AND LEGAL CONSIDERATIONS 
 
 
This study will be conducted in accordance with the Declaration of Helsinki and in 
compliance with all applicable laws and regulations of the locale where the study is 
conducted. 
 
It is the responsibility of the investigator that the patient is made aware and consent is given 
that personal information may be scrutinized during audits by competent authorities and 
properly authorized persons, but that personal information will be treated as strictly 
confidential and not be publicly available.  The investigator is responsible for the retention 
of the patient log and patient records. 
 
 


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APPENDIX I – PATIENT MEDICATION DIARY - BINIMETINIB 
 (Binimetinib twice daily, every day in 28-day cycles) 
 
Patient Name____________________________ Patient Study ID _________________  Cycle # ____________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. You will take Binimetinib ______ mg (___ tablets) twice per day on Days 1- 28 of every 28-day cycle. Take 
doses about 12 hours apart at approximately the same times each day. You may take binimetinib with or without 
a meal. Tablets should be swallowed whole, do not chew or crush. 
2. Record the date and the time you took each Binimetinib dose.   
Record missed or skipped dose(s). If you miss a dose you may make up that dose if you take it within 6 hours 
of the time you normally take it. There must be at least 6 hours before the next dose. 
If you vomit a dose, do not re-take the study drug. Take the next dose at the time that you normally take the next 
scheduled dose.  
3. Bring this form and any remaining Binimetinib tablets when you return for each appointment. 
Week Day 
Date 
Time of 
morning 
dose 
# of   
15 mg 
tablets 
Time of 
evening 
dose 
# of  15 
mg 
tablets 
Comments 
1 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
2 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
3 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
4 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Patient’s Signature ________________________________________    Date ____________________________ 
 
Nurse’s Signature _________________________________________    Date ____________________________  


73 
 
 
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APPENDIX II – PATIENT MEDICATION DIARY - ENCORAFENIB 
 
  
 
(Encorafenib once every day in 28-day cycles) 
 
Patient Name____________________________ Patient Study ID _________________  Cycle # ____________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. You will take Encorafenib ______ mg (___ capsules) once daily on Days 1- 28 (daily) of every 
28-day cycle. Take Encorafenib with one of your daily doses of Binimetinib. Encorafenib may be 
taken with or without a meal. Capsules should be swallowed whole, do not open or crush. 
2. Record the date and the time you took each Encorafenib dose.   
Record missed or skipped dose(s). If you miss a dose you may make up that dose if you take it 
within 12 hours of the time you normally take it. There must be at least 12 hours before the next 
dose. 
If you vomit a dose, do not re-take the study drug. Take the next dose at the time that you normally 
take the next scheduled dose.  
3.  Bring this form and any remaining Encorafenib tablets when you return for each appointment. 
 
Week 
 
Day 
 
Date 
 
Time of 
dose 
 
# of 75 mg 
capsules 
 
 
Week 
 
Day 
 
Date 
 
Time of 
dose 
 
# 75 of mg 
capsules 
1 
1 
 
 
 
 
3 
15 
 
 
 
 
2 
 
 
 
 
 
16 
 
 
 
 
3 
 
 
 
 
 
17 
 
 
 
 
4 
 
 
 
 
 
18 
 
 
 
 
5 
 
 
 
 
 
19 
 
 
 
 
6 
 
 
 
 
 
20 
 
 
 
 
7 
 
 
 
 
 
21 
 
 
 
2 
8 
 
 
 
 
4 
22 
 
 
 
 
9 
 
 
 
 
 
23 
 
 
 
 
10 
 
 
 
 
 
24 
 
 
 
 
11 
 
 
 
 
 
25 
 
 
 
 
12 
 
 
 
 
 
26 
 
 
 
 
13 
 
 
 
 
 
27 
 
 
 
 
14 
 
 
 
 
 
28 
 
 
 
 
Patient’s Signature ________________________________________    Date ____________________________ 
 
Nurse’s Signature _________________________________________    Date ____________________________  


74 
 
 
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APPENDIX III – PRE-SURGICAL TREATMENT MEDICATION DIARY  
Encorafenib (once daily) and Binimetinib (twice daily) for 10-14 days prior to surgery. 
Patient Name____________________________           Patient Study ID _________________   
INSTRUCTIONS TO THE PATIENT: 
1. You will take Encorafenib ______ mg (___ capsules) every day in the morning starting 10-14 days prior 
to surgery. Also take encorafenib 2 hours before your scheduled surgery with a small amount of water. 
2. You will take Binimetinib ______ mg (___ tablets) twice per day starting 10-14 days prior to surgery. 
Also take binimetinib 2 hours before your scheduled surgery with a small amount of water. 
3. Encorafenib and Binimetinib may each be taken with or without a meal. Pills should be swallowed whole, do 
not chew or crush. Encorafenib can be taken at the same time as binimetinib. If you miss a dose of encorafenib 
you may make up that dose if you take it within 12 hours of the time you normally take it. There must be at 
least 12 hours before the next dose of encorafenib. If you miss a dose of binimetinib you may make up that 
dose if you take it within 6 hours of the time you normally take it. There must be at least 6 hours before the 
next dose of binimetinib. If you vomit a dose of either study drug, do not re-take the study drug. Take the next 
dose of each study drug at the time that you normally take the next scheduled dose. 
4. Record the date and the time you took each Encorafenib or Binimetinib dose and the number of pills you took. 
Record any missed or skipped dose(s). If you vomit a dose, do not re-take the study drug.  
5. Bring this form and any remaining Encorafenib and Binimetinib pills when you return for each surgery. 
Day 
Date 
Timeframe Time of 
Dose 
# pills of 
binimetinib  
# pills of 
encorafenib  
Comments 
13 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
12 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
11 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
10 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
9 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
8 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
7 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
6 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
5 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
4 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
3 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
2 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
1 days prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
(add’l day if surgery delayed) 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
(add’l day if surgery delayed) 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
Day of Surgery: 2 hours 
prior to surgery 
 
Morning 
 
 
 
 
Evening 
 
 
--- 
Patient’s Signature ________________________________________    Date ____________________________ 
Nurse’s Signature _________________________________________    Date ____________________________  


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APPENDIX IV – PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
                                          
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your healthcare 
providers and keep it with you in case you 
go to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:       ABTC-1802 
Study Drug(S):        
Encorafenib 
Binimetinib 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
Version 04/2019