Clinical trial NCT04221438
Conditions: Melanoma of Unknown Primary Metastatic Malignant Neoplasm in Lymph Node Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IIID Cutaneous Melanoma AJCC v8 Recurrent Cutaneous Melanoma
Sponsor: ECOG-ACRIN Cancer Research Group
Start date: 2021-09-22; Completion date: 2025-01-31
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well encorafenib and binimetinib work before surgery in treating patients with BRAF V600-mutated stage IIIB-D melanoma that has spread to the lymph nodes. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial also studies how well 18F-FLT positron emission tomography (PET)/computed tomography (CT) works in predicting the response of melanoma to encorafenib and binimetinib. 18F-FLT is an imaging agent, sometimes called a tracer. PET and CT are types of imaging scans. Using 18F-FLT PET/CT together with encorafenib and binimetinib may provide more information on melanoma over time.

Detailed description:
PRIMARY CLINICAL OBJECTIVE:

I. To evaluate the pathologic complete response (pCR) rate of neoadjuvant treatment with encorafenib and binimetinib.

SECONDARY CLINICAL OBJECTIVES:

I. To determine response rate (RR) (Response Evaluation Criteria in Solid Tumors \[RECIST\]), disease-free survival (DFS) and overall survival (OS).

II. To describe correlation of pCR with RR, DFS and OS. III. To assess safety and toxicity.

CORRELATIVE SCIENCE OBJECTIVES:

I. To evaluate CD8 positive (+) T cell infiltration and Ki-67 status in tumor or tumor bed pre, during, and post neoadjuvant treatment and the change in CD8+ tumor infiltrating lymphocyte (TIL) with neoadjuvant treatment and correlate with clinical response.

II. To compare local review for pathologic response with central pathology review.

III. To assess the correlation between change in fluorothymidine F-18 (18F-FLT) PET/CT uptake and change in Ki-67.

IMAGING OBJECTIVES:

I. To compare the change in 18F-FLT PET/CT uptake (from baseline to post-neoadjuvant therapy) among patients with and without pathologic complete response.

II. To compare post-neoadjuvant 18F-FLT PET/CT uptake among patients with and without pathologic complete response.

III. To estimate an optimal threshold for prediction of pathologic complete response using i) change in 18F-FLT PET/CT uptake, and ii) post-neoadjuvant 18F-FLT PET/CT uptake.

IV. To assess the correlation between change in 18F-FLT PET/CT uptake and change in Ki-67.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive 18F-FLT intravenously (IV) and undergo a PET/CT scan approximately 60 minutes later. Within 2 weeks, patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive 18F-FLT IV and undergo a second PET/CT scan approximately 60 minutes later.

SURGICAL RESECTION: Within 2 weeks of completing therapy with encorafenib and binimetinib, patients undergo surgery.

ADJUVANT TREATMENT: Within 2-7 days after surgery, patients resume treatment with encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 11 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, then every 6 months for 3 years.

Arms: arm 1: NEOADJUVANT TREATMENT: Patients receive 18F-FLT IV and undergo a PET/CT scan approximately 60 minutes later. Within 2 weeks, patients receive encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive 18F-FLT IV and undergo a second PET/CT scan approximately 60 minutes later.

SURGICAL RESECTION: Within 2 weeks of completing therapy with encorafenib and binimetinib, patients undergo surgery.

ADJUVANT TREATMENT: Within 2-7 days after surgery, patients resume treatment with encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 11 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Binimetinib intervention 2: Conventional Surgery intervention 3: Encorafenib intervention 4: Fluorothymidine F-18
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo surgery intervention 3: Given PO intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
EA6183 
1 
A Phase II Neoadjuvant Study of Encorafenib With 
Binimetinib in Patients With Resectable Locoregional 
Metastases From Cutaneous or Unknown Primary 
Melanoma (Stages III N1B/C/D) 
STUDY CHAIR: Leslie Fecher, MD 
MEDICAL ONCOLOGY CO-CHAIR: Ragini Kudchadkhar, MD 
SURGICAL CO-CHAIR: Michael Lowe, MD 
PATHOLOGY AND LABORATORY CO-CHAIR: Ari Karunamuthy, MD 
IMAGING CO-CHAIRS: Anthony Shields, MD 
Michael Yu, MD, FACNM, FRCPC 
THERAPEUTIC STATISTICIAN: Sandra Lee, ScD 
IMAGING STATISTICIAN: Bradley S. Snyder, MS 
COMMUNITY CO-CHAIR Gary I. Cohen, MD 
MELANOMA COMMITTEE CHAIR: John M. Kirkwood, MD  
Version Date: August 2, 2021 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology 
NRG / NRG Oncology 
SWOG / SWOG 
 
 
February 18, 2020 
Addendum #1 
Addendum #2 
Addendum #3 
 
 
 
NCTN STUDY CHAMPION:  
Christopher Lao, MD (SWOG) 
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Encorafenib 
147279 
807064 
Pfizer 
Binimetinib 
147279 
788187 
Pfizer 
18F-FLT 
147279 
743144 
Supplied by sites qualified by 
ECOG-ACRIN NCI Cancer 
Imaging Program 
IND Sponsor: ECOG-ACRIN 
Rev Add2 


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Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 
Importance ................................................................................................ 8 
1.2 
MAPK pathway inhibitor therapy .............................................................. 8 
1.3 
Adjuvant Therapy ...................................................................................... 9 
1.4 
Rationale for Neoadjuvant Therapy ........................................................ 11 
1.5 
FLT-PET .................................................................................................... 14 
1.6 
Ki67 and CD8+ T Cell Infiltration ............................................................. 15 
1.7 
Trial Rationale ......................................................................................... 15 
1.8 
Hypotheses .............................................................................................. 16 
2. Objectives ......................................................................................................... 17 
2.1 
Primary Clinical Objective ....................................................................... 17 
2.2 
Secondary Clinical Objectives ................................................................. 17 
2.3 
Correlative Science Objectives ................................................................ 17 
2.4 
Imaging Objectives .................................................................................. 17 
3. Selection of Patients ......................................................................................... 18 
3.1 
Eligibility Criteria ..................................................................................... 18 
4. Registration Procedures .................................................................................... 24 
4.1 
Registration Information ......................................................................... 28 
4.2 
Eligibility Verification .............................................................................. 28 
4.3 
Additional Requirements ........................................................................ 28 
4.4 
Instructions for Patients who Do Not Start Assigned Protocol Treatment31 
5. Treatment Plan ................................................................................................. 32 
5.1 
Administration Schedule ......................................................................... 32 
5.2 
Imaging Schedule .................................................................................... 33 
5.3 
18F-FLT Whole Body Imaging Protocol ................................................... 35 
5.4 
Adverse Event Reporting Requirements ................................................. 38 
5.5 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ........... 48 
5.6 
Dose Modifications ................................................................................. 52 
5.7 
Supportive Care ....................................................................................... 58 
5.8 
Duration of Therapy ................................................................................ 58 
5.9 
Duration of Follow-up ............................................................................. 59 
6. Measurement of Effect ..................................................................................... 61 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 61 
6.2 
Progression before surgery ..................................................................... 68 
6.3 
Local, Regional Recurrence ..................................................................... 68 
6.4 
Distant Recurrence .................................................................................. 68 
6.5 
Disease-Free Survival .............................................................................. 68 
6.6 
Survival .................................................................................................... 69 
6.7 
Recurrence .............................................................................................. 69 


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7. Study Parameters .............................................................................................. 70 
7.1 
Therapeutic Parameters .......................................................................... 70 
7.2 
Biological Sample Submissions ............................................................... 73 
8. Drug Formulation and Procurement ................................................................. 75 
8.1 
Binimetinib (NSC 788187) ....................................................................... 75 
8.2 
Encorafenib (LGX818) ............................................................................. 79 
8.3 
18F-FLT .................................................................................................... 86 
9. Statistical Considerations .................................................................................. 89 
9.1 
Study Design and Objectives ................................................................... 89 
9.2 
Study Endpoints ...................................................................................... 89 
9.3 
Sample Size Considerations and Monitoring Plan .................................. 90 
9.4 
Secondary Lab Endpoints ........................................................................ 90 
9.5 
Statistical Analysis Plan ........................................................................... 91 
9.6 
Gender and Ethnicity .............................................................................. 91 
9.7 
Imaging Statistical Considerations .......................................................... 92 
10. Specimen Submissions ...................................................................................... 96 
10.1 Submissions to ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) .......................................................................................... 96 
10.2 Peripheral Blood Submissions: ................................................................ 99 
10.3 Central Laboratory: Processing and Routing......................................... 101 
10.4 ECOG-ACRIN Sample Tracking System .................................................. 101 
10.5 Sample Inventory Submission Guidelines ............................................. 102 
11. Specimen Analyses: Diagnostic Review and Research Studies ....................... 103 
11.1 Central Diagnostic Review .................................................................... 103 
11.2 Ki67 and CD8+ infiltration ..................................................................... 103 
11.3 Lab Data Transfer Guidelines ................................................................ 104 


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12. Electronic Data Capture .................................................................................. 105 
13. Patient Consent and Peer Judgment .............................................................. 105 
14. References ...................................................................................................... 105 
Appendix I  Pathology Submission Guidelines ...................................................... 111 
Appendix II  Patient Thank You Letter ................................................................... 116 
Appendix III  Patient Pill Calendar ......................................................................... 117 
Appendix IV  ECOG Performance Status ............................................................... 120 
Appendix V  Instructions for Reporting Pregnancies on a Clinical Trial ................ 121 
Appendix VI  Contraception Guidance .................................................................. 123 
Appendix VII  EA6183 Binimetinib and Encorafenib Study Drug Request Form 
Download Instructions .................................................................................... 125 
Appendix VIII  EA6183 Collection and Shipping Kit Order Instructions ................. 126 
Appendix IX  Clinical Trial Wallet Card .................................................................. 127 
Appendix X  CYP3A4 Inducers and Inhibitors ........................................................ 128 
Appendix XI  Tumor Tissue Biopsy Reimbursement Instructions .......................... 129 
Appendix XII  Guidelines for Radiopharmaceutical Production Facilities Shipping 
18F-FLT to Sites ............................................................................................... 132 


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STUDY CHAIR 
Leslie Fecher, MD 
1500 East Medical Center Drive, SPC 5848 
C343 MIB 
Ann Arbor, MI 48109-5848 
Phone: 734-615-4762 
Fax: 734-936-4940 
Email: lfecher@med.umich.edu 
 
IMAGING PROJECT MANAGER 
Diana Ewen, MPH, CCRP 
ACR, Center for Research and Innovation 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
Phone: 215-717-0833 
Email: dewen@acr.org 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. (Sign in at 
www.ctsu.org, and select the 
Regulatory > Regulatory 
Submission.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please see 
the data submission section 
of the protocol for further 
instructions. 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at https://www.ctsu.org 
 


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Schema 
Surgical 
resection 
F
O
L
L
O
W
-
U
P
FLT-PET1,2
Cycle length = 28 days
R
E
G
I
S
T
R
A
T
I
O
N
1. FLT-PET: The first FLT-PET is to be done at baseline prior to initiation of neoadjuvant treatment.  The second FLT-PET is to be done after the 
8 weeks of neoadjuvant treatment is completed and prior to surgery. (See Section 5.3)
2. Tumor biopsies: From consenting patients, tumor biopsies are requested to be performed at baseline (if inadequate material is available from 
prior procedure) and after 2 weeks of neoadjuvant treatment is completed.  If baseline biopsy is performed after study registration, the 
baseline FLT-PET scan should be completed prior to the biopsy (can be done same day).
Neoadjuvant Treatment
Encorafenib 450 mg po 
once daily x 8 weeks 
(2 cycles) 
Binimetinib 45 mg 
po twice daily x 8 weeks 
(2 cycles)
Post 
neoadjuvant 
FLT-PET1,2
Adjuvant Treatment
Encorafenib 450 mg 
po once daily x 44 
weeks 
(11 cycles) 
Binimetinib 45 mg po 
twice daily x 44 weeks 
(11 cycles)
 


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1. 
Introduction 
1.1 
Importance 
Melanoma, despite multiple recent advances and improvements in overall 
survival, remains a lethal disease for many patients. The incidence of melanoma 
continues to rise, with an estimated 96,480 new cases in 2019 and 7,230 deaths 
in the United States [Siegel, 2019]. Five-year melanoma specific survival rates 
for stage III patients vary widely from 93% to 32% [Gershenwald, 2017] where 
patients with clinically evident nodal disease, including stage IIIB, IIIC, and IIID 
melanoma have higher risk of relapse despite complete surgical resections. The 
dramatic improvements in overall survival in advanced unresectable melanoma 
has come about due to checkpoint inhibitor therapy and mitogen activated 
protein kinase (MAPK) pathway inhibitors. These agents are now moving into the 
adjuvant setting and neoadjuvant setting. 
1.2 
MAPK pathway inhibitor therapy 
Somatic mutations in BRAF are present in approximately 40% of all melanomas 
[Davies, 2002]. BRAF inhibitors (BRAFi) either with or without MEK inhibitors 
(MEKi) offer high response rates in patients with metastatic melanoma whose 
tumors have BRAF mutations. However, typically resistance evolves. Single 
agent BRAF inhibitor therapy with vemurafenib [Genentech-Roche, South San 
Francisco, CA] and dabrafenib [Novartis, Basel, Switzerland] initially 
demonstrated significant overall survival (OS) and progression free survival 
(PFS) benefits compared with dacarbazine (DTIC) in the treatment of BRAF 
V600mutant advanced melanoma patients in randomized phase III studies. 
[Chapman, NEJM 2011; Hauschild, Lancet, 2012] The addition of MEKi to BRAFi 
in the treatment of advanced melanoma improved response rates, duration of 
response, overall survival as well as mitigating some of the toxicity of this 
therapy. [Long, NEJM 2014, Larkin, NEJM 2014, Robert, NEJM 2015] There are 
extensive safety data in support of the combination BRAFi +MEKi therapy in the 
metastatic disease setting. The most common adverse events for patients 
receiving BRAFi are skin rash, hyperkeratosis, dry skin, photosensitivity, 
headache, pyrexia, arthralgia, myalgias, skin papillomas and skin cancers and 
fatigue. [Chapman, NEJM 2011, Hauschild, Lancet, 2012] The most frequent and 
notable adverse events with MEKi are skin rash, diarrhea, nausea, vomiting, 
edema, hypertension, fatigue, chorioretinopathy, elevated creatinine 
phosphokinase (CPK), and left ventricular dysfunction.[Flaherty, NEJM, 2012] 
Combinations of BRAFi and MEKi have resulted in decreased skin toxicity 
including decrease in the incidence of nonmelanoma skin cancers. [Long, NEJM 
2014, Larkin, NEJM 2014, Robert, NEJM 2015] 
A third selective BRAF inhibitor, Encorafenib (LGX818) [Pfizer, Boulder, CO], has 
shown a favorable safety profile and efficacy in a phase I study as a single agent, 
as well as in phase 1B/2 combination study with binimetinib [Pfizer, Boulder, CO], 
a MEKi. [Dummer, JCO, 2013, Sullivan, JCO, 2015] The preliminary results of 
the phase I study identified 450mg daily as the RP2D with 7 patients 
experiencing a DLT: hand-foot skin reaction, foot pain, fatigue, 
diarrhea/rash/headache, insomnia/asthenia, facial paresis/confusion, 
pain/neuralgia- all of which were reversible. [Dummer, JCO, 2013] A total of 54 
patients, including 26 BRAFi naïve were treated and the most common AEs 


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included: rash, dry skin, hand foot palmar plantar dysesthesia, pruritis, alopecia, 
nausea, decreased appetite, fatigue and arthralgias. Fever was seen in only 
5.6% and squamous cell carcinoma in 3.7% (n=2) and keratoacanthoma in 3.7% 
(n=2). Single-agent encorafenib demonstrated a confirmed RR of 58% in BRAFi 
naïve patients, without any CRs. The median PFS was 217 days in this cohort 
and median duration of response was estimated to be 45.3 weeks. Treatment-
related grade 3 toxicities were present in 33.3% and all reversible. The Phase 
1B/2 study of encorafenib + binimetinib treated 55 BRAFi naïve patients with no 
MTD declared. [Sullivan, JCO, 2015] Encorafenib at a variety of doses was 
combined with binimetinib 45mg bid and showed an ORR of 74.5%. For 
encorafenib 400/450mg with binimetinib 45mg bid, the ORR was 77.8% (n=9). 
The median PFS was 11.3 months for the entire trial. Grade 3/4 AEs were 
55.5%(5/9) for encorafenib 400/450mg + binimetinib 45mg bid cohort; most 
common AEs included nausea, diarrhea, AST/ALT elevation, fatigue. Only 1/9 
had pyrexia, and 1/9 had CPK elevation, 1/9 with retinal pigment epithelium 
detachment, 1/9 with EF decreased, 1/9 with a neoplasm of the skin. Toxicities 
for encorafenib 600mg daily were greater. The Columbus study, a three arm 
1:1:1 randomized study of vemurafenib 960mg bid vs encorafenib 300mg daily vs 
the combination of encorafenib 450mg daily and binimetinib 45mg bid in 
untreated patients with BRAF mutant advanced melanoma enrolled 577 
patients.[Dummer, Lancet Oncol, 2018] The primary endpoint was PFS for the 
combination therapy vs vemurafenib, and the secondary endpoint was PFS for 
combination therapy vs encorafenib alone. Preliminary results of this study were 
presented demonstrating PFS [per central review] of 14.9 mos for the 
combination vs 7.3 mos for vemurafenib alone[p<0.001]; 14.9mos for 
combination vs 9.6mos [p=0.051] for encorafenib alone.[Flaherty, SMR, 2016] 
The ORR (central review) was 63% for the combination therapy vs 51% and 40% 
for Encorafenib 300mg daily and vemurafenib, respectively. The CR rate for 
combination therapy was 8%. This led to approval by the FDA of this combination 
therapy for the treatment of metastatic melanoma. Safety was acceptable with 
58% grade 3/4 AEs in the combination arm, versus 66% and 63% in the other 
arms respectively. The incidence of secondary non-melanoma skin neoplasms 
was 4% [n= 192] for combination therapy vs 9% [n=192] for encorafenib alone vs 
18% [n=192] for vemurafenib.[Flaherty, SMR, 2016]. The incidence in the 
combination arm of elevated CPK was 23%, pyrexia 18%, which is similar or less 
frequent compared with other combinations of BRAFi/MEKi. [Long, NEJM 2014, 
Larkin, NEJM 2014, Robert, NEJM 2015] Additionally, this pair of agents had 
fewer AEs leading to dose interruption or requiring dose reduction compared with 
single agent BRAFi in the Columbus study. Median overall survival for the 
combination arm of 33.6 mos versus 16.9 mos for vemurafenib was presented in 
2018.[Dummer, JCO, 2018] Updated grade 3/4 toxicity incidence for combination 
arm was 64%, compared with 67% for encorafenib alone and 66% for 
vemurafenib alone. 
1.3 
Adjuvant Therapy 
Adjuvant therapy in the management of advanced stage II and stage III 
melanoma remains controversial. Interferon alfa 2b [Merck, Kenilworth, NJ] has 
been tested in various doses and schedules over the years and has consistently 
shown an effect on relapse free survival but inconsistently shown an impact on 
overall survival. [Mocellin, 2010]. Ipilimumab [Bristol Myers Squibb, New York, 
NY] 10mg/kg IV over 3 years was approved by the Food and Drug Association 


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for the treatment of stage III melanoma after showing improved overall survival 
and relapse free survival compared with placebo. However, the grade 3-4 toxicity 
rate of approximately 45% with a 1% rate of deaths due to toxicities has 
impacted its utility.[Eggermont NEJM, 2016] More recently, preliminary data from 
Checkmate 238 was published and led the FDA to approval of nivolumab [Bristol 
Myers Squibb, New York, NY] for one year in the adjuvant treatment of stage III 
melanoma.[Weber, NEJM, 2017] This trial randomized subjects with resected 
stage IIIB/C/IVM1a/b (AJCC 7th edition) to nivolumab 3mg/kg IV every 2 weeks 
for one year or Ipilimumab 10mg/kg IV every 3 weeks for 4 doses, then every 3 
months for up to one year. Nivolumab demonstrated a superior 12 month RFS of 
70.5% (95% CI, 66.1-74.5] compared with 60.8% (95% CI, 56.0-65.2] for 
ipilimumab with a minimum follow up of 18 months; hazard ratio for disease 
recurrence/death was 0.65 [97.56% CI, 0.51-0.83]. Updated results showed a 24 
month RFS improvement favoring nivolumab (63% v 50% with a hazard ratio for 
disease recurrence/death of 0.66 [95% CI, 0.54, 0.81]. [Weber, 2018, ASCO] The 
four year update upheld the RFS improvement for nivolumab compared with 
ipilimumab [51.7 (95% CI46.8-56.3) vs 41.2% (36.4-45.9)] but there was no 
difference in overall survival [77.9% (95% CI 73.7-81.5) vs 76.6% (72.2-
80.3)].Ascierto, 2020, Lancet Oncol]. Similar preliminary results were reported for 
pembrolizumab [Merck, Kenilworth, NJ], compared with placebo, in the adjuvant 
setting. [Eggermont, NEJM 2018] This double blind phase III study randomized 
1019 subjects with resected stage IIIA/B/C (7th edition; for IIIA –at least one SLN 
deposit >1mm required and no in transit metastases) melanoma to 
pembrolizumab 200mg IV every 3 weeks x 18 doses or placebo. After a median 
follow up of 15 months, the 1 year RFS for pembro versus placebo was 75.4% 
[95% CI, 71.3-78.9] vs 61% [95% CI, 56.5-65.1] with a HR for recurrence/death 
of 0.57 [98.4% CI, 0.43-0.74, p<0.001]. Grade 3-5 AEs for both PD-1 inhibitors 
were approximately 14%. The RFS at 3 years was greater for pembrolizumab 
compared with placebo (63.7% vs 44.1%). [Eggermont, 2020, J Clin Oncol]. 
Overall survival data remains immature for this study. 
MAPK inhibitors in the adjuvant setting has also been investigated and reported. 
The combination of dabrafenib with trametinib [Novartis, Basel, Switzerland] was 
compared to matched placebos in 870 subjects with resected stage IIIA-IIIC 
(AJCC 7th edition) who had had a completion lymph node dissection in a double-
blind, randomized phase III study. [Long, NEJM, 2017] Patients with stage IIIA 
melanoma were required to have at least a 1mm SLN metastatic focus. The 
estimated 3 years RFS was 58% vs 39% favoring dabrafenib with trametinib [HR 
for relapse/death 0.47, 95% CI 0.39-0.58; p <0.001] at a median follow up of 2.8 
years. The 3-year OS was 86% vs 77%, again favoring Dabrafenib with 
Trametinib [HR 0.57; 95% CI 0.42-0.79; p=0.0006] but did not cross the 
prespecified interim analysis boundary of p=0.000019. A five-year analysis 
reported 52% RFS for patients treated with dabrafenib and trametinib compared 
with 36% for placebo [HR 0.51; 95% CI 0.42-0.61]. [Dummer, 2020, NEJM]. The 
most common AEs for combination dabrafenib with trametinib were similar to 
other trials with pyrexia, fatigue, and nausea being most common. In the 
combination therapy group, 38% had an AE that led to dose reduction and 26% 
had an AE that led to permanent discontinuation. Similar incidence of 
melanomas and nonmelanoma skin cancers were reported for both groups. 
Single agent vemurafenib was evaluated in a double-blinded randomized phase 
III study in 498 subjects with resected stage IIC/IIIA/IIIB and IIIC assessed in two 
cohorts (AJCC 7th edition). [Maio, Lancet Oncol 2018] at median follow ups of 


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33.5 months for stage IIIC subjects, the median disease free survival (DFS) was 
23.1 months for vemurafenib vs 15.4 months for placebo [HR 0.80, 95% CI 0.54-
1.18; log rank p=0.26]. For subjects with stage IIC/IIIA/IIIB, the median DFS was 
not reached in the group treated with vemurafenib but was 36.9 months for the 
placebo group at median follow up of 30.8 months [HR 0.54 [95% CI 0.37-0.78; 
log rank p =0.0010]. However, as cohort 2 did not meet its primary endpoint, the 
results of the other cohort were interpreted as exploratory. 
1.4 
Rationale for Neoadjuvant Therapy 
Traditionally, therapeutic agents have not evidenced response rates great 
enough to explore in a neoadjuvant approach in melanoma. Given the described 
successes, a neoadjuvant treatment paradigm is being considered in melanoma 
with BRAF/MEK inhibitors as well as with other agents. Several small prospective 
studies are completed or ongoing, including three which have been reported, that 
evaluated Dabrafenib and Trametinib in patients with bulky stage IIIB/C or IV 
melanoma. Amaria et al published a single institution study of patients with 
resectable stage IIIB/C or IV melanoma that randomized subjects 2:1 to 
dabrafenib with trametinib for 8 weeks then complete resection followed by 44 
weeks of treatment vs upfront surgery [standard of care]. [Amaria, Lancet Oncol 
2018] This was designed to evaluate 12 mos EFS (event free survival) and 
showed a significant improvement in EFS for systemic therapy (19.7 mo) vs 
surgery (2.9 mo) [HR 0.016] for the first 21 enrolled patients and thus, the trial 
was halted early. Of note, 7/12 pts in the neoadjuvant arm achieved a pathologic 
CR [58%], with 2 pPR [16%]. There was no correlation between RECIST 
responses and pathologic responses in this study. Therapy was temporarily 
stopped in 92% (12/13) of patients during the neoadjuvant phase for fevers with 
38% requiring at least one dose reduction. There were no surgical delays or 
unexpected surgical complications. Of the 11 patients who accepted adjuvant 
therapy, 4 discontinued treatment due to toxicities. A single institution phase II 
single arm study of neoadjuvant dabrafenib with trametinib was also carried out 
at the Melanoma Institute Australia [Menzies, Ann Oncol, 2017] Thirty-five 
patients were treated with dabrafenib and trametinib for 12 weeks, then 
proceeded to resection, followed by additional D+T for 40 weeks. All patients had 
bulky stage IIIB/C disease, and pCR was the primary endpoint. The pathologic 
CR rate was 52% (17/33). RECIST and pathologic responses were discordant. At 
a median follow up of 12.9 months after resection, 12 (36%) recurred including 6 
with prior pCR and 4 while on D+T. Toxicities were as expected, with 79% of 
patients experiencing drug fever. An initial report stated that 12/14 (86%) of 
patients had treatment interruption in the first 12 weeks for a median of 7 days. 
[Saw, JCO, 2016] Published results reported a pCR rate of 17/35 (49% for this 
study with a median follow up of 27 months. [Long, Lancet Oncol, 2019] Eighty-
six percent of patients achieved a RECIST response; 57% (20/35) experienced 
recurrence: 8 during the first year: 4 on treatment and 4 off treatment (stopped 
for toxicities), and 12 after 52 weeks. One year RFS was 77.1% [64.4 to 92.4], 
two year RFS was 43.4% [28.6 to 65.7] with median RFS of 23.3 months [95% CI 
17.7 to not reached]. Another neoadjuvant study was presented at ECCO and 
was designed to assess the ability to convert unresectable stage III/IV patients to 
resectability with 8 weeks of dabrafenib and trametinib followed by surgery. 
[Haanen, ECCO 2017]. Twenty one patients were enrolled and treated, 2 
progressed and 19 proceeded to surgery, with 17 achieving an R0 resection 
(tumor free margins) and one patient had an R1 resection while one patient was 


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deemed unresectable due to vessel encasement.[Blankenstein, Ann Surg, 2021]. 
Six patients required treatment interruption for toxicities but all completed 
neoadjuvant treatment. The pathologic responses included: pathologic CR in 
28.6% (6/18), near pCR in 14.3% (3/18), pPR in 19% (4/18) and pNR in 23.8% 
(5/18). Radiologic response on CT or PET did not predict pathologic response. 
Surgical complications occurred in 80%, mainly seromas, wound infections, and 
lymphedema. Of these 18 patients who had surgery, 9 patients have recurred, 
including 6 with distant metastases. Five of the 6 patients with a pCR have not 
had a recurrence. 
Of the 35 patients treated with Dabrafenib with Trametinib neoadjuvantly for 12 
weeks in Long et al: 0/35 with clinical or radiologic PD before surgery (16 with 
CR, 14 with PR); all proceeded to surgery, Surgical complications (including 
infection requiring antibiotics, seroma, bleeding, lymphedema, thrombus) of any 
grade occurred in 63% (22) with 26% (9) being grade 3. Two patients stopped 
treatment before 12 weeks due to treatment related adverse events. Of the 14 
patients treated with neoadjuvant Dabrafenib and Trametinib for 8 weeks in 
Amaria et al: 1 withdrew consent before starting treatment, one withdrew consent 
for surgery given partial response to oral treatment and 12 patients received 
surgery. No patients evidenced radiologic or clinical progression prior to surgery: 
2 CR, 9 PR and 2 SD. In the 12 who had surgery, 7 had a pCR and 2 had a pPR, 
while 3 had a pathologic non-response (>50% viable tumor in surgical specimen). 
They reported no unexpected peri-operative or post-operative treatment-related 
toxicities, nor were there any treatment related delays in surgery. 
Neoadjuvant trials with immunotherapies continue as well. Initial studies 
evaluated high dose (HD) interferon in patients with palpable stage IIIB/C 
melanoma which yielded a pCR rate of 15%(3/20), [Moschos JCO 2006] HD 
Interferon was also evaluated in combination with ipilimumab in palpable stage 
IIIB/C/IV which yielded a pCR rate of 32% (9/28) but with significant toxicities. 
[Tarhini JCO 2016] Pembrolizumab was also evaluated in combination with HD 
interferon in a similar group of patients (n=20) and demonstrated a pCR rate of 
35%, [Tarhini JCO 2018] A recent presentation at the American Association for 
Cancer Research reported on 27 patients enrolled in a single institution trial of 
neoadjuvant pembrolizumab in patients with resected stage IIIB/C/IV melanoma. 
[Huang, AACR, 2018] Patients were treated with one dose of pembrolizumab 
200mg prior to planned surgery with no delays in planned surgery. The 1 year 
RFS was 55%, with 8/27 achieving a near pCR or pCR (5/27 with pCR) after one 
dose and all 8 who have remained relapse free. These data were recently 
published and updates included a one year DFS rate of 63%, all major or pCR 
responders remain disease free at 24 months. In paired pre- and post-treatment 
specimens (n=20), there was a significant decrease in viable tumor cells where 
≤10% viable tumor at resection correlated with low risk of recurrence regardless 
of stage. [Huang, Nat Med, 2019]. There was a greater number of samples post 
treatment samples with brisk TILs and brisk TIL s was associated with major or 
pCR and improved DFS. In a subset of 6 patients with 3 week on treatment FDG-
PET scans, while tumor size decrease directly correlated with histologic 
percentage of viable tumor, the change in FDG avidity did not correlate with 
response. Three additional studies evaluated combination immunotherapy in 
resectable stage III melanoma. One trial [OpACIN] randomized 20 patients to 
either neoadjuvant ipilimumab in combination with nivolumab for two cycles 
followed by surgery and then two additional cycles, while the other arm received 
surgery followed by 4 cycles of adjuvant combination therapy. [Blank, Nat Med, 


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2018]. In the 10 patients treated with neoadjuvant therapy, a pCR rate of 33% 
was achieved with significant toxicities. Another small trial randomized 23 
patients to either combination ipilimumab with nivolumab or nivolumab pre and 
post surgery which achieved pCR rates of 45% and 25%, respectively. [Amaria, 
Nat Med, 2018] Lastly, another larger study [OpACIN-neo] randomized 86 
patients to ipilimumab 3mg/kg with nivolumab 1mg/kg for two cycles versus to 
ipilimumab 1mg/kg with nivolumab 3mg/kg for two cycles versus to ipilimumab 
3mg/kg for 2 cycles followed by nivolumab 3mg/kg for two cycles and then 
surgical resection. [Rozeman, ESMO, 2018] The pathologic response rates were 
47%, 57% and 23% respectively. The last arm was closed early due to toxicities.  
An update after 4 years of follow up for OpACIN, there were no relapses in the 7 
patients who achieved a pathologic response and the 4 year EFS and OS rates 
were 80% and 90%, respectively, in the neoadjuvant arm and 60% and 70% in 
the adjuvant arm. [Rozeman, Nature Med, 2021] In the OpACIN-neo study, the 
estimated 2yr RFS was 90%, 78%, and 83%, respectively, for the above 
treatment arms. This included two patients who progressed during neoadjuvant 
treatment and 12 who progressed after surgery. Outcomes correlated with 
pathologic response in both studies and baseline interferon-gamma gene 
signature expression was associated with lower risk of relapse. 
Given evolving data, limited patient numbers and multiple variables in studies to 
date, the neoadjuvant therapeutic paradigm, as well as the endpoint of pathologic 
CR remain investigational in melanoma. Most of the past and current 
neoadjuvant trials are designed as single arm studies due to the limited patient 
numbers and limitations of randomizing to surgery, the current standard of care: 
NCT01972347, NCT01972347, NCT02036086, NCT02303951, NCT02306850. 
The Amaria study has been redesigned based on preliminary information to a 
single arm study. While the above data is intriguing, the optimal agents, 
schedule, response assessments (radiographic and pathologic) have yet to be 
determined. Toxicities of all agents, including those of dabrafenib and trametinib, 
while expected, did impact treatment. A pooled analysis of 6 neoadjuvant studies 
of immunotherapy and targeted therapies reported an overall pCR rate of 40%: 
47% for targeted therapies and 33% for immunotherapy. [Menzies, Nature, 2021] 
In this analysis of 192 patients, 189 patients proceeded to surgery. pCR 
correlated with improved RFS and OS. No patients treated with targeted therapy 
progressed before surgery while 5% treated with immunotherapy did so.  
Recurrences were reported in 32% of patients.  The authors reported a 1 and 2 
year RFS for the entire group of 77% and 65%. In a cross trial comparison, the 
authors report lower 1 and 2 year RFS for targeted therapy, 75% and 47%,than 
for immunotherapy treated patients: 78% and 75%. 
Table 1. 
Baseline pCR Estimation from published/presented Data 
pCR 
n 
Regimen 
Reference 
15% 
20 
HDI 
Moschos JCO 2006 
32% 
28 
HDI+Ipi 
Tarhini JCO 2016 
35% 
20 
Pembro+HDI 
Tarhini JCO 2018 
18.5% 
27 
Pembro 
Huang Nat Med 2019 
33% 
10 
Ipi+Nivo 
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45% 
11 of 23 
Ipi+Nivo 
Amaria Nat Med 2018 
25% 
12 of 23 
Nivo 
 
47% 
30 of 86 
Ipi3+Nivo1 
Rozeman LancetOncol 2019 
57% 
30 of 86 
Ipi1+Nivo3 
 
23% 
26 of 86 
Ipi3->Nivo3 
 
1.5 
FLT-PET 
Response rates for metastatic melanoma patients treated with selective BRAF 
inhibitors are high, and early evaluation (day 15) with FDG-PET/CT show fairly 
uniform decreases in FDG activity regardless of duration or depth of benefit 
[McArthur, JCO, 2012]. Thus, predictive biomarkers of long-term response are 
needed. Specifically, there was no correlation between time to RECIST response 
and metabolic response, or between metabolic response at Day 15 and duration 
of RECIST response, progression free survival (PFS) or overall survival (OS). 
Potentially, this could be related to change in glucose uptake due to alterations in 
GLUT1 expression rather than true response to therapy [Ma, JCO, 2009; 
Parmenter, Ca Discovery 2014]. PET imaging using 18F-fluorothymidine (FLT), a 
tracer that measures cellular proliferation in an S-phase-dependent manner, has 
been explored in several malignancies within the first several weeks of treatment 
in an effort to predict early response or resistance. This is based on the 
hypothesis that FLT will be more specific for true tumor response, but has yielded 
variable results [Kenny, EJNMMI, 2007; Sohn, Clin Ca Res, 2008; Bollineni, Eur 
J Canc, 2016]. Under the auspices of ACRIN, ACRIN 6688 investigated whether 
early change in FLT-PET SUV could predict pCR in patients with breast cancer 
receiving neoadjuvant chemotherapy [Kostakoglu, J Nucl Med, 2015]. FLT-PET 
was performed at baseline (FLT1), 5-10 days after cycle 1 of treatment (FLT2), 
and after completion of neoadjuvant therapy within 3 weeks of surgery (FLT3). 
While the predictive value of %change in SUV between FLT1 and FLT2 to predict 
pCR was minimal, the change between FLT1 and FLT3 was a strong indicator of 
pCR. Additionally, post therapy FLT uptake significantly correlated with post 
therapy Ki-67 in the surgical specimens. 
In vivo data investigating a role for FLT-PET in melanoma, or with MEK or BRAF 
inhibitor therapy, are sparse [Solit, Cancer Res, 2007; Leyton, Molec Canc 
Thera, 2008; McKinley, J Nuc Med, 2013, Geven CMMI, 2015]. There is currently 
a study underway in patients with advanced unresectable melanoma being 
treated with vemurafenib and cobimetinib, another BRAF/MEK doublet in which 
FDG-PET are performed at baseline, at C1D15 and C2D21 (where a cycle is 28 
days), and at progression; in addition, FLT-PET are performed at baseline, at 
C1D14, and at progression [van der Hiel, BMC Cancer, 2017]. The primary aim is 
to determine if change in either of the PET studies can predict early response 
compared with standard RECIST response or predict PFS in advanced 
unresectable melanoma. A pilot study of 5 patients recently reported that 
decreased tumor volume and tumor proliferation on a 6-week FLT-PET scan 
compared with baseline after treatment with pembrolizumab correlated with 
response per RECIST on 12-week CT scans. Specifically, better objective 
responses were seen in patients with a greater decrease in FLT uptake [delta-
PTV(proliferative tumor volume), delta-SUVmax, and delta TLP (total lesion 
proliferation) and a trend toward higher OS in patients FLT-PET response.[Yeh, 
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1.6 
Ki67 and CD8+ T Cell Infiltration 
CD8+ T cell infiltration: 
There are data to suggest that CD8+ T cell tumor infiltration correlates with 
clinical response to BRAFi and BRAFi + MEKi.[ Wilmott, CCR, 2012; Frederick, 
CCR, 2013; Wargo, JCO, 201; Long, Lancet Oncol, 2019] A small retrospective 
analysis did not show any significant change in serum immunologic profiles after 
treatment with dabrafenib in metastatic melanoma. [Hong, 2012] We hypothesize 
that CD8+ T cell infiltration, and the change in this in response to treatment, in 
the tumor or tumor bed directly correlates with pCR, DFS and OS. Early on 
treatment biopsies have demonstrated unique and informative information 
regarding response. [Amaria, Nat Med, Chen, Cancer Discov]. We hypothesize 
that CD8+ T cell infiltration at baseline, and/or the change in CD8+ tumor 
infiltrating lymphocytes (TIL) with treatment early (on treatment biopsy) and late 
(at resection), in the tumor or tumor bed directly correlates with pCR, disease 
free survival (DFS) and overall survival (OS). 
Ki67 and proliferation: 
Low baseline Ki67 and early large change in Ki67 correlate with OS in melanoma 
patients treated with BRAFi [Long, et al, PCMR, 2013]. Ki-67 tumor cell IHC will 
be evaluated in all specimens and correlated with FLT-PET. It is hypothesized 
that change in FLT-PET uptake will correlate with Ki-67 changes. Correlation of 
Ki67 in tumor cells may provide evidence that FLT-PET is a true imaging 
measure of proliferation. 
1.7 
Trial Rationale 
This trial is a single arm phase 2 study to investigate encorafenib, a selective 
BRAF inhibitor, in combination with binimetinib, a MEK inhibitor, in the 
neoadjuvant treatment of resectable clinically or radiographically-detected stage 
IIIB/C/D melanoma. The treatment period planned will be a total of one year, with 
8 weeks of therapy prior to planned surgery followed by 44 weeks of combination 
treatment postoperatively. Responses to combination BRAFi/MEKi usually occur 
within 2 months, hence an 8-week treatment period was chosen to evaluate 
response as well as not to delay definitive surgical resection. The Columbus trial 
of encorafenib with binimetinib yielded favorable response and safety data in 
advanced metastatic melanoma. [Dummer, Lancet Oncol, 2018] The planned 
clinical primary end-point is pathologic complete response (pCR) as determined 
by local assessment of surgical pathologic specimens and radiology studies. 
Central pathology review of the pre-study biopsy and post-neoadjuvant treatment 
surgical specimens will also be accomplished retrospectively, as has been 
customary for ECOG-ACRIN Melanoma Committee studies. This trial will 
evaluate the benefit of these agents, the role of pathologic CR (pCR) as an 
endpoint, and the toxicity profile of encorafenib with binimetinib in this setting and 
population. It is possible that the toxicity profile may be distinct from that seen 
with other BRAF/MEKi doublets. 
Additional hypotheses center upon translational components, which are seeking 
markers of clinical response and/or early indicators of response (or resistance). 
In all cases, the relationships of these components to each other will also be 
explored, e.g., whether changes in measures of melanoma immunity correlate 
with changes in imaging. This trial will include a radiologic key secondary 
endpoint with a molecular imaging marker FLT PET, designed to test an early 


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response indicator that could be used to guide BRAF/MEK targeted therapy. 
FLT-PET scans will be evaluated at two time points (baseline and eight weeks 
after therapy initiation) and correlated with pCR. The decrease in FLT-PET 
uptake, based on the maximum standard uptake value (SUVmax), from baseline 
to eight weeks will be assessed. Measures of proliferation obtained from FLT-
PET will be compared to the tissue reference standard for proliferation, Ki-67. 
Additional secondary endpoints will explore CD8+T cell infiltration as possible 
early indicators of clinical response (or resistance) in melanoma patients treated 
in the neoadjuvant setting with these agents. This trial will collect tumor tissue 
and blood at multiple time points in the treatment process for correlative studies. 
Material will be banked for future studies involving resistance mechanisms and 
more extensive immunologic testing. 
1.8 
Hypotheses 
1.8.1 
Primary 
1.8.1.1 
Neoadjuvant treatment with a combination of binimetinib 
and encorafenib in Stage IIIB/C/D clinically evident nodal 
resectable melanoma will yield a pathologic complete 
response (pCR) rate of at least 57%.  
1.8.1.2 
Summarizing current pCR data (Table1), a weighted 
average pCR rate for immunotherapy neoadjuvant trials 
with ranges from 15%-57%, would be 33%. The two small 
studies of neoadjuvant BRAF + MEK inhibitors have shown 
response rates of 52% and 58%. It is hypothesized that 
encorafenib and binimetinib will have a similar response 
rate as the other BRAF/MEK inhibitors, and greater than 
that seen with immunotherapies. 
1.8.2 
Secondary  
1.8.2.1 
Patients achieving pCR based on neoadjuvant treatment 
with a combination of binimetinib and encorafenib will 
demonstrate a greater decrease in FLT-PET uptake (from 
baseline to 8 weeks post neoadjuvant treatment initiation) 
compared to non-pCR patients. 
1.8.2.2 
Lower post-therapy FLT-PET SUVmax is associated with 
higher likelihood of pCR. 
1.8.2.3 
Change in FLT-PET uptake will correlate with Ki-67 
changes in tumor cells. In particular, the change in FLT-
PET uptake (from baseline to 8 weeks post neoadjuvant 
treatment initiation) will directly correlate with the change in 
early (from baseline to 2 weeks) and post therapy (from 
baseline to 8 weeks after neoadjuvant treatment initiation) 
specimen Ki-67 assays. 
1.8.2.4 
Immune effects of treatment with BRAFi + MEKi. CD8+ T 
cell infiltration at baseline, and/or the change in CD8+ 
tumor infiltrating lymphocytes (TIL) with treatment early (on 
treatment biopsy) and late (at resection), in the tumor or 
tumor bed directly correlates with pCR, disease free 
survival (DFS) and overall survival (OS). 


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2. 
Objectives 
2.1 
Primary Clinical Objective 
2.1.1 
To evaluate the pathologic complete response (pCR) rate of 
neoadjuvant treatment with encorafenib and binimetinib. 
2.2 
Secondary Clinical Objectives  
2.2.1 
To determine RR (RECIST), DFS and OS. 
2.2.2 
To describe correlation of pCR with RR, DFS and OS. 
2.2.3 
To assess safety and toxicity. 
2.3 
Correlative Science Objectives 
2.3.1 
To evaluate CD8+ T cell infiltration and Ki-67 status in tumor or tumor 
bed pre, during, and post neoadjuvant treatment and the change in 
CD8+ TIL with neoadjuvant treatment and correlate with clinical 
response. 
2.3.2 
To compare local review for pathologic response with central 
pathology review. 
2.4 
Imaging Objectives 
2.4.1 
To compare the change in 18F-FLT PET/CT uptake (from baseline to 
post-neoadjuvant therapy) among patients with and without pathologic 
complete response. 
2.4.2 
To compare post-neoadjuvant 18F-FLT PET/CT uptake among 
patients with and without pathologic complete response. 
2.4.3 
To estimate an optimal threshold for prediction of pathologic complete 
response using i) change in 18F-FLT PET/CT uptake, and ii) post-
neoadjuvant 18F-FLT PET/CT uptake. 
2.4.4 
To assess the correlation between change in 18F-FLT PET/CT uptake 
and change in Ki-67. 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patient must be ≥ 18 years of age. 
3.1.2 
Patient must have histologically proven melanoma that is clinically 
evident (macroscopic LAD) stage III B/C/D, (AJCC 8th Edition) of 
cutaneous origin or unknown primary. Patient must have at least one 
clinically evident lymph node metastasis (N1c patients are not 
eligible). Patients with stage IV melanoma are not eligible. 
3.1.2.1 
This may be an initial presentation with primary tumor and 
nodal metastases or locoregional nodal relapse with 
history of resected primary melanoma. 
3.1.2.2 
Stage IIIB 
T0- 3a N1b M0  
Yes _____ No _____ 
T1a-3a N2b M0  
Yes _____ No _____ 
3.1.2.3 
Stage IIIC 
T0 or T3b-4b N2b M0 Yes _____ No _____ 
T3b-4b N1b M0 
Yes _____ No _____ 
Any T N2c M0 (at least 1 clinically evident node) 
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T0-4a N3b M0 
Yes _____ No _____ 
3.1.2.4 
Stage IIID 
T4b N3b/c M0 (if 3c: at least 1 clinically evident node) 
Yes _____ No _____ 
3.1.3 
Patient must have measurable disease on baseline imaging scans, 
obtained within 4 weeks prior to registration as defined by RECIST in 
Section 6.1.3 and by the following criteria. 
3.1.3.1 
All melanoma tumors must be completely resectable as 
determined by a surgical oncologist or experienced 
melanoma surgeon prior to registration. 
3.1.3.1.1 
Extensive satellitosis or extensive in transit 
metastases are not considered completely 
resectable. 
3.1.4 
Patient must have BRAF V600 mutation positive based on report from 
CLIA certified laboratory. 
3.1.5 
Patient must be medically fit to undergo surgery. 
3.1.6 
Patient must have adequate bone marrow, organ function and 
laboratory parameters (labs must be obtained ≤ 14 days prior to 
registration) as defined below: 
3.1.6.1 
ANC ≥ 1.5 × 109/L 
ANC:_________ Date of Test:______________ 
3.1.6.2 
Hemoglobin ≥ 8 g/dL without transfusion 
Hemoglobin:________ Date of Test:__________ 
3.1.6.3 
Platelets ≥ 100 × 109/L without transfusion 
Platelets:____________ Date of Test:__________ 
3.1.6.4 
AST and ALT ≤ 2.0 × Institutional ULN; 
AST:____________ Institutional ULN:__________ 
Date of Test:________________ 
ALT:_____________ Institutional ULN:___________ 
Date of Test:_________________ 
3.1.6.5 
Total bilirubin ≤ 1.5 × Institutional ULN and < 2 mg/dL; OR 
total bilirubin >1.5 × Institutional ULN with indirect bilirubin 
< 1.5 × Institutional ULN 
Total Bilirubin:____________ Institutional ULN:_____ 
Indirect Bilirubin:__________ Institutional ULN:______ 
Date of Test:_____________ 
3.1.6.6 
Serum creatinine ≤ 1.5 × Institutional ULN, or calculated 
creatinine clearance > 50 mL/min by Cockroft-Gault 
formula 
Creatinine:__________ Institutional ULN:_________ 
Date of Test:___________ 


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Creatinine Clearance:________ Date of Test:_______ 
3.1.6.7 
PT, INR, and PTT ≤ 1.5 × Institutional ULN 
PT:_________ Institutional ULN:_____________ 
Date of Test:_______ 
INR:_____Institutional ULN:_____ 
Date of Test:_______ 
PTT:_____Institutional ULN:____ 
Date of Test:_______ 
3.1.7 
Patient must have an ECOG Performance status 0-1.  
3.1.8 
Patient must not have any prior treatment with BRAFi or MEKi. 
3.1.9 
Patient must not have any evidence of distant metastases.  
3.1.10 
Patient must be able to take oral medications. 
3.1.11 
Patient must not have any prior adjuvant therapy at this disease 
presentation; prior immune therapy (such as adjuvant interferon or 
checkpoint inhibitors) is permitted if date of registration is ≥ 6 months 
from last treatment 
3.1.12 
Patient must not have any prior radiation to the site of evaluable 
disease. 
3.1.13 
Patient must not have active infection requiring treatment with 
parenteral antibiotics. 
3.1.14 
Patient must be able to lie still during the 18F-FLT PET/CT scan for the 
duration of the imaging study (up to 1.5 hours), have no previous 
indication of allergic reaction to the radiotracer, and meet the size 
limits of the qualified PET/CT scanner. 
3.1.15 
Patient must be participating in this study at an institution which has 
completed the ECOG-ACRIN defined PET/CT scanner qualification 
procedures and received ECOG-ACRIN PET Scanner approval as 
outlined in Section 4. 
3.1.16 
Patient must not have active Hepatitis B, and/or active Hepatitis C 
infection given concerns for drug interactions or increased toxicities. 
Testing is not required. 
3.1.17 
Patients known to be HIV positive are eligible if they have 
undetectable HIV viral load and stable and adequate CD4 counts  
(≥ 500mm3) on screening labs provided they meet all other protocol 
criteria for participation and that there is no high risk drug interactions. 
See Appendix X. 
3.1.18 
Patient must not have other significant medical, surgical, or 
psychiatric conditions that in the opinion of the investigator may 
interfere with compliance, or make the administration of study 
medications hazardous. 
3.1.19 
Patient must not have had previous or concurrent other malignancy 
with the following exceptions: 


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3.1.19.1 
Adequately treated basal cell or squamous cell carcinoma 
of the skin, in situ carcinoma of the cervix. 
3.1.19.2 
Other solid tumor: if treated and without evidence of 
recurrence for at least 2 years prior to date of registration. 
3.1.20 
Patient must not be pregnant or breast-feeding due to potential harm 
to an unborn fetus and possible risk for adverse events in nursing 
infants with the systemic antineoplastic medications, as well as 
surgery and radiation being used.  
All patients of childbearing potential must have a blood test or urine 
study within 14 days prior to registration to rule out pregnancy. 
A patient of childbearing potential is defined as anyone, regardless of 
sexual orientation or whether they have undergone tubal ligation, who 
meets the following criteria: 1) has achieved menarche at some point, 
2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) 
has not been naturally postmenopausal (amenorrhea following cancer 
therapy does not rule out childbearing potential) for at least 24 
consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Patient of childbearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.21 
Patients must not expect to conceive or father children by using 
accepted and effective method(s) of contraception (please refer to 
Appendix VI) or to abstain from sexual intercourse from the time of 
registration, while on study treatment and for at least 30 days after the 
last dose of protocol treatment for female patients, and for at least 90 
days after the last dose of protocol treatment for male patients. In 
addition, patients must not donate ova from the time of registration 
until 30 days after the last dose of study treatment or donate sperm 
from the time of registration until 90 days after the last dose of 
protocol treatment. 
3.1.22 
Patient must not have known hypersensitivity or contraindication to 
any component of binimetinib or encorafenib or their excipients. 
3.1.23 
Patient must not have impaired cardiovascular function or clinically 
significant cardiovascular disease including, but not limited to, any of 
the following: 
3.1.23.1 
History of acute coronary syndromes (including myocardial 
infarction, unstable angina, coronary artery bypass 
grafting, coronary angioplasty or stenting) < 6 months prior 
to registration: 
3.1.23.2 
Congestive heart failure requiring treatment (New York 
Heart Association Grade ≥ 2). 
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3.1.23.3 
Left ventricular ejection fraction (LVEF) < 50% as 
determined by MUGA or ECHO. 
3.1.23.4 
Uncontrolled hypertension defined as persistent systolic 
blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 
100 mmHg despite current therapy. 
3.1.23.5 
History or presence of clinically significant cardiac 
arrhythmias (including resting bradycardia, uncontrolled 
atrial fibrillation or uncontrolled paroxysmal 
supraventricular tachycardia). 
3.1.23.6 
Baseline QTc interval ≥ 480 ms. 
3.1.24 
Patient must not have 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 (≤ 3 months) history of a partial or 
complete bowel obstruction, or other conditions that will interfere 
significantly with the absorption of oral drugs. 
3.1.25 
Patient must not have any known history of acute or chronic 
pancreatitis. 
3.1.26 
Patient must not have any concurrent neuromuscular disorder that is 
associated with elevated CK (e.g., inflammatory myopathies, 
muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular 
atrophy). 
3.1.27 
Patient must not have any known history or current evidence of 
Retinal Vein Occlusion (RVO) or current risk factors for RVO (e.g., 
uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity, factor V Leiden or activated protein C resistance); 
history of retinal degenerative disease. 
3.1.28 
Patient must not use any medication (including herbal medications, 
supplements, or foods), as described in Section 8.1.14 and Section 
8.2.15, or use of a prohibited medication ≤ 1 week prior to registration. 
See Appendix X. 
3.1.29 
Patient may be on anticoagulation at prophylactic or therapeutic 
levels. Patients must not be using specific anticoagulants at 
therapeutic levels that may interfere with encorafenib and binimetinib. 
See Appendix X. 
3.1.30 
Patient must not have a history of thromboembolic or cerebrovascular 
events ≤ 12 weeks prior to registration. Examples include transient 
ischemic attacks, cerebrovascular accidents, hemodynamically 
significant (i.e. massive or sub-massive) deep vein thrombosis or 
pulmonary emboli. 
NOTE: 
Patients with thromboembolic events related to indwelling 
catheters or other procedures may be registered. 
NOTE: 
Patients with either deep vein thrombosis or pulmonary 
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allowed to register as long as they are on a stable dose of 
anticoagulants for at least 4 weeks. 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 


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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (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 OPEN, RAVE, or TRIAD 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. 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) 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 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 


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participating organization (i.e., Alliance). 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>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. International 
sites should continue to submit Research Ethics Board (REB) approval to the CTSU 
Regulatory Office following country-specific regulations. 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol.  


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• 
Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
Click on Protocols in the upper left of your screen 
• 
Enter the protocol number in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand, then select ECOG-ACRIN, 
and protocol number EA6183; 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. 
NOTE: 
For sites under the CIRB initiative, IRB data will load automatically to the 
CTSU as described above. 
Requirements For EA6183 Site Registration 
• 
This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider. To manage provider associations or to add 
or remove associated providers, access the Provider Association page from the 
Regulatory section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at least 
one Imaging and Radiation Oncology Core (IROC) provider to participate on trials 
with an RTI component. Enrolling sites are responsible for ensuring that the 
appropriate agreements and IRB approvals are in place with their RTI provider. A 
primary role on any roster is required to update provider associations, though all 
individuals at a site may view provider associations. To find who holds primary roles 
at your site, please view the Person Roster Browser under the RUMS link on the 
CTSU website. 
• 
To complete protocol-specific credentialing the RTI provider or enrolling site 
should follow instructions in the protocol to submit documentation or other materials 
to the designated IROC Quality Assurance (QA) center. Upon the IROC QA center 
approving the RTI provider for the study modality, IROC will automatically send the 
approval to the Regulatory Support System (RSS) to comply the protocol specific 
requirement. IROC will continue to copy the provider and/or enrolling site on modality 
approvals. 
• 
Upon site registration approval in RSS, the enrolling site may access OPEN to 
complete enrollments. The enrolling site will select their credentialed provider 
treating the subject in the OPEN credentialing screen, and may need to answer 
additional questions related to treatment in the eligibility checklist. 
• 
Imaging Requirements: Sites will be required to meet PET/CT Scanner 
Qualification requirements and approval. Please refer to the EA6183 Site Imaging 
Manual for guidance on the PET/CT Scanner Qualification process. The EA6183 Site 
Imaging Manual is available for download on the CTSU members’ website. For FLT 
PET/CT related questions, please contact Diana Ewen at dewen@acr.org. See 
study specific training outlined in Sections 4.3.3 and 4.3.4. 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU Website. 
To access the Regulatory Submission Portal log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
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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. 
• 
Log on to the CTSU members’ website; 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab at the top of your screen 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does 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.  
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Study treatment must start within 14 days after registration. 
The baseline FLT scan must be completed within 2 weeks prior to initiating neo-adjuvant 
treatment. The post neoadjuvant scan, must be completed after 2 cycles of study 
treatment are completed (ideally 8 weeks after starting neoadjuvant treatment, but the 
scan can be completed up to 9 weeks after starting neoadjuvant treatment). If patient 
comes off treatment early, the post neoadjuvant scan should not be completed any 
sooner than 4 weeks after starting treatment. Scan must be completed when patients 
have completed neoadjuvant therapy and before surgery. 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments: Be on a LPO roster, ETCTN Corresponding roster, or 
PO roster with the role of Registrar. Registrars must hold a minimum of an AP 
registration type; and 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
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NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Registration Information 
The following information is to be provided at the time of registration: 
4.1.1 
Protocol Number 
4.1.2 
Site/Investigator Identification 
• 
Institution CTEP ID 
• 
Treating Investigator 
• 
Consenting Person 
• 
Site Registrar 
• 
Network Group Credit 
• 
Credit Investigator 
4.1.3 
Patient Identification 
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3.1. 
4.3 
Additional Requirements 
4.3.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
NOTE: 
Participation in the optional biopsy and additional 
specimen collections, as outlined in the patient consent, 
must be offered to all patients. 
4.3.2 
Bio-specimens are to be submitted as outlined in Section 10. 
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4.3.3 
Study Specific Training: 
Each site must ensure all relevant site personnel responsible for 
handling 18F-FLT in any manner have reviewed and completed the 
training on handling and use of FLT. A review of the FLT Investigator 
Brochure and completion of ECOG-ACRIN generated training related 
to tracer administration will be required and documented via a training 
log. This training will be completed as a site initiation webinar prior to 
activation of the site. Any change in staff will require training of 
appropriate designated staff and this can be done through a self-study 
module with slides available on CTSU. 
4.3.4 
The Primary Investigator Authorized User 
The ordering of 18F-FLT should be done with a written order from the 
responsible authorized user, and administration of 18F-FLT should be 
performed by the authorized user or a qualified staff member under 
the authorized user's supervision (e.g. nuclear medicine technologist). 
Institutions should follow institutional practice for the injection of 
investigational radiopharmaceuticals. 
Sites must be a qualified user and/or manufacturer of 18F-FLT prior or 
have access to obtaining 18F-FLT to site activation. A list can be found 
on the CTSU website, on the EA6183 protocol page under the 
“Miscellaneous” tab. 
4.3.5 
Medidata Rave 
Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. To 
access Rave via iMedidata, site staff will need to be registered with 
CTEP and have a valid and active CTEP-IAM account; and assigned 
one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the 
enrolling site: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), 
Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. To the hold Rave CRA 
role or Rave CRA (Lab Admin) role, the user must hold a minimum of 
an AP registration type. To hold the Rave Site Investigator role, the 
individual must be registered as an NPIVR or IVR. Associates can 
hold read-only roles in Rave. 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. 
To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user 
name and password, and click on the “accept” link in the upper right-
corner of the iMedidata page. 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 in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. If an 
eLearning is required and has not yet been taken, the link to the 
eLearning will appear under the study name in iMedidata instead of 
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the Rave EDC link; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a 
Rave EDC link will display under the study name. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.3.6 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, 
delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, and DQP Delinquent 
Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details 
or reports specified on the DQP. A protocol must have the 
Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details 
and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
4.3.7 
Image Data Submission Using TRIAD 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application. TRIAD provides sites participating in clinical trials a 
secure method to transmit DICOM formatted image data, RT data and 
other objects. TRIAD anonymizes and validates the images as they 
are transferred. 
TRIAD Access Requirements: 
• 
Site staff that will be submitting images via TRIAD will 
need to register with CTEP and have a valid and active 
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CTEP-IAM account. Must be registered as an Associate, 
Associate Plus, Non-Physician Investigator, or Investigator 
registration type. Refer to the CTEP Registration 
Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in 
Registration and Credential Repository (RCR). 
• 
To submit images, site staff must hold the TRIAD Site User 
role on an NCTN or ETCTN roster. Individuals requiring a 
TRIAD Site User role should contact the person holding a 
primary role at the site for their affiliated NCTN or ETCTN 
roster. 
• 
All individuals on the Imaging and Radiation Oncology 
Core provider roster have access to TRIAD, and may 
submit images for credentialing purposes, or for 
enrollments to which the provider is linked in OPEN. 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with the proper user 
role, he/she will need to have the TRIAD application installed on 
his/her workstation to be able to submit images. TRIAD installation 
documentation can be found by following this link 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM 
account username and password and RCR registration. 
If you have any questions regarding this information, please send an 
e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org or 1-
703-390-9858. 
Required Submission of Images for EA6183 via TRIAD 
• 
Baseline 18F-FLT Whole Body PET/CT 
• 
Week 8 18F-FLT Whole Body PET/CT scan. Scan should 
take place after all neo-adjuvant treatment is completed 
and before surgery. 
• 
All Standard of care 18F-FDG PET/CT imaging acquired 
4.4 
Instructions for Patients who Do Not Start Assigned Protocol Treatment 
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EA6183 Forms Completion Guidelines. 


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5. 
Treatment Plan 
5.1 
Administration Schedule 
5.1.1 
Neoadjuvant Treatment (pre-surgery)  
Patients will receive the following: 
• 
Encorafenib 450 mg po once daily x 8 weeks (2 cycles) 
with or without food. Capsules should be swallowed whole 
and should not be chewed. Do not make up the dose if 
vomiting occurs after encorafenib administration. 
• 
Binimetinib 45 mg po twice daily (approximately 12 hours 
apart) with or without food x 8 weeks (2 cycles). Tablets 
should be swallowed whole. Do not make up the dose if 
vomiting occurs after binimetinib administration. 
Cycle length = 28 days 
• 
Patients must begin treatment with encorafenib and 
binimetinib within 14 working days of registration 
(timeframe to allow for baseline testing). 
• 
Missed doses will not be made up prior to surgery. 
• 
Less than 8 weeks of treatment may be permitted in the 
event of progressive disease requiring surgery or due to 
toxicity. 
• 
If medication(s) are being held for a toxicity and overlap 
with the surgical window and the toxicity resolves 
according to the dose modification section, and the 
investigator feels that further treatment will benefit the 
patient, treatment can resume in the adjuvant setting with 
the appropriate dose adjustments 
5.1.2 
Surgical resection 
The patient will proceed to surgical resection after neoadjuvant 
treatment 
• 
Surgery should be performed as soon as possible after 
completing 8 weeks of therapy; it must be performed within 
2 weeks of completing the 8 weeks of neoadjuvant 
therapy, assuming the patient has adequately recovered 
from protocol therapy and no other new sites of distant 
disease are evident and histologically confirmed as 
specified on post-treatment imaging. 
• 
Resectability, as determined by a surgical 
oncologist or experienced melanoma surgeon, is necessary 
prior to registration. 
• 
Surgery date should be arranged in advance. 
• 
Neoadjuvant treatment duration (8 weeks) cannot 
be extended to accommodate surgery scheduling. 
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• 
Encorafenib and binimetinib will be stopped within 48 
hours of planned surgery or at 8 weeks, whichever is 
sooner. 
• 
If there are any reversible issues precluding surgery such 
as treatment related toxicities or unrelated medical issues, 
surgery may be delayed by an additional 2 weeks as 
needed. 
• 
Encorafenib and binimetinib treatment time would 
not be extended beyond 8 weeks. 
• 
Patients must be surgically managed with complete 
removal of all target site(s) of metastatic melanoma, i.e. 
complete lymph node dissection, as feasible by the treating 
surgeon at the time of surgery. 
• 
If initial presentation with a primary melanoma with nodal 
metastases, wide local excision of the primary should be 
carried out per standard of care. 
• 
If the residual target tumor is not visible on post-treatment 
imaging, surgical exploration and formal lymphadenectomy 
with excision of primary/ in transit lesions, if applicable, as 
per standard recommendations is required. 
• 
The treating surgeon should attempt to mark the target 
lesion with a suture at the time of surgery to facilitate 
pathologic analysis. 
5.1.3 
Adjuvant Treatment (post-surgery) 
• 
After surgery, treatment with encorafenib and binimetinib resumes 
for an additional 44 weeks (11 cycles) of adjuvant treatment at the 
same doses that were tolerated during the initial 8 weeks (2 
cycles) of neoadjuvant treatment. 
• 
Treatment will resume within 2-7 days after surgery, as possible, 
depending on oral intake, post-operative issues. 
• 
If in the opinion of the investigator, there are medical issues post-
operatively that preclude resuming treatment, this must be 
discussed with the study chair. 
• 
The total planned course of systemic therapy with encorafenib 
with binimetinib is: 8 (neoadjuvant) + 44 weeks (adjuvant) = 52 
weeks. 
• 
Adjuvant treatment will not be extended past 44 weeks. 
• 
Radiation therapy is not permitted after surgery. 
5.2 
Imaging Schedule 
See Section 5.3 for Imaging Protocol details. 
• 
Baseline FLT-PET/CT: If the baseline biopsy is done on-study and after 
registration, then the baseline FLT-PET/CT scan must be performed prior to 
the baseline biopsy (same day acceptable). The FLT scan needs to be 
completed within 2 weeks prior to the start of the study-mandated 
neoadjuvant therapy. If the baseline biopsy of nodal/ in transit melanoma was 
done prior to study enrollment (can be up to 2 months prior), then the 


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baseline FLT-PET/CT scan must be performed within 2 weeks prior to the 
start of the study-mandated neoadjuvant therapy. 
• 
Post Neo-adjuvant FLT-PET/CT: A FLT-PET/CT scan will be completed 
after 8 weeks (or up to 9 weeks) of neoadjuvant therapy and before surgery. 
The scan must be completed after all neoadjuvant treatment is complete, but 
prior to surgery. If a patient comes off treatment early, this FLT-PET/CT 
should not be completed any sooner than 4 weeks after starting neoadjuvant 
therapy. 
NOTE: 
Institutions getting FLT from outside suppliers should allow time for 
arranging delivery of FLT. 
5.2.1 
AE monitoring period for F-18 (18F-FLT) PET: 
The AE monitoring period for 18F-FLT, an 18F based radioisotope 
imaging agent with a half-life (t ½ of 110 minutes and a 10 half-life 
equivalent of 18.33 hours) is 24 hours after administration of the 
imaging agent 18F-FLT. 
During the 24 hour period (the “Monitoring period”) after 
administration (including the infusion of the 18F-FLT), the patient will 
be evaluated for Adverse events (AEs) at each imaging session, 
during any follow up (in person, by phone or by email), and at the end 
of the monitoring period (can be done by phone call or email). 
AEs for imaging agents are defined as any signs of illness or 
symptoms that have appeared or worsened since the infusion of the 
imaging agent. Patients will be queried for potential AEs at multiple 
time points. These may include: 
• 
At the time of injection; 
• 
Before leaving the PET suite; 
• 
If they call the site as instructed for any concerns at any 
time during the monitoring period; 
• 
At the end of the monitoring period 
5.2.2 
Adverse Events to Monitor following the 18F-FLT dose 
Certain adverse events that will specifically be monitored during and 
after the administration include, but are not limited to: 
• 
localized discomfort at the intravenous (IV) injection site 
• 
pain 
• 
respiratory difficulties 
• 
blood pressure instability 
• 
flushing 
• 
dizziness 
• 
pruritus/hives 
• 
any other symptoms that could be related to an allergic or 
anaphylactic-type reaction 
• 
any previously unreported AE which occurring after the 
administration should be reported via Medidata Rave 
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When any AE is reported, concomitant medication taken by the 
participant in the 2 weeks prior to the event and/or during the time of 
the AE need to be collected and documented in the patient record and 
within Medidata Rave (for routine reporting) and CTEP-AERS (for 
expedited reporting) so that the patient’s record may be updated in 
the CDUS. 
5.3 
18F-FLT Whole Body Imaging Protocol 
5.3.1 
FLT PET Imaging Studies 
NOTE: 
Institutions getting FLT from outside suppliers should allow 
time for arranging delivery of FLT. 
5.3.2 
18F-FLT and 18F-FDG PET Imaging Studies 
The required PET/CT data to be submitted for EA6183 are listed 
below: 
• 
Baseline 18F-FLT Whole Body PET/CT scan 
• 
Week 8 18F-FLT Whole Body PET/CT scan 
• 
All Standard of care 18F-FDG PET/CT scans acquired 
Instructions for image submission is provided in Section 4.3.6 
5.3.3 
18F-FLT Administration 
18F-FLT will be synthesized according to the standard operating 
procedures provided by the NCI. A summary of the synthesis 
procedure and associated quality control can be found in the 
investigator’s brochure. 
The injectable activity of 18F-FLT will be ≤ 0.07 mCi/kg of Flourine-18, 
not to exceed 5mCi with a specific activity greater than 200 Ci/mmol 
at the time of injection. The amount of injected drug is ≤ 6.1 μg (≤ 25 
nmol per dose) of FLT. FLT is administered to subjects by intravenous 
injection of ≤ 10 mL. The drug solution is stored at room temperature 
in a gray butyl septum sealed, sterile, pyrogen-free glass vial and has 
an expiration time of 8 hours. There is no evidence that 
nonradioactive and radioactive FLT molecules display different 
biochemical behavior. 
18F-FLT will be administered in the PET imaging suite under physician 
supervision. 
An appropriately licensed individual will administer the 18F-FLT by 
intravenous infusion over one minute, followed by a saline flush. 
A fully equipped emergency cart and ACLS certified personnel will be 
available. The infusion and imaging procedure will be terminated in 
any patient who exhibits anaphylaxis, chest pain, dyspnea, or grand 
mal seizure. 
5.3.4 
Timing of FLT PET/CT Studies 
Two 18F-FLT Whole Body PET/CT imaging sessions, a baseline and 
post-neoadjuvant treatment will be performed (see Study Parameters 
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5.3.4.1 
Baseline FLT-PET/CT: 
If the baseline biopsy is done on-study and after 
registration, then the baseline FLT-PET/CT scan must be 
performed prior to the baseline biopsy (same day 
acceptable). The FLT scan needs to be completed within 2 
weeks prior to the start of the study-mandated neoadjuvant 
therapy. If the baseline biopsy of nodal/ in transit 
melanoma was done prior to study enrollment (can be up 
to 2 months prior), then the baseline FLT-PET/CT scan 
must be performed within 2 weeks prior to the start of the 
study-mandated neoadjuvant therapy. 
5.3.4.2 
Post Neo-adjuvant Imaging: 
A FLT-PET/CT scan will be completed after 8 weeks (up to 
9 weeks) of neoadjuvant therapy and before surgery. The 
scan must be completed after all neoadjuvant treatment is 
complete, but prior to surgery. 
All patients who received at least one dose of 
neoadjuvant therapy are expected to complete post 
FLT PET/CT regardless of radiologic, clinical or 
pathologic response. If a patient comes off treatment 
early the second 18F-FLT PET/CT scan should not be 
completed any sooner than four weeks after starting 
neoadjuvant therapy. 
Both 18F-FLT imaging time points must be scanned on 
the same qualified PET/CT scanner with imaging 
technique and parameters to be as close as possible 
to that of the baseline scan. 
NOTE: 
Institutions getting FLT from outside suppliers 
(academic or commercial) should allow time for 
arranging delivery of FLT. 
5.3.5 
Imaging Quality Assurance (QA)/Quality Control (QC) Procedure 
Participant must be scanned on PET/CT scanners that have been 
qualified by the ACR Imaging Core Laboratory per the protocol-
specific instructions made available to participating sites in the 
EA6183 Site Imaging Manual The Site Imaging Manual is available on 
the CTSU website, under the protocol specific page, “Site 
Registration” Tab. 
Qualification Utility for the Imaging Core Laboratory (QUIC); 
https://quic.acr.org) is the web-based tool for managing the PET/CT 
scanner qualification process and communicating with the reviewing 
physicist and core lab staff 
A hybrid PET/CT scanner is mandatory. The ability to calculate 
standardized uptake values (SUVs) is also mandatory. 
All sequential imaging sessions are to be performed on the same 
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include review of DICOM files against study FLT imaging protocol 
specifications and EA6183 Site Imaging Manual parameters. 
The PET/CT scanner must be kept calibrated in accordance with the 
manufacturer’s recommendations. 
The scanner should routinely be assessed for quantitative integrity 
and stability by being tested using various imaging protocols on a 
standard phantom. 
For SUV measurements, this assessment should include a 
comparison against a dose calibrator to ensure accuracy; that is, a 
comparison of the absolute activity measured versus the measured 
activity injected, should be performed. 
A daily QC check must be performed at the beginning of the day, 
including PET/CT scanner and dose calibrator, in accordance with the 
manufacturer recommendations. 
If any of the QC results are outside of the manufacturer’s guidelines, 
the study must be rescheduled and the problem rectified before 
scanning any patients. 
NOTE: 
Further details and procedures related to the PET/CT 
Scanner Qualification process and scanner Quality Control 
procedures can be found in the EA6183 Site Imaging 
Manual located on the CTSU Protocol Page under under 
“Site Registration” tab. 
5.3.6 
18F-FLT Imaging Sessions 
The participant will report to the PET suite and undergo 18F-FLT 
injection. 
Approximately 60 minutes (± 10 min) after injection, a static whole 
body PET/CT scan will be acquired. 
The whole body scan (top of the head [vertex] to toes) will be 
obtained. 
Upon completion of image acquisition, the PET/CT data will be 
reconstructed/corrected per scanner manufacturer recommendations 
including, but not limited to, random coincidences, system dead time, 
scatter correction and attenuation algorithms. 
Both 18F-FLT imaging time points must be scanned on the same 
qualified PET/CT scanner with imaging technique and reconstruction 
parameters as close as possible to that of the baseline scan. 
Specific information related to the 18F-FLT Whole Body PET/CT 
acquisition component of this study are found in the EA6183 Site 
Imaging Manual. The Site Imaging Manual serves as a supplement 
to the EA6183 clinical protocol and is best suited for technical 
guidance with regard to PET/CT Scanner Qualification, Quality 
Control Procedures, 18F-FLT preparation,18F-FLT administration, 
Whole Body PET/CT procedures, PET/CT image acquisition and 
reconstruction procedures and image submission via TRIAD to the 
ACR Core Laboratory for analysis. 


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5.3.7 
Supportive Care Guidelines 
Any adverse effects, related or non-related to the injection of 18F-FLT, 
will be treated as clinically indicated with no study-related restrictions. 
5.3.8 
Dosing Delays/Dose Modifications 
18F-FLT Dose 
The dose of 18F-FLT is based on the radiation dosimetry estimates. 
Due to the potential of a poor radiosynthetic yield or unavoidable time 
delays, a lesser amount of radioactivity may be administered at the 
discretion of the site PI, based on whether clinically acceptable 
images can be acquired with the dose administered. Any such 
modifications of the agent infusion will be recorded. 
5.4 
Adverse Event Reporting Requirements 
All adverse event grades described throughout this protocol and all 
reportable adverse events will be graded using 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 website (http://ctep.cancer.gov). 
5.4.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents. 
5.4.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using Medidata Rave, the electronic clinical data 
management system. Please refer to Section 4 of the protocol for 
more information on how to access the Medidata Rave system and 
the EA6183 forms packet for instructions on where, when and what is 
to be reported routinely on this protocol for both therapeutic agent and 
imaging agent related adverse events. 
5.4.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care using CTEP-AERS (CTEP’s Adverse Event Reporting 
System). The remainder of this section provides information and 
instructions regarding expedited adverse event reporting. 
5.4.4 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of a therapeutic agent or imaging 
agent in humans, whether or not considered therapeutic 
agent or imaging agent related. Therefore, an AE can be 
ANY unfavorable and unintended sign (including an 


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abnormal laboratory finding), symptom, or disease that 
worsens or is emergent after the use of a therapeutic agent 
or imaging agent, whether or not considered related to the 
therapeutic agent or imaging agent. 
• 
Attribution: An assessment of the relationship between 
the adverse event and any protocol agent (therapeutic or 
imaging), using the following categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to any protocol 
agents (therapeutic or imaging) 
Unlikely 
The AE is doubtfully related to any protocol 
agents (therapeutic or imaging). 
Possible 
The AE may be related to any protocol agents 
(therapeutic or imaging). 
Probable 
The AE is likely related to any protocol agents 
(therapeutic or imaging). 
Definite 
The AE is clearly related to any protocol agents 
(therapeutic or imaging). 
• 
CAEPR (Comprehensive Adverse Events and Potential 
Risks List): An NCI generated list of reported and/or 
potential AEs associated with an agent currently under an 
NCI IND (an agent whose use is being investigated). 
Information contained in the CAEPR is compiled from the 
Investigator’s Brochure, the Package Insert, as well as 
company safety reports. 
• 
CTCAE: The NCI Common Terminology Criteria for 
Adverse Events provides a descriptive terminology that is 
to be utilized for AE reporting. A grade (severity) is 
provided for each AE term. 
• 
Hospitalization (or prolongation of hospitalization): For 
AE reporting purposes, a hospitalization is defined as an 
inpatient hospital stay equal to or greater than 24 hours. 
• 
Life Threatening Adverse Event: Any AE that places the 
subject at immediate risk of death from the AE as it 
occurred. 
• 
Serious Adverse Event (SAE): SAEs are events as 
outlined in FDA guidance (21 CRF Part 312.32) Any 
adverse event occurring at any dose that results in ANY of 
the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours) 
• 
A persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions 
• 
A congenital anomaly/birth defect 


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• 
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. 
5.4.5 
Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov. 
A CTEP-AERS report must be submitted electronically via the CTEP-
AERS Web-based application located at http://ctep.cancer.gov, so 
that ECOG-ACRIN and all appropriate regulatory agencies will be 
notified of the event in an expeditious manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
• 
the AE Team at ECOG-ACRIN (857-504-2900) for all 
events 
For this study, an electronic CTEP-AERS report MUST be submitted 
via CTEP-AERS immediately upon re-establishment of internet 
connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
Many factors determine the requirements for expedited reporting of 
adverse events on each individual protocol. The instructions and 
tables in the following sections have been customized for protocol 
EA6183 and outline the specific expedited adverse event reporting 
requirements for study EA6183. 
5.4.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner – (Treatment Arm Code (TAC) = Arm A in CTEP-
AERS) 
5.4.6.1 
Guidelines for adverse events occurring while on protocol 
treatment and within 24 hours after the administration 
of the imaging agent 18f-flt and within 30 days of the 
last administration of the therapeutic agents 
encorafenib and binimetinib. 
NOTE: 
Patients should be queried for potential AEs at 
multiple time points in the 24 hours following 
administration of the 18F-FLT: 
• 
At the time of injection; 
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• 
Before leaving the PET suite; 
• 
If they call the site as instructed for any 
concerns at any times during the monitoring 
period (24 hours) 
• 
At the end of the monitoring period by 
phone or in person (24 hours post infusion 
administration). 
See Section 5.2.2 for specific adverse events to 
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Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the six 
criteria in the top portion of the table 
below in Section 5.4.7. 
Yes 
No 
Identify the type and 
grade of the event using 
the CTCAE. 
Determine if the patient was 
hospitalized for  
≥ 24 hours for the event. 
With this information, review 
the chart in Section 5.4.8 to 
determine if event requires 
expedited reporting. 
Refer to Section 5.4.8 to 
determine if the event meets 
the protocol specific 
expedited reporting 
requirements for this study. 
If so, report the event via 
CTEP-AERS. If not, refer to 
the EA6183 Forms Packet 
for instructions on if the 
event requires routine 
reporting in Medidata Rave. 
Refer to Section 5.4.8 to determine if 
the event meets the protocol specific 
reporting requirements for this study. If 
so, report the event via CTEP-AERS. 
If not, refer to the EA6183 Forms 
Packet for instructions on if the event 
requires routine reporting in Medidata 
Rave. 
Is the event 
reportable? 
No 
Yes 
Report the event via CTEP-AERS 


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5.4.6.2 
Guidelines for adverse events occurring greater than 24 
hours after the administration of the imaging agent 18f-
flt or greater than 30 days of the last administration of 
the investigational therapeutic agents encorafenib and 
binimetinib. 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.4.7, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 3, 4 and Grade 5 AEs 
NOTE: 
Any death occurring greater than 24 hours and 
up to 30 days after the administration of the 
imaging agent 18F-FLT must be reported 
expeditiously via CTEP-AERS even if the 
patient is off study. 
NOTE: 
Any death occurring greater than 30 days after 
the last dose of the therapeutic agents 
Encorafenib and Binimetinib or the imaging 
agent 18F-FLT with an attribution of possible, 
probable or definite must be reported 
expeditiously via CTEP-AERS even if the 
patient is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
5.4.7 
Expedited Reporting Requirements on protocol EA6183 
Investigational Agents: Encorafenib, Binimetinib, and 18F-FLT 
Commercial Agents: None 
Phase 1 and Early Phase 2 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND within 30 Days of the Last Administration of the Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention. 


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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-
AERS Rave within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour; 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
• 
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 


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5.4.8 
Additional instructions, requirements and exceptions for protocol 
EA6183 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, or 
birth defect events via CTEP-AERS, please contact the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
Reporting a death on study:  
A death occurring while on study treatment or within 30 days of the 
last dose of any protocol agent (therapeutic or imaging) requires both 
routine and expedited reporting, regardless of causality. Attribution to 
treatment or other cause must be provided. 
NOTE: 
A death due to progressive disease should be reported as 
a Grade 5 “Disease progression” under the System Organ 
Class (SOC) “General disorder 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. 
 
EA6183 specific expedited reporting requirements: 
• 
Pregnancies: Pregnancies and 
suspected pregnancies (including a positive or inconclusive 
pregnancy test, regardless of age or disease state) occurring 
while the female patient is on Encorafenib, Binimetinib or 18F-FLT 
, or within 28 days the female patient’s last dose of Encorafenib, 
Binimetinib or 18F-FLT , are considered immediately reportable 
events. The pregnancy, suspected pregnancy, or positive/ 
inconclusive pregnancy test must be reported via CTEP-AERS 
within 24 hours of the Investigator’s knowledge. Please refer to 
Appendix V for detailed instructions on how to report the 
occurrence of a pregnancy as well as the outcome of all 
pregnancies 
 
EA6183 specific expedited reporting exceptions: 
• 
There are no exceptions to expedited adverse event reporting on 
this study 
5.4.9 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN, the IND sponsor, will forward CTEP-AERS reports to 
all appropriate regulatory agencies and pharmaceutical company, if 
applicable. 
A drug supporter representative may call a site for additional or 
supplemental information regarding a serious adverse event. Any 


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additional written AE information requested by the drug supporter 
MUST be submitted to BOTH ECOG-ACRIN and the drug supporter. 
Adverse events determined to require expedited reporting must also 
be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.4.10 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported as 
follows: 
• 
A second malignancy is a cancer that is UNRELATED 
to any prior anti-cancer treatment (including the 
treatment on this protocol). Second malignancies 
require ONLY routine reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any 
prior anti-cancer treatment (including the treatment on 
this protocol). Secondary malignancies require both 
routine and expedited reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis on the Adverse Event Form or Late 
Adverse Event Form in the appropriate Treatment Cycle or 
Post Registration folder in Medidata Rave 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
NOTE: 
When reporting attribution on the AE Form, assess 
the relationship between the secondary malignancy 
and the current protocol treatment ONLY (and NOT 
relationship to any anti-cancer treatment received 
either before or after protocol treatment). 
3. Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov. 
4. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 


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5. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the 
CTEP-AERS report should not be used to report 
recurrence or development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary 
Form must be submitted for the most recent trial. 
ECOG-ACRIN must be provided with a copy of the 
form and the associated pathology report and 
cytogenetics report (if available) even if ECOG-ACRIN 
was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are 
no longer required by the protocol, no follow-up data 
should be submitted in CTEP-AERS or by the ECOG-
ACRIN Second Primary Form. 


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5.5 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
5.5.1 
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. Frequency is provided based on 662 patients. Below is 
the CAEPR for Binimetinib. 
Version 2.1, September  11, 20191 
Adverse Events with Possible 
Relationship to Binimetinib 
 (CTCAE 5.0 Term) 
[n= 1374] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
CARDIAC DISORDERS 
 
 
Cardiac disorders - Other (bradycardia) 
 
 
Heart failure 
EYE DISORDERS 
 
Blurred vision 
 
 
 
Eye disorders - Other (ocular 
hypertension) 
 
 
Eye disorders - Other (retinal vascular 
occlusion) 
Eye disorders - Other (visual disorder)2  
 
 
 
Periorbital edema 
 
Retinopathy3 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Constipation 
 
Diarrhea 
 
 
 
Mucositis oral 
 
Nausea 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Edema face 
 
Edema limbs 
 
 
Fatigue 
 
 
 
Fever 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure 
INFECTIONS AND INFESTATIONS 
 
Skin infection 
 


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Adverse Events with Possible 
Relationship to Binimetinib 
 (CTCAE 5.0 Term) 
[n= 1374] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
 
Aspartate aminotransferase 
increased 
 
 
CPK increased4 
 
 
Ejection fraction decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Generalized muscle weakness 
 
 
Musculoskeletal and connective 
tissue disorder - Other 
(myopathy) 
 
 
Myalgia 
 
 
 
Rhabdomyolysis 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Dyspnea 
 
 
 
Pneumonitis  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Dry skin 
 
 
Pruritus 
 
Rash acneiform 
 
 
Rash5 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (nail disorders) 
 
 
 
Skin and subcutaneous tissue disorders - 
Other (severe cutaneous reaction)6 
 
Skin and subcutaneous tissue 
disorders - Other (skin fissures) 
 
VASCULAR DISORDERS 
 
Hypertension 
 
 
Thromboembolic event 
 
 
Vascular disorders - Other 
(hemorrhage)7 
 
1 This 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 


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PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Visual disorders may include visual disturbance, blurred vision, visual acuity reduced, flashing light, and 
floaters.  
3 Retinopathy may include chorioretinopathy, chorioretinitis, and retinal detachment. 
4 CPK increased may be associated with muscle pain and muscle weakness. 
5 Rash may include rash maculo-papular and erythematous rash. 
6 Severe cutaneous reactions may include bullous dermatitis, exfoliative dermatitis, erythema multiforme, 
and toxic skin eruptions. 
7 The 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); 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; 


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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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5.6 
Dose Modifications 
Doses of encorafenib and/or binimetinib should be adjusted for AEs (based on 
assessment per the CTCAE) throughout the study (see Table 3 Recommended 
Dose Modifications). In general, doses should not be reduced or interrupted for 
Grade 1 AEs unless the AE is a specific ocular AE referred to in the 
Recommended Dose Modifications Table but treatment to control symptoms 
should be provided as appropriate, if applicable. 
An individual patient may have their dose of encorafenib and/or binimetinib 
reduced to the dose levels in Table 2 below: 
Table 2. 
Recommended Dose Levels 
 
Encorafenib 
(mg QD) 
Binimetinib 
(mg BID) 
Starting Dose 
450 (6 capsules) 
45 (3 tablets) 
Dose Level -1 
300 (4 capsules) 
30 (2 tablets) 
Dose Level -2 
225 (3 capsules) 
15 (1 tablet) 
Dose reductions below the lowest dose levels for each agent are not allowed. 
Doses may not be re-escalated. 
Missed Doses 
• 
Doses of Binimetinib that are omitted for AEs or missed for any other 
reason should not be taken within 6 hours of the next scheduled dose. 
• 
Doses of Encorafenib that are omitted for AEs or missed for any other 
reason should not be taken within 12 hours prior to the next scheduled dose. 
• 
If vomiting occurs after taking either medication, the dose should not be 
repeated. 
Lowest Doses 
The lowest recommended dose level of encorafenib is 225 mg QD and the 
lowest recommended dose level of binimetinib is 15 mg BID. Dose may not be 
re-escalated. 
• 
In most circumstances, both encorafenib and binimetinib will both be held 
for toxicities with exceptions listed below: 
• 
If binimetinib is withheld, encorafenib must be reduced to a maximum 
dose of 300 mg daily until binimetinib is resumed. 
• 
If binimetinib is permanently discontinued, treatment with encorafenib 
alone is permitted but only to a maximum dose of 300 mg once daily. 
• 
If encorafenib is permanently discontinued, treatment with binimetinib 
alone is permitted 
• 
If a drug is held for greater than 42 consecutive days, the drug will be 
permanently discontinued. 
• 
If both drugs are held for greater than 42 consecutive days, they will both 
be permanently discontinued and the patient will come off study 
treatment. 


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Please refer to Dose Modification Table 3 below for recommended dose 
modifications for encorafenib and/or binimetinib, if applicable, based on the 
occurrence of treatment-related AEs. 
Follow-up for Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed up (by 
phone or in person) at least once a week (or more frequently if required by 
institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. 
Appropriate clinical experts such as an ophthalmologist, cardiologist or 
dermatologist should be consulted as deemed necessary. 
Table 3: 
Recommended Encorafenib and Binimetinib Dose Modifications 
Adverse Event and Grade/Severity  
Dose Modifications  
New Primary Malignancies  
Non-cutaneous RAS mutation-positive 
malignancies 
Permanently discontinue encorafenib. 
Cutaneous malignancies (SCC, BCC, additional 
primary melanoma) – surgical removal as per 
institutional practice 
No interruption or modification indicated 
Eye Toxicities  
Uveitis 
Grade 1-2 
Interrupt dosing of encorafenib and binimetinib for 
visual complaints and obtain ophthalmology 
evaluation within 7 days and initiate treatment as 
recommended.  
If Grade 1 or 2 does not respond to specific ocular 
therapy, withhold encorafenib and binimetinib for 
up to 6 weeks. 
• 
If improved, resume both encorafenib and 
binimetinib at same or reduced dose at the 
investigator’s discretion. 
• 
If not improved, permanently discontinue both 
agents. 
Grade 3 
Withhold encorafenib and binimetinib for up to 6 
weeks: 
• 
If improved within 6 weeks, resume both 
encorafenib and binimetinib at same or 
reduced dose, at the Investigator’s discretion. 
• 
If not improved within 6 weeks, permanently 
discontinue both drugs. 
Grade 4 
Permanently discontinue both encorafenib and 
binimetinib. 
Serous 
Retinopathy 
Symptomatic serous 
retinopathy/ Retinal pigment 
epithelial detachments 
Withhold binimetinib for up to 10 days. 
• 
If improves and becomes asymptomatic, 
resume binimetinib at the same dose. 
• 
If not improved, resume at a lower dose level 


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Adverse Event and Grade/Severity  
Dose Modifications  
or permanently discontinue binimetinib at the 
investigator’s discretion. 
Retinal Vein 
Occlusion (RVO) 
Any grade 
Permanently discontinue binimetinib and follow-up 
with ophthalmic monitoring until stabilization or 
resolution. 
Other Eye 
Disorders 
Grade 1 
Maintain dose level of encorafenib and binimetinib 
and monitor symptoms 
Grade 2 
Interrupt dosing of encorafenib and binimetinib and 
obtain ophthalmology evaluation within 7 days and 
institute treatment as recommended. 
• 
If resolved to Grade ≤ 1 in ≤ 21 days, resume 
treatment at 1 reduced dose level of 
encorafenib and binimetinib. 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and follow-up with ophthalmic 
monitoring 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 1 reduced dose level of 
encorafenib and binimetinib. 
• 
If not resolved to Grade ≤ 1 in ≤ 21 days, 
permanently discontinue encorafenib and 
binimetinib and follow-up with ophthalmic 
monitoring until stabilization or resolution. 
Grade 4 
Permanently discontinue encorafenib and 
binimetinib and immediately follow-up with 
ophthalmic monitoring until stabilization or 
resolution. 
Cardiac Toxicities 
QTc Prolongation 
QTc ≥ 500 ms and ≤ 60 ms 
increase from baseline 
1st occurrence:  
• 
Temporarily interrupt dosing of encorafenib 
until QTc < 500 ms. Then resume treatment at 
1 reduced dose level of encorafenib. 
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. 
QTcF ≥500 ms and > 60 ms 
increase from baseline 
Permanently discontinue encorafenib. 
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 4 weeks. 
Resume binimetinib at a reduced dose if the 
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Adverse Event and Grade/Severity  
Dose Modifications  
• 
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 controlled on anticoagulation, resume at 
reduced dose.  
• 
If not controlled on anticoagulation, 
permanently discontinue binimetinib. 
Life threatening PE 
Permanently discontinue binimetinib 
Hepatic Toxicities 
Elevated AST/ALT 
Grade 2  
• 
Maintain Encorafenib and Binimetinib doses 
• 
If no improvement within 2 weeks and 
assessed as related to binimetinib, withhold 
binimetinib (for up to 4 weeks). 
• 
If no improvement within 2 weeks, and 
assessed as related to encorafenib, withhold 
encorafenib (for up to 4 weeks). 
• 
Both drugs may be held if assessed as related 
to both. 
• 
Resume drug(s) at the same dose(s) if 
improved to Grade 0-1 or to 
pretreatment/baseline levels. 
Recurrent Grade 2 or first 
occurrence of any Grade 3 
• 
Withhold encorafenib and/or binimetinib for up 
to 4 weeks, based on Investigator’s 
assessment of causality. 
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume at 
reduced dose(s). 
• 
If no improvement, permanently discontinue 
encorafenib and binimetinib.  
Recurrent Grade 3 
Consider permanently discontinuing both study 
agents 
First occurrence of Grade 4 
Withhold encorafenib and/or binimetinib for up to 4 
weeks, based on Investigator’s assessment of 
causality. 
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, then resume at a 
reduced dose. 


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Adverse Event and Grade/Severity  
Dose Modifications  
• 
If no improvement, permanently discontinue 
encorafenib and binimetinib. 
Recurrent Grade 4  
Permanently discontinue both study agents. 
Dermatologic Toxicity 
Dermatologic 
(Except Hand-foot 
Skin Reactions) 
First occurrence of Grade 2 
Systemic management 
• 
If no improvement within 2 weeks, withhold 
encorafenib and/or binimetinib for up to 4 
weeks (based on Investigator’s assessment of 
causality), until Grade 0-1. The resume at 
same dose(s). 
First occurrence of Grade 3 
Symptomatic management and withhold 
encorafenib and/or binimetinib for up to 4 weeks 
(based on Investigator’s assessment of causality), 
until Grade 0-1. Then resume at same dose(s). 
• 
Consider referral to dermatology 
Recurrent Grade 2-3 
Symptomatic management and withhold 
encorafenib and/or binimetinib for up to 4 weeks 
(based on Investigator’s assessment of causality), 
until Grade 0-1. The resume at reduced dose(s). 
• 
Consider referral to dermatology 
Grade 4 
Permanently discontinue encorafenib and/or 
binimetinib. 
• 
Consider referral to dermatology 
Hand-foot Skin 
Reaction (HFSR)/ 
Palmar-plantar 
Erythodysesthisa 
Syndrome (dose 
adjustment for 
Encorafenib 
ONLY) 
Grade 1 
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 
modification. 
Grade 2 
1st occurrence:  
• 
Maintain dose of encorafenib and closely 
monitor. Promptly institute supporting 
measures, such as topical therapy, for 
symptomatic relief. Give instruction on life-style 
modification. 
• 
If no improvement, ≤ 14 days, withhold 
encorafenib for up to 4 weeks until resolved to 
Grade ≤ 1. Resume treatment with encorafenib 
at same dose level. Continue supportive 
measures. 
Recurrent Grade 2 
Treatment with encorafenib may be maintained or 
interrupted at the Investigator’s discretion. If 
interrupted dosing of encorafenib per Investigator’s 
judgment, interrupt until resolved to Grade ≤ 1. 
Resume treatment with encorafenib at the same 
dose level or 1 reduced dose level based upon the 
Investigator’s discretion. 
Continue supportive measures, such as topical 
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Adverse Event and Grade/Severity  
Dose Modifications  
lifestyle modifications. 
Grade 3  
1st or 2nd occurrence:  
• 
Interrupt dosing of encorafenib. Promptly 
initiate supportive measures, such as topical 
therapy, for symptomatic relief. Give instruction 
on life-style modifications. Reassess the 
patient weekly. If resolved to grade 0-1, then 
resume encorafenib at one reduced dose level.  
• 
Consider referral to dermatologist and manage 
HFSR per dermatologist’s recommendation. 
≥ 3nd occurrence: 
• 
Interrupt dosing of encorafenib 
• 
If resolved to Grade ≤ 1, resume treatment with 
encorafenib at reduced dose or permanently 
discontinue encorafenib should be based upon 
the Investigator’s discretion 
Gastrointestinal Toxicity  
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. Promptly institute antiemetic 
measure. Resume treatment at 1 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 1 reduced dose level 
if considered related. 
Grade 4 
Permanently discontinue encorafenib and 
binimetinib. 
Pulmonary 
Interstitial Lung 
Disease 
Grade 2 
Withhold binimetinib for up to 4 weeks. 
• 
If improved to Grade 0-1, resume at a reduced 
dose. 
• 
If not resolved within 4 weeks, permanently 
discontinue binimetinib. 
Grade 3 or Grade 4 
Permanently discontinue binimetinib. 
Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations 
 
Grade 4 asymptomatic CPK 
elevation or 
Any Grade CPK elevation 
with symptoms or with renal 
impairment 
Withhold binimetinib dose for up to 4 weeks. 
• 
If improved to Grade 0-1 resume at a reduced 
dose. 
• 
If not resolved within 4 weeks, permanently 
discontinue binimetinib. 


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Adverse Event and Grade/Severity  
Dose Modifications  
Other Adverse Reactions (Including renal and hemorrhage) 
 
Recurrent Grade 2 or First 
occurrence of any Grade 3  
Withhold encorafenib and/or binimetinib (based on 
Investigator’s assessment of causality), for up to 4 
weeks. 
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume held 
drug(s) at reduced dose. 
• 
If no improvement, permanently discontinue 
encorafenib and/or biniteminb. 
Recurrent Grade 3 
Consider permanent discontinuation of encorafenib 
and/or binimetinib, based on Investigator’s 
assessment of causality. 
First occurrence of any 
Grade 4 
Withhold encorafenib and/or binimetinib (based on 
Investigator’s assessment of causality) for up to 4 
weeks. Investigator may elect to permanently 
discontinue drug(s). 
• 
If improves to Grade 0-1 or to 
pretreatment/baseline levels, resume both 
agents at a reduced dose(s).  
• 
If no improvement, permanently discontinue 
both agents. 
Recurrent Grade 4  
Permanently discontinue both agents.  
5.7 
Supportive Care 
5.7.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study per investigator discretion or institutional 
guidelines. 
• 
Skin: Encourage good skin care 
• 
Regular use of topical emollients 
• 
Avoid unnecessary exposure to sunlight, apply broad 
spectrum sunscreen and/or sun protective clothing 
• 
Topical steroids or topical antibiotics may be applied to 
affected areas as needed (mild-strength topical steroid 
(hydrocortisone 1% cream) or topical antibiotic (e.g. 
clindamycin) or oral antibiotics 
• 
Gastrointestinal: 
• 
Antiemetic and anti-diarrheal agents may be prescribed 
per investigator or institutional guidelines. 
5.8 
Duration of Therapy 
Neoadjuvant Phase: 8 weeks (2 cycles) 
Adjuvant Phase: 44 weeks (11 cycles) 
Patients will receive protocol therapy unless: 
• 
New progressive lesions are seen on post neoadjuvant treatment CT, 
MRI and/or PET scans and confirmed as distant metastatic disease. 


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• 
If a new/progressive lesion is noted on imaging after neoadjuvant 
therapy, histologic evaluation with a biopsy is required to confirm 
disease progression, unless the lesion is not accessible or a 
biopsy would cause undue risk to the patient. 
• 
If the progressive disease is still considered eligible for a complete 
surgical resection, the patient may proceed on to surgery per 
investigator discretion and a biopsy is not required before surgery. 
• 
If pathology review of surgical specimen confirms progressive disease, 
these patients will then come off study treatment and not receive the 
adjuvant phase of therapy, and will be followed for survival. 
• 
If pathology review of surgical specimen shows treatment effect, these 
patients will continue on study and receive adjuvant phase of therapy. 
• 
If the progressive disease is not considered resectable based on 
post treatment scans, biopsy, and surgical consultation/opinion, 
surgical resection will not be carried out and the patient will be off 
study treatment and followed for survival. 
NOTE: 
All patients who received at least one dose of neoadjuvant 
therapy are expected to complete post FLT PET/CT 
regardless of radiologic, clinical or pathologic response and 
prior to coming off study treatment. If a patient comes off 
treatment early the second 18F-FLT PET/CT scan should 
not be completed any sooner than four weeks after 
starting neoadjuvant therapy.  
NOTE: 
Date of neoadjuvant progression will be the earliest date of 
confirmed progression before surgery. 
Additional Reasons for Treatment Discontinuation 
• 
Extraordinary Medical Circumstances: If at any time the 
constraints of this protocol are detrimental to the patient's health, 
protocol treatment should be discontinued per investigator 
discretion. In this event submit forms according to the instructions 
in the EA6183 Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Progression of disease per RECIST 1.1 before surgery that 
renders the patient ineligible for surgery. 
• 
Relapse of disease after surgery. 
• 
Treatment delay/hold of greater than > 42 consecutive days for 
any reason. 
NOTE: 
All reasons for treatment discontinuation must be documented 
on the case report forms in Medidata Rave. 
5.9 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 5 years from the date of registration. Patients will 
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be followed every 3 months for the planned year of treatment and for 1 additional 
year, then every 6 months for 3 years. All patients must also be followed through 
completion of all protocol therapy. 
• 
For patients who have confirmed progression per RECIST 1.1 prior to 
surgery and do not undergo surgery, the patient will come off study treatment 
and be followed for survival. 
• 
For patients who have confirmed progression per RECIST 1.1 prior to 
surgery, but are still deemed eligible for surgical resection – they will be 
followed for progression and survival. 
• 
For patients who come off study treatment for intolerable toxicities at any 
time, they will be followed for progression and survival. If a patient comes off 
treatment early for anything other than progression of disease, follow up for 
the planned year of treatment with scans and H/P will continue at every 3 
months. 
 


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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors  
6.1.1 
Neoadjuvant Effect – Solid Tumors 
• 
Pathologic response: will be assessed once at 
approximately 10-12 weeks: following surgery and 8 weeks 
of systemic therapy as assessed on local review. Central 
review will be performed retrospectively. The following 
definitions will be employed: [Tetzlaff, Annal Oncol, 2018] 
• 
Pathologic Complete Response (pCR) 
• 
Complete absence of viable tumor in the treated 
tumor bed 
• 
Major PR 
• 
≤10% of viable tumor in the treated tumor bed 
• 
Partial Pathologic Response (pPR) 
• 
Less than or equal to 50% of the treated tumor bed 
is occupied by viable tumor cells 
• 
Pathologic Non-Response (pNR) 
• 
Great than 50% of the treated tumor bed is 
occupied by viable tumor cells 
• 
Radiologic Response: For the purposes of this study, 
patients should be evaluated for radiologic/clinical 
response after 8 weeks of therapy but prior to surgery, and 
then every 12 weeks (+2 weeks) (20 weeks, 32 weeks and 
44 weeks and 56 weeks (end of treatment) for one year, 
then every 12 weeks (+4 weeks) x 1 year, then every 24 
weeks (+4 weeks) x 3 (until year 5). 
Post-neoadjuvant treatment CT (or MRI) scan of chest, abdomen, 
pelvis and/or any other involved sites with contrast (unless 
contraindicated) will be performed and the response to systemic 
treatment assessed in addition to clinical assessment. Response and 
progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 
2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in RECIST. If a 
new/progressive lesion is noted on imaging after neoadjuvant therapy, 
histologic evaluation with a biopsy is required unless the lesion is not 
accessible or a biopsy would cause undue risk to the patient. If the 
progressive disease is still considered eligible for a complete surgical 
resection, the patient may proceed onto surgery per investigator 
discretion and a biopsy is not required before surgery. Pathologic 
evaluation would then confirm if true disease progression versus 
treatment effect. If the progressive disease is not considered 
resectable based on post treatment scans, biopsy, and surgical 


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consultation/opinion, surgical resection will not be carried out and the 
patient will be off treatment and followed for survival. 
The following general principles must be followed: 
2. To assess objective response, it is necessary to estimate the 
overall tumor burden at baseline to which subsequent 
measurements will be compared. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment 
and never more than four weeks before registration. 
3. Measurable disease is defined by the presence of at least one 
measurable lesion. 
4. All measurements should be recorded in metric notation by use of 
a ruler or calipers. 
5. The same method of assessment and the same technique must 
be used to characterize each identified lesion at baseline and 
during follow-up. 
6.1.2 
Definitions 
Evaluable for Response 
Evaluable patients are defined as eligible patients (per Section 3) who 
receive at least one dose of neoadjuvant therapy with encorafenib and 
binimetinib and are resectable at enrollment. 
• 
Patients who do receive treatment but demonstrate 
progression of disease per RECIST and do not proceed to 
surgery will be classified as pathologic non response 
(pNR). 
• 
Patients who receive at least one dose of treatment but do 
not receive surgery for other reasons will be evaluated for 
radiographic/clinical response. 
6.1.3 
Disease Parameters: evaluation of radiographic response 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm 
with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. If the 
investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered 
must be defined in the protocol. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be  


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≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and 
in follow-up, only the short axis will be measured and followed. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of 
unequivocal progression of each should be noted throughout follow-
up. 
6.1.4 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest X-ray 
Lesions on chest x-ray are not acceptable as measurable lesions. 


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Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. FDG-PET/CT will 
not be mandated for the study. However, patients who undergo FDG-
PET/CT for clinical indications, and had the FDG scan performed on 
the qualified scanner, will have FDG-PET/CT scans collected for an 
exploratory comparison to outcomes and to FLT-PET results. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 


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Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
6.1.5 
Response Criteria 
6.1.5.1 
Pathologic Response Rate (pCR) 
Pathologic complete response (pCR) is defined as the 
absence of residual melanoma in resected tissue as 
assessed on local pathology review. These will have 
central review retrospectively. 
• 
Pathologic complete response (pCR) 
• 
Complete absence of viable tumor in the treated 
tumor bed 
• 
Major PR 
• 
≤10% of viable tumor in the treated tumor bed 
• 
Partial pathologic response (pPR) 
• 
Less than or equal to 50% of the treated tumor bed 
is occupied by viable tumor cells 
• 
Pathologic non-response (pNR) 
• 
Greater than 50% of the treated tumor bed is 
occupied by viable tumor cells 
Pathologic Response 
Remarks 
pCR 
Complete absence of 
viable tumor in the 
treated tumor bed 
 
Major 
PR 
≤ 10% of viable tumor in 
the treated tumor bed 
 
pPR 
Less than or equal to 
50% of the treated tumor 
bed is occupied by viable 
tumor cells 
 
pNR 
Great than 50% of the 
treated tumor bed is 
occupied by viable tumor 
cells 
Patients that 
demonstrate objective 
RECIST progression, 
they will be classified at 
pathologic NR 
6.1.5.2 
RECIST Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to  
< 10 mm. 


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Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.5.4. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
NOTE: 
A change of 20% or more that does not 
increase the sum of the diameters by 5 mm or 
more is coded as stable disease. 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once. 
6.1.5.3 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump target 
lesion status. It must be representative of overall disease 
status change, not a single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 


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basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
Principal Investigator). 
6.1.5.4 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
c) new effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.5.5 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the neoadjuvant treatment until surgery or 
disease progression/recurrence or non-protocol therapy 
(taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
Best response will be collected at one time point: 
• 
After 8 weeks of neoadjuvant therapy (best response to 
oral treatment) 


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RECIST response with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
6.1.5.6 
Duration of disease control 
Duration of Overall Response 
The duration of disease control is measured from the time 
of enrollment to the first date of any of the following events: 
progression prior to surgery such that surgery is not 
recommended/performed; at time of surgery if resection 
does not eradicate all disease, progression after surgery, 
death. If none of the events occur, the date of last contact. 
6.2 
Progression before surgery 
Progression of disease per RECIST 1.1 before surgery that renders the patient 
ineligible for complete surgical resection per protocol should be classified as 
local/ regional or distant. 
6.3 
Local, Regional Recurrence 
The development of a local or regional recurrence of melanoma after surgery 
6.4 
Distant Recurrence 
The development of a distant recurrence of melanoma after surgery 
6.5 
Disease-Free Survival 
Date of surgical resection to the date of first treatment failure (recurrence or 
death before recurrence) 


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6.6 
Survival 
Date of registration to date of death 
6.7 
Recurrence 
Recurrence must be documented by radiologic exams and with biopsy in all 
cases except for brain metastases (biopsy not required). Abnormal blood studies 
alone (e.g., elevated transaminases or alkaline phosphatase) are not sufficient 
evidence of relapse. Whenever possible, histologic proof of recurrence should be 
obtained unless the lesion is not accessible or a biopsy would cause undue risk 
to the patient. 
Documentation of recurrence must specify all involved sites to establish the 
pattern of recurrence. 
A new primary melanoma is not considered recurrence. 
 


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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
1. Screening and baseline assessments must occur within 4 weeks of registration, unless otherwise specified. 
2. Patients must have been seen and evaluated by a melanoma-experienced surgeon prior to enrollment and deemed 
surgically resectable. 
3. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done within 4 
weeks prior to registration. 
4. Prestudy laboratory assessments must be completed < 14 days prior to registration. 
 
Neo-Adjuvant 
Surgery 
Adjuvant 
 
Screening/
baseline 
Week 
0 
D1 
Week 
210 
Week 
4 
Week 
8 
 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
52 
EOT 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History/ Physical 
Exam/ ECOG 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/ Vital 
signs 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications8 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT c/a/p + 
additional sites as 
indicated 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
MRI brain (up to 4 
weeks prior to 
registration) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry Labs1 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
Labs1 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum or Urine 
Pregnancy Test2 
X 
 X2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill Count/Diary3 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rev Add2 


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Neo-Adjuvant 
Surgery 
Adjuvant 
 
Screening/
baseline 
Week 
0 
D1 
Week 
210 
Week 
4 
Week 
8 
 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
52 
EOT 
Echocardiogram/ 
MUGA7 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
EKG7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology 
Exam4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CK5 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Surgical 
Resection9 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FLT-PET6 
X 
 
 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biological Sample 
Submissions 
 
See Section 7.2 
1 
CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be done < 24 
hours prior to the treatment cycle. PT, PTT, INR will be collected at screening. Additional labs and frequency as clinically indicated per 
investigator discretion. Screening labs will be obtained within the one-week period prior to administration of FLT. Chemistry labs include; 
Sodium, chloride, CO2 or bicarbonate, potassium, creatinine, BUN, glucose, calcium, total protein, albumin, total bilirubin, AST, ALT, alkaline 
phosphatase, LDH. If patient data is available from clinical records in the appropriate time window, they need not be repeated for the scans. 
2 
All patients of childbearing potential must have a negative [blood test or urine test] within 14 days prior to study registration to rule out 
pregnancy. If the pregnancy test done at baseline is greater than 14 days prior to Day 1 of treatment, it should be repeated prior to initiating 
treatment. A pregnancy test must also be done prior to starting adjuvant treatment. 
3 
Patients will record medication use of Encorafenib and Binimetinib per scheduled visits. See Appendix III. 
4 
A full ophthalmic examination will be performed by an ophthalmologist at baseline and include best corrected visual acuity, slit lamp examination, 
intraocular pressure, dilated fundoscopy. Ocular Coherence Tomography (OCT) will only be performed if clinically indicated at the discretion of 
the ophthalmologist. Examination of the retina is required, especially to identify findings associated with serous retinopathy and RVO. After 
baseline, patients should be assessed at every physical examination for visual complaints. 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. Full ophthalmologic exam will be pursued as 
needed throughout the study as clinically indicated. 
5 
CK will be performed at the same time points as the hematology collections. Troponin may be drawn as clinically indicated for abnormal CK. 
Follow up for total creatine kinase (CK) ≥3 X ULN will include weekly assessment of isoenzymes and myoglobin in blood/or urine, and troponin 
as applicable. 
6 
The baseline FLT scan must be done within two weeks prior to starting neoadjuvant treatment and the post-treatment FLT scan should be 
completed after 2 cycles (8 weeks or up to 9 weeks) of treatment and prior to surgery. All study related neoadjuvant treatment should be 


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completed prior to post-treatment scan. Refer to Section 5.3.4 for more details on scan timing. Specific image acquisition and reconstruction 
protocols will be provided in a Site Imaging Manual to participating institutions. Patient should be monitored for AE’s to the FLT after the imaging 
is complete and 24 hours after completion of scan, this can be done by phone or email. 
7 
EKG should be performed at baseline. Additional EKGs are to be performed as clinically indicated. ECHO/MUGA scans are to be performed at 
screening, on Cycle 2 Day 1 and Cycle 5 Day 1, then every 12 weeks and EOT to determine cardiac ejection fraction. If scheduled 
ECHO/MUGA was performed and within normal limits within 4 weeks of the end of treatment timeframe, a second ECHO/MUGA does not need 
to be performed. Whichever modality was used at baseline should be continued throughout the study. 
8 
See Section 8.1.13 and Section 8.2.14. 
9 
Surgery should not be delayed if the FLT PET scan cannot be done prior to planned surgery. 
10 Week 2 visit can be done by phone if patient does not consent for week 2 biopsy. 
 


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7.2 
Biological Sample Submissions 
1. Specimens are to be submitted as outlined in Section 10. 
2. All specimens submitted must be entered and tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
Biological Materials 
Baseline  
After Two [2] 
Weeks of 
Treament4 
After Eight 
[8] Weeks of 
Treatment 
Week 206 
Week 326 
Week 446 
End of 
Treatment 
Mandatory for Central Diagnostic Review 
FFPE Tumor Tissue7 
X1 
 
X5 
 
 
 
 
Collect and submit from patients who answer “Yes” to “I agree to have one or two research biopsies to collect tissue for known 
laboratory research studies.” 
Tumor Tissue Biopsy7 
X3 
X 
 
 
 
 
 
Collect and submit from patients who answer “Yes” to “I agree to have my tissue samples collected from procedures performed 
as part of my standard of care and I agree that my tissue samples and related health information may be used for the laboratory 
research studies described above.”8 
FFPE Tumor Tissue 
X1 
 
X5 
 
 
 
 
Collect and submit from patients who answer “Yes” to “I agree to provide additional blood samples for future health research.”8 
Peripheral Blood (ten 
10mL green top heparin 
tubes)2 
X 
X 
X 
X 
X 
X 
X 
Peripheral Blood (two 
10mL SST red top tubes)2 
X 
X 
X 
X 
X 
X 
X 
Peripheral Blood (one 
10mL Streck Cell-Free 
DNA tube)2 
X 
X 
X 
X 
X 
X 
X 
1 
Tumor tissue collected within two (2) months prior to performance of imaging and from the surgical resection with the related 
pathology reports must be submitted for central diagnostic review within one (1) month following registration and the procedure 
respectively. Failure to submit the required materials may render the case unevaluable. Additional materials are requested for 
laboratory research studies from patients who consent “Yes” to “I agree to have my tissue samples collected from procedures 
performed as part of my standard of care and I agree that my tissue samples and related health information may be used for the 
laboratory research studies described above.” 
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2 
Kits are being provided for the collection and shipment of the peripheral blood specimens. See Appendix VII for instructions. Kit 
orders will on average be delivered within three (3) business days from the time the order is placed. 
3 
If baseline biopsy is performed after study registration, the baseline FLT-PET/ CT scan should be completed prior to biopsy (can 
be done same day). 
4 
+/- 1 week. 
5 
Surgical resection specimen. 
6 
At every scan evaluation while on treatment. 
7 
Biopsies are to be performed, if considered at or less than minimal risk (no more than 2% risk of serious complication requiring 
hospitalization). 
8 
As outlined in the Informed Consent patient participation in tumor tissue and peripheral blood submissions is optional. Sites 
must offer participation in these optional studies to all patients. 


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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Pfizer is supplying Encorafenib and Binimetinib free of charge and will be distributed 
by McKesson Specialty Pharmacy, LP. Under no circumstances can commercially 
supplied Encorafenib and Binimetinib be used or substituted for the patient specific 
Encorafenib and Binimetinib supplied by Pfizer. 
Encorafenib: 
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, yellow or black depending on the particular strength. 
Encorafenib capsules should be stored at room temperature, not above 25°C and 
protected from moisture. Capsules are packaged in square, high-density polyethylene 
bottles that are induction sealed and closed with a polypropylene, child-resistant screw 
cap. Encorafenib bottles will be labelled, at a minimum, with the lot number, contents 
(number of tablets), dosage strength, and storage conditions. Encorafenib should be 
dispensed to patients in the bottles provided by Pfizer and should not be repackaged at 
the site or pharmacy. 
Binimetinib: 
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. 
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. Binimetinib bottles will be labelled, at a minimum, with the lot number, contents 
(number of tablets), dosage strength, and storage conditions. Binimetinib should be 
dispensed to patients in the bottles provided by Pfizer and should not be repackaged at 
the site or pharmacy. 
8.1 
Binimetinib (NSC 788187) 
Please refer to the package insert or institutional preparation guidelines for 
additional information. 
8.1.1 
Chemical Name or Amino Acid Sequence 
5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-
methyl-1Hbenzimidazole-6-carboxamide 
8.1.2 
Other Names 
MEK162, ARRY-438162, Mektovi® 


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8.1.3 
Classification 
MEK 1/2 inhibitor 
8.1.4 
CAS Registry Number 
606143-89-9 
8.1.5 
Molecular Formula 
C17H15BrF2N4O3 
M.W.: 441.23 
8.1.6 
Approximate Solubility 
Binimetinib’s solubility is pH dependent. At pH 1 solubility is 0.993 
mg/mL. At pH 7.4 solubility is 0.012 mg/mL. 
8.1.7 
Mode of Action 
Binimetinib is a potent, selective, allosteric small-molecule inhibitor of 
mitogen-activated protein (MAP) kinase kinase (MEK 1 and MEK 2) 
that is uncompetitive with adenosine triphosphate (ATP). 
8.1.8 
Availability 
Binimetinib is provided free of charge by Pfizer and distributed by 
McKesson Specialty Pharmacy, LP. 
Initial Drug Orders for Each Patient 
Once a patient has been registered on this study, a supply of 
Binimetinib may be ordered. Investigators must email a completed 
EA6183 Binimetinib Study Drug Request Form to the ECOG-ACRIN 
Drug Team at DrugOrder@ecog-acrin.org. A copy of the EA6183 
Binimetinib Study Drug Request Form is available for download from 
the CTSU website (www.ctsu.org). 
Please refer to Appendix VII for the EA6183 Binimetinib Study Drug 
Request Form download instructions. 
Binimetinib will be shipped to a responsible person (e.g., a 
pharmacist) at the investigator’s institution. Sites should order 
enough drug for 2 cycles of treatment. 
Institutions should allow up to 4 business days to receive drug 
onsite. McKesson Specialty Pharmacy, LP will ship and arrange 
drug deliveries to sites on business days only; there will be no 
weekend or holiday delivery of drugs. 
IMPORTANT REORDER INSTRUCTIONS 
Once it is determined that the patient will continue treatment, please 
reorder 2 cycles of study drug immediately by emailing a completed 
EA6183 Binimetinib Study Drug Request Form to the ECOG-ACRIN 
Drug Team at DrugOrder@ecog-acrin.org. 
Institutions should allow up to 4 business days to receive drug onsite. 
McKesson Specialty Pharmacy, LP will ship and arrange drug 
deliveries to sites on business days only; there will be no weekend or 
holiday delivery of drugs. 


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Drug Destruction and Return 
At the completion of each patient’s treatment at your institution, all 
unused drugs, partially used, or empty containers must be destroyed 
at the site according to the institution’s policy for drug destruction. 
Please maintain appropriate records of the disposal, including dates 
and quantities. 
Agent Inventory Records 
The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing 
and final disposition of all agents using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available 
on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator on this protocol. 
8.1.9 
Storage 
Store below 25°C, protect from light 
All deviations from the required storage condition of IMP provided by 
Pfizer, whether the deviation occur in-transit or on-site, need to be 
reported to Pfizer for evaluation of the impact the event may have to 
the usability of the IMP. 
Please report temperature deviation events to the Pfizer Clinical 
Supply team using the following email address: 
GCSTempExcursionSupport@pfizer.com 
8.1.10 
Stability 
Stability studies are ongoing. Tablets should be dispensed in the 
original packaging. 
8.1.11 
Route and Method of Administration 
Orally with or without food. Tablets should be swallowed whole. 
8.1.12 
Potential Drug Interactions 
In vitro, binimetinib is metabolized primarily by glucuronidation mainly 
via UGT1A1 but also UGT1A3 and 1A9. Binimetinib is a substrate of 
CYP1A1, 1A2, 2C19, 3A4 in vitro but the potential for a clinical drug 
interaction is expected to be minimal. Binimetinib is also a substrate of 
P-gp and BCRP. Inhibitors or inducers of UGT1A1, P-gp, and BCRP 
should be co-administered with caution. 
In vitro, binimetinib showed relatively potent inhibitory effect on 
CYP2B6 and weak inhibition of CYP1A2 and 2C9. Avoid co-
administration with agents that are substrates of CYP2B6. It has little 
or no inhibition of CYP2A6, 2C8, 2C19, 2D6, 2E1, and 3A4/5. 
Binimetinib is a weak inhibitor of UGT1A-mediated SN-38 conjugation 
in vitro. Binimetinib was not found to be an in vitro inhibitor of BCRP, 
P-gp, or OCT1 but is a weak inhibitor of OCT2. There is a low 
potential for binimetinib to cause a clinical drug interaction with 
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Binimetinib is an in vitro inducer of CYP3A4 but this was not 
confirmed clinically. Slight induction of CYP2C9 mRNA was also 
found but did not translate into induction of activity. 
Binimetinib is highly protein bound (97.2%). Use caution in patients 
who are receiving concomitant medications that are also highly 
protein-bound. 
Drugs with a conditional, possible, or known risk to induce Torsades 
de Pointes or QT prolongation should be co-administered with 
caution. Patients that take these medications should be monitored 
frequently or according to protocol. 
8.1.13 
Side Effects 
See Section 5.5.1 for the Comprehensive Adverse Event and 
Potential Risks (CAEPR) list.  
Refer to Section 5.6 for dose modification instructions. 
8.1.14 
Concomitant Medications 
Concomitant strong systemic CYP3A4 inhibitors and moderate/strong 
CYP3A4 inducers are likely to significantly increase or decrease 
encorafenib exposure, respectively, and thus, they are not allowed 
during this study (see Appendix X). 
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. 
8.1.15 
Nursing/ Patient Care Implications 
There is some data that suggest binimetinib exposure may be 
associated with reproductive toxicity. Binimetinib must not be used in 
pregnant or nursing women. Educate the patient that diarrhea, 
nausea, and vomiting has been reported in patients taking binimetinib. 
Recommend anti-diarrheal medications appropriate anti-emetics, and 
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8.1.16 
Lifestyle Considerations 
Meals and Dietary Restriction 
Patients 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. 
Activity 
Strenuous physical activities, such as competitive sports, can result in 
significant increases in CK levels while on binimetinib treatment. 
Patients should be cautioned not to start a new strenuous exercise 
regimen after first dose of study treatment. 
8.2 
Encorafenib (LGX818) 
Please refer to the package insert or institutional preparation guidelines for 
additional information. 
8.2.1 
Chemical Name or Amino Acid Sequence 
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-2-yl}carbamate 
8.2.2 
Other Names 
LGX818 or ONO-7702 
8.2.3 
Classification 
BRAF Inhibitor 
8.2.4 
CAS Registry Number 
1269440-17-6 
8.2.5 
Molecular Formula 
C22H27ClFN7O4S 
 
 
M.W.: 540.01 
8.2.6 
Approximate Solubility 
8.2.7 
Mode of Action 
Encorafenib is a highly selective ATP-competitive small-molecule RAF 
kinase inhibitor which suppresses the RAF/MEK/ERK pathway in 
tumor cells expressing BRAF V600-mutant kinase. 
8.2.8 
Availability 
Encorafenib is provided free of charge by Pfizer and distributed by 
McKesson Specialty Pharmacy, LP. 
Initial Drug Orders for Each Patient 
Once a patient has been registered on this study, a supply of 
Encorafenib may be ordered. Investigators must email a completed 
EA6183 Encorafenib Study Drug Request Form to the ECOG-ACRIN 
Drug Team at DrugOrder@ecog-acrin.org. A copy of the EA6183 


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Encorafenib Study Drug Request Forms available for download from 
the CTSU website (www.ctsu.org). 
Please refer to Appendix VII for the EA6183 Encorafenib Study Drug 
Request Form download instructions. 
Encorafenib will be shipped to a responsible person (e.g., a 
pharmacist) at the investigator’s institution. Sites should order 
enough study drug for 2 cycles of treatment.  
Institutions should allow up to 4 business days to receive drug 
onsite. McKesson Specialty Pharmacy, LP will ship and arrange 
drug deliveries to sites on business days only; there will be no 
weekend or holiday delivery of drugs. 
IMPORTANT REORDER INSTRUCTIONS 
Once it is determined that the patient will continue treatment, please 
reorder 2 cycles of study drug immediately by emailing a completed 
EA6183 Encorafenib Study Drug Request Form to the ECOG-ACRIN 
Drug Team at DrugOrder@ecog-acrin.org. 
Institutions should allow up to 4 business days to receive drug onsite. 
McKesson Specialty Pharmacy, LP will ship and arrange drug 
deliveries to sites on business days only; there will be no weekend or 
holiday delivery of drugs. 
Drug Destruction and Return 
At the completion of each patient’s treatment at your institution, all 
unused drugs, partially used, or empty containers must be destroyed 
at the site according to the institution’s policy for drug destruction. 
Please maintain appropriate records of the disposal, including dates 
and quantities. 
Drug Inventory Records 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
8.2.9 
Storage 
Encorafenib capsules should be stored according to the conditions 
specified on the drug product package labels. 
All deviations from the required storage condition of IMP provided by 
Pfizer, whether the deviation occur in-transit or on-site, need to be 
reported to Pfizer for evaluation of the impact the event may have to 
the usability of the IMP. 
Please report temperature deviation events to the Pfizer Clinical 
Supply team using the following email address: 
GCSTempExcursionSupport@pfizer.com 


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8.2.10 
Route and Method of Administration 
Encorafenib capsules are intended for oral administration with water; 
capsules should be swallowed whole and should not be chewed.  
Encorafenib may be taken without regard to food. The administration 
of encorafenib without regard to food is supported by a formal food-
effect study. 
8.2.11 
Formulation and Presentation 
The encorafenib drug product is supplied as a capsule formulation in 
dosage strengths of 75 mg. The dosage forms for each strength have 
identical formulations which are packaged in different colored 
capsules: 
75 mg capsule (FMI): Size #00 hard gelatin capsules; flesh opaque 
cap and white opaque body, with the markings “NVR” or stylized “A” 
on the cap and “LGX 75mg” on body. 
Encorafenib drug substance and the following excipients: copovidone, 
poloxamer 188, succinic acid, microcrystalline cellulose, colloid silicon 
dioxide, crospovidone, and magnesium stearate of vegetable origin. 
The capsule shell is commercially available and contains gelatin, 
titanium dioxide and iron oxide red, yellow and black depending on 
particular strength. 
8.2.12 
Potential Drug Interactions 
Formal PD drug interaction studies in nonclinical cancer models have 
not been performed. 
Clinical Study ARRAY-162-105 investigated the PK of encorafenib in 
the presence of the proton-pump inhibitor rabeprazole in 15 healthy 
subjects. Co-administration of 4 consecutive days of rabeprazole 20 
mg QD resulted in no effect on the total exposure (i.e., AUCinf) of 
single-dose encorafenib 100 mg due to higher gastric pH, indicating 
that no dose adjustments are required for patients being treated with 
gastric pH modifying agents or for patients with achlorhydria. 
Furthermore, the results indicate that encorafenib can be taken 
without regard to co-administration of proton pump inhibitors, antacids 
or H2 antagonists. 
Clinical Study ARRAY-818-105 investigated the effect of both CYP3A 
and P-gp transporter inhibitors on encorafenib exposure in 32 healthy 
subjects as encorafenib is a substrate of both CYP3A and P-gp. 
Administration of posaconazole 400 mg (a strong CYP3A inhibitor) 
with encorafenib 50 mg increased overall encorafenib exposure (i.e., 
AUC) by approximately 3fold. Administration of diltiazem 240 mg (a 
moderate CYP3A inhibitor and P-gp transporter inhibitor) with 
encorafenib 50 mg increased overall encorafenib exposure by 
approximately 2-fold. The Tmax values were similar for both 
treatments in each part of the study, suggesting the observed DDIs 
were not due to differences in absorption rates, but were 
mechanistically due to inhibition of CYP3A metabolism. Although the 
contribution of P-gp transporter inhibition by posaconazole and 
diltiazem is difficult to assess with the results of this study, the intent 


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was to investigate dual inhibition of CYP3A and P-gp transporter 
inhibition. 
8.2.13 
Side Effects 
Reasonably foreseeable side effects and risks of the study 
8.2.13.1 
Side Effects of Encorafenib: 
Encorafenib is an investigational drug and not all of the 
side effects are known. Serious side effects, including 
death, are a possibility. The long-term effects of 
encorafenib are also unknown. 
Side effects in cancer patients treated with encorafenib 
may include those described below. 
Most likely side effects (greater than 20%): 
• 
Dry skin 
• 
Feeling tired 
• 
Hair loss 
• 
Itching 
• 
Muscle pain or joint pain 
• 
Nausea 
• 
Reddening, swelling, numbness and peeling on palms 
and soles (hand foot skin reaction) 
• 
Skin rash including redness, itching, hives and raised 
areas of skin 
• 
Thickening of external part of the skin 
• 
Tingling, numbness or abnormal sensitivity to pain or 
touch and nerve pain 
Less likely side effects (greater than 10% up to 20%): 
• 
Decreased appetite 
• 
Difficulty sleeping 
• 
Increase in blood test results that check how well the 
liver is working 
• 
Pain including pain in the arms and legs and back pain 
• 
Skin tags, new moles on the skin or changes in existing 
moles 
• 
Small, rough bumps on the skin 
• 
Vomiting 
• 
Weakness 
Side effects that occurred at a lower rate (1% up to 10%): 
• 
Abdominal pain 
• 
Change in how food tastes or change in ability to taste 
• 
Constipation 
• 
Feeling that you are dizzily turning around 


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• 
Fever 
• 
High blood sugar 
• 
Inflammation of the eye causing eye discomfort, 
redness and sensitivity to light 
• 
Increase in a blood test result that checks how well 
your kidneys are working 
• 
Low red blood cell count 
• 
Muscle weakness and spasms 
• 
New skin growths, including skin cancer 
• 
Weakness of facial muscles or loss of facial movement 
Rare but important serious side effects seen in patients 
receiving encorafenib (less than 1%): 
• 
Inflammation (swelling) of the pancreas causing pain in 
the stomach that may also be felt in the back, and may 
be associated with nausea or vomiting. The symptoms 
can be mild and may go away without treatment, but in 
some cases can be more severe, needing treatment. 
• 
In addition, there may be a rare side effect of changes 
in the electrical activity of your heart called QT 
prolongation. QT prolongation can cause irregular 
heartbeats that can be life-threatening. Associated 
symptoms might include shortness of breath, fast or 
slow heartbeat and lightheadedness or fainting. 
8.2.13.2 
Side Effects of Encorafenib When Used in Combination 
with Binimetinib: 
Side effects in cancer patients treated with encorafenib in 
combination with binimetinib may also include those 
described below. 
Most likely side effects (greater than 20%): 
• 
Alteration of the light sensing part of the back of the 
eye that may affect your vision. 
• 
Increase in a lab test result for creatine phosphokinase 
(an enzyme found in the blood) that may indicate 
muscle inflammation or damage. 
Less likely side effects (greater than 10% up to 20%): 
• 
Swelling of or damage to the light sensing part of the 
eye or impaired vision. 
Side effects that occurred at a lower rate (1% up to 10%): 
• 
Decrease in a test of the heart’s ability to pump blood 
(decreased ejection fraction or left ventricular 
dysfunction) 
• 
Dizziness 
• 
High blood pressure 


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• 
Inflammation in the intestine that may cause pain, 
spasms, diarrhea or bleeding 
• 
Reduction in the kidney’s ability to filter wastes 
Rare but important serious side effects seen in patients 
receiving encorafenib when used in combination with 
binimetinib (less than 1%): 
• 
Bleeding in the stomach, intestines or rectum 
• 
Blood clots in the lungs 
Refer to Section 5.6 for dose modification instructions. 
8.2.14 
Nursing/ Patient Care Implications 
Encorafenib capsules should be swallowed whole with water and 
should not be chewed. Encorafenib capsules may also be opened and 
the powder mixed with sweetened applesauce. The soft food 
preparation should be administered orally with water. Encorafenib 
may be taken without regard to food. 
Patients receiving encorafenib should be monitored for skin toxicities 
include hand food syndrome/palmar plantar erythrodysethesia. 
Educate the patient on lifestyle modifications to prevent and manage 
PPE such as avoiding hot water and sources of heat, applying cool 
compresses to hands and feet, and avoiding activities that may cause 
friction. Topical remedies may also be recommended. 
Monitor patient for anemia: 
The majority of toxicities are generally reversible and manageable by 
appropriate supportive medical care and/or dose modifications or 
discontinuation. Educate the patient to promptly report side effects so 
that early supportive care interventions may be initiated. 
8.2.15 
Concomitant Medications 
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 contraception is 
required for females of childbearing potential during participation in 
this study. Caution should be used in patients receiving concomitant 
treatment with other drugs that are substrates of CYP3A4 as the 
efficacy of these drugs could be reduced when administered with 
encorafenib. 
Encorafenib has been identified in vitro to be metabolized by CYP3A4 
and to a lesser extent by CYP2C19. The use of strong inhibitors of 
CYP3A4 is prohibited. Concomitant use of moderate CYP3A4 


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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. Use of moderate and strong inducers of CYP3A4 is 
prohibited. 
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. 
Prohibited Concomitant Therapy 
Concomitant strong systemic CYP3A4 inhibitors and strong or 
moderate systemic CYP3A4 inducers are likely to significantly 
increase or decrease encorafenib exposure, respectively, and thus 
should not be used during this study. 
See Appendix X 
8.2.16 
Patient Care Implications 
• 
Monitor patients who already have or who are at significant risk of 
developing QTc prolongation, including patients with known long 
QT syndromes, clinically significant bradyarrhythmias, severe or 
uncontrolled heart failure and those taking other medicinal 
products associated with QT prolongation. 
• 
Dermatologic evaluations should be performed by the investigator 
predose and every 8 weeks on protocol and for up to 6 months 
following discontinuation of encorafenib treatment, to monitor for 
the possible development of keratoacanthoma (KA) and/or 
squamous cell carcinoma (SCC), as these have been reported to 
occur with selective BRAF inhibitor treatment. In case of 
occurrence of KA or SCC, patients will undergo complete surgical 
excision of the skin lesion following institutional standards. 
Dermatologic evaluations should be performed by a dermatologist 
as clinically indicated. 
8.2.17 
Lifestyle Considerations 
Meals and Dietary Restriction 
Patients 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 


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drugs, due to potential CYP3A4 interaction with encorafenib. Orange 
juice is allowed. 
Activity 
Strenuous physical activities, such as competitive sports, can result in 
significant increases in CK levels while on binimetinib. 
8.3 
18F-FLT 
For complete information, please refer to the Investigator’s Brochure: 
“3'-deoxy-3'-F [18] fluorothymidine: [F-18]FLT, An Investigational Positron 
Emission Tomography (PET) Radiopharmaceutical for Injection intended for use 
as an in vivo diagnostic for imaging active cellular proliferation of malignant 
tumors”, Edition Number 9, Edition date August 27, 2014. 
8.3.1 
Other Names 
3'-deoxy-3'- 18F fluorothymidine, 18F-FLT, FLT 
8.3.2 
Classification 
Investigational new drug: Radiopharmaceutical/radiotracer 
8.3.3 
Mode of Action 
The pharmacology of FLT as a therapeutic agent is based on its 
action as an inhibitor of DNA synthesis. As a diagnostic imaging 
agent, phosphorylation by thymidine kinase leads to tracer retention in 
proliferating tissue. 
8.3.4 
Storage and Stability 
In accordance with regulations, the radioisotope vendor conducts 
several quality control tests on the FLT product prior to release for 
human administration. Once delivered to the participating institution, 
doses will be stored in the appropriate storage area in the nuclear 
medicine facility until they are administered to the patient. 
The drug solution is stored at room temperature in a gray butyl 
septum sealed, sterile, pyrogen-free glass vial and has an expiration 
time of 8 hours. 
All manufacturing sites that are delivering to other sites must have in 
place the minimum requirements outlined in Appendix XII before 
shipping 18F-FLT to another site. Receiving sites must also abide to 
what is outlined in Appendix XII. 
8.3.5 
Dose Specifics 
The administered activity will be 0.07 mCi/kg with a maximum of 5 
mCi. The amount of injected drug is ≤ 6.1 µg (≤ 25 nmol per dose) of 
FLT. 
8.3.6 
Preparation 
The injectable activity of FLT for most studies will be ≤ 0.07 mCi/kg of 
fluorine-18, not to exceed 5 mCi with a specific activity greater than 
200 Ci/mmol at the time of injection. In the dose of FLT, only a small 
fraction of the FLT molecules are radioactive. 
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8.3.7 
Route of Administration 
FLT is administered to subjects by intravenous injection. There is no 
evidence that nonradioactive and radioactive FLT molecules display 
different biochemical behavior. 
8.3.8 
Incompatibilities 
N/A 
8.3.9 
Availability 
8.3.9.1 
Drug Ordering 
18F-FLT will be supplied by approved manufacturing sites 
under the ECOG-ACRIN IND. The manufacturing site 
(supplier) and receiving site including site personnel must 
meet all requirements and training qualifications as 
outlined in Sections 4.3.3 & 4.3.4. A list of approved 
manufacturing sites can be found on the CTSU website, on 
the EA6183 protocol page under the “Miscellaneous” tab. 
For those sites designated as on-site manufacturing, [F-18] 
FLT chemistry manufacturing and control procedures must 
be filed with and approved by ECOG-ACRIN IND. For 
additional information about on-site manufacturing, contact 
Diana Ewen at dewen@acr.org. 
The ordering of 18F-FLT should be done with a written 
order from the responsible authorized user, and 
administration of 18F-FLT should be performed by the 
authorized user or a qualified staff member under the 
authorized user's supervision (e.g. nuclear medicine 
technologist). Institutions should follow institutional practice 
for the injection of investigational radiopharmaceuticals. 
All approved manufacturing sites may only deliver to 
another site if delivery of tracer is completed within the 
stability time limit. Manufacturing sites may release the 18F-
FLT to a commercial radiopharmacy shipper once it 
passes all quality control testing (excluding sterility). 
8.3.9.2 
Drug Returns 
If for any reason the study imaging is unable to be 
completed, sites will allow the radioactivity of the FLT 
solution to decay and then discard it appropriately per 
site’s policies and procedures. A copy of the policy should 
be available upon request. 
8.3.9.3 
Drug Accountability 
The investigator or the investigator-designee must 
maintain a detailed record of receipt, disposition, and 
destruction dates of FLT solution, using the Drug 
Accountability Record form available through CTSU. 
In accordance with regulations, the radioisotope vendor 
conducts several quality control tests on the FLT product 
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prior to release for human administration. Once delivered 
to the participating institution, doses will be stored in the 
appropriate storage area in the nuclear medicine facility 
until they are administered to the patient. 
https://ctep.cancer.gov/forms/docs/agent_accountability.pd
f 
8.3.10 
Side Effects 
There is a chance of a rare but serious allergic reaction to the FLT. 
8.3.11 
Nursing/Patient Implications 
Standard safety precautions required when handling radioactive 
materials, predominantly during the injection and uptake period should 
be followed. FLT requirements are similar to those used for other PET 
tracers, such as FDG. 
 


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9. 
Statistical Considerations 
9.1 
Study Design and Objectives 
In this phase II study, patients with resectable locoregional metastases from 
cutaneous or unknown primary melanoma (Stages III N1B/C/D) will be enrolled. 
The primary objective is to evaluate the pCR rate for the neoadjuvant 
combination of encorafenib and binimetinib. It is hypothesized that this 
combination of treatment will yield at least 57% pCR rate. Simon’s two-stage 
design will be used, enrolling with up to 42 patients (for 39 evaluable). 
Evaluable patients are defined as eligible patients (per Section 3) who receive at 
least one dose of neoadjuvant therapy with encorafenib and binimetinib and are 
resectable at enrollment. The likelihood of progression, delay in resection or 
failure to proceed to surgery during the neoadjuvant period is expected to be very 
low. Therefore, we expect at least 39 out of 42 patients will be evaluable. 
All patients who receive at least one dose of neoadjuvant therapy will be included 
in the 15 patient-cohort that will trigger the interim analysis. 
Secondary clinical endpoints include: i) to evaluate clinical response rate (RR), 
DFS, OS, ii) to assess correlation of pCR with RR, DFS, OS, iii) to assess safety 
and toxicity iv) to evaluate CD8+ T cell infiltration in tumor or tumor bed pre, 
during and post neoadjuvant treatment and the change in CD8+ TIL with 
neoadjuvant treatment and correlate with clinical response, and v) to compare 
local review for pathologic response with central pathology review. Secondary 
imaging endpoints are addressed in Section 9.7. 
9.2 
Study Endpoints 
Of the 42 patients accrued, we expect at least 39 patients will be evaluable. The 
main analysis for clinical endpoints will be based on 39 evaluable patients. Based 
on prior studies, it is not expected that there will be significant issues with 
disease progression or severe toxicities that interfere with planned surgical 
resection. 
A pCR will be defined as the absence of residual viable melanoma in the 
resected metastasis site as assessed on local pathology review. 
Overall Survival (OS) will be defined as the time from enrollment to death from 
any cause. Patients who have not died will be censored at the date last known to 
be alive. Disease-Free Survival (DFS) will be defined as the time from complete 
surgical resection to disease progression or death (whichever occurs first). 
Patients who are not eligible for resection will not be included in this analysis. 
Cases who have not had an event will be censored at the date of last disease 
assessment documenting the patient was free of progression. Progression will be 
evaluated based on international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) as 
described in Section 6. Response will be defined by the RECIST guidelines 
(version 1.1) as described in Section 6. Toxicity will be defined using the CTCAE. 
Ki-67 IHC in tumor cells will be graded as a percentage of total number of tumor 
cells with nuclear staining (to the nearest 10%) over 10 high powered fields (at 
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9.3 
Sample Size Considerations and Monitoring Plan 
A Simon’s optimal two-stage design will be used to allow for an interim analysis 
for futility. Accrual will be held during the interim analysis. Fifteen (for 14 
evaluable) subjects will be enrolled and pCR will be assessed. If 5 or fewer 
subjects achieve a pCR, the trial will be stopped for futility. If greater than 5 
subjects achieve a pCR, then the trial will enroll an additional 27 (for 25 
evaluable) patients. If 18 or more subjects out of 39 total evaluable subjects 
achieve a pCR the study will be considered ‘positive‘. The study was designed to 
evaluate the pCR rate improving from 33% to 57%. This design provides 87% 
power with approximately one-sided type I error rate of 0.05 for the primary 
endpoint. 
The hypothesis states that encorafenib with binimetinib will yield a pCR rate of 
57%. The baseline pCR rate of 33% was estimated from published values as 
summarized in Table 1 in Section 1 and is thus the null pCR rate. 
We anticipate an average accrual of 1-3 patients per month. The first stage 
analysis will occur when the first 15 patients have a pCR assessed. Under the 
null pCR rate of 33%, there is 70% chance of stopping the study after the first 
stage evaluation. Adverse events will be closely monitored during the study. 
Interim safety analyses based on the first 15 patients will evaluate: 
• 
Proportion of patients who develop progressive disease per RECIST 1.1 
before surgery but proceed with surgical resection 
• 
Proportion of patients who develop progressive disease per RECIST 1.1 
before surgery and are unresectable 
• 
Proportion of patients who develop toxicities that delay or prohibit surgery 
• 
Surgical complications as defined by the operating surgeon as being 
related to surgery or oral therapy, at any point during follow up 
We anticipate that the proportion of patients who experience any of the event 
listed in i) -iv) will be less than 15%. If at least one patient (out of 15 patients) 
experiences any of the event listed in i) - iv), the proposed treatment will be 
considered unsafe and the result will be discussed with the ECOG-ACRIN 
DSMC. The probability of observing at least one patient with the event in i) ii), iii) 
or iv) is 0.794 if the true event rate is 10% and is 0.913 if the true event rate is 
15%. 
9.4 
Secondary Lab Endpoints 
CD8+ T cell infiltration: 
Given the expected 57% pCR rates, there will be at least 13 responders and 10 
non - responders among cases with samples. If the standardized change ((mean 
value for post-treatment samples – mean value for pre-treatment samples)/sd) is 
at least 1.1 for responders vs. non-responders, there will be at least 81% power 
for this comparison. If the post-treatment samples are not available, during-
treatment samples will be used. This is based on the two-sample t-test using two-
sided type I error rate of 0.1. If normality assumption is not appropriate, Wilcoxon 
rank sum test will be used during the analysis. Using the median change value, 
cases will be divided to high and low change groups. 


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9.5 
Statistical Analysis Plan 
Efficacy endpoints will be analyzed in evaluable patients (as defined in Section 
9.1. The primary endpoint of pCR rate will be estimated and 90% CI adjusting for 
the first stage analysis will be provided. OS and DFS distributions will be 
estimated using the Kaplan-Meier method. Median OS and DFS will be described 
with 95% confidence intervals. Clinical response rate (RR) (per RECIST 1.1) will 
be estimated with 95% confidence interval. Clinical data from unevaluable 
patients will be summarized separately.  
Safety analyses will be conducted on all patients who received at least one dose 
of trial therapy (i.e., treated patients). Adverse events will be graded using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. All treatment-emergent and baseline adverse events and 
hematological/biochemical toxicities based on laboratory measurements, as well 
as drug related AEs, will be summarized by NCI CTCAE v. 5.0 worst grade. The 
incidence of deaths and treatment-emergent serious adverse events (defined as 
number of patients experiencing the AE divided by all treated patients) will be 
summarized. Also, the incidence of adverse events leading to discontinuation of 
investigational product and/or withdrawal from the study will be summarized and 
listed. Changes in the CD8 T cell infiltration in tumor or tumor bed pre-, during 
and post- neoadjuvant treatment will be assessed and summarized using the 
descriptive statistics. The change in CD8+ TIL between pre-and post-treatment 
will be compared among patients achieving a pCR vs. no pCR using the 
Wilcoxon rank sum test. The concordance of pCR assessed based on local 
review vs. central pathology review will be evaluated. Kendall’s Tau test will be 
used for this comparison. 
In the event of missing data, it will be assumed that the data will be missing at 
random and no imputation will be performed. 
9.6 
Gender and Ethnicity 
Based on previous data from E1609, the anticipated accrual in subgroups 
defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 
Not Hispanic or Latino 
15 
27 
42 
Ethnic Category: Total of all subjects 
15 
27 
42 
 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
0 
0 
0 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
15 
27 
42 
Racial Category: Total of all subjects 
15 
27 
42 


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9.7 
Imaging Statistical Considerations 
9.7.1 
3'deoxy-3'-(18)F-fluorothymidine (18F-FLT) PET/CT 
18F-FLT is a tracer used in PET imaging that measures cellular 
proliferation in an S-phase-dependent manner. 18F-FLT PET/CT has 
been explored in several malignancies, within the first several weeks 
of treatment, in an effort to predict early response or resistance to 
therapy. However, in vivo data investigating a role for 18F-FLT PET/CT 
in either melanoma, or more generally with MEK or BRAF inhibitor 
therapy, are sparse. We propose to study the utility of 18F-FLT 
PET/CT as an imaging biomarker to guide BRAF/MEK targeted 
neoadjuvant therapy in melanoma. Demonstrating a significant 
difference in change in 18F-FLT PET/CT uptake between patients with 
and without a pathologic complete response after neoadjuvant 
therapy, as well as providing data on the diagnostic performance of 
18F-FLT PET/CT uptake in predicting pCR, would yield valuable data 
toward this end. In addition, demonstrating correlation between the 
change in 18F-FLT PET/CT and the change in Ki-67 immunostaining in 
tumor cells may provide evidence that 18F-FLT PET/CT is a true 
imaging measure of proliferation. 
9.7.2 
Imaging Schedule 
All registered subjects are expected to undergo 18F-FLT PET/CT at 
the following time points: 
• 
Baseline FLT-PET/CT: If the baseline biopsy is done on-study 
and after registration, then the baseline FLT-PET/CT scan must 
be performed prior to the baseline biopsy (same day acceptable). 
The FLT scan needs to be completed within 2 weeks prior to the 
start of the study-mandated neoadjuvant therapy. If the baseline 
biopsy of nodal/in transit melanoma was done prior to study 
enrollment (can be up to 2 months prior), then the baseline FLT-
PET/CT scan must be performed within 2 weeks prior to the start 
of the study-mandated neoadjuvant therapy. 
• 
Post Neo-adjuvant Imaging: A FLT-PET/CT scan will be 
completed after 8 weeks of neoadjuvant therapy and 
before surgery. Note: All neoadjuvant study treatment 
should be completed prior to post-treatment imaging. 
Refer to section 5.3.4 for more details on scan timing. 
Both 18F-FLT imaging time points must be scanned on the same 
qualified PET/CT scanner with imaging technique and 
parameters to be as close as possible to that of the baseline 
scan. 
NOTE: 
Institutions getting FLT from outside suppliers should allow 
time for arranging delivery of FLT. 
All 18F-FLT PET/CT images are to be submitted centrally to ECOG-
ACRIN via TRIAD as outlined in Section 4.3.6. 
It is not expected that the required needle biopsies will have a 
significant effect upon the 18F-FLT PET/CT scans. However, the 
baseline 18F-FLT PET/CT will be scanned prior to the baseline biopsy, 


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even if on the same day, to avoid any confounding. The next 
scheduled biopsy is 2 weeks after initiation of neoadjuvant treatment. 
The post-neoadjuvant 18F-FLT PET/CT will take place 5-7 weeks after 
this interim biopsy, and thus is unlikely to be impacted. 
9.7.3 
Imaging Aims and Statistics 
There are four imaging aims, which are secondary to the main trial. All 
imaging aims will be based on data derived from central review of the 
acquired 18F-FLT PET/CT scans, and are distinguished into primary 
and secondary. 
9.7.3.1 
Primary imaging aim 
To compare the change in 18F-FLT PET/CT uptake 
(from baseline to post-neoadjuvant therapy) among 
patients with and without pathologic complete 
response. 
The primary imaging aim consists of evaluating whether 
the anticipated decrease in 18F-FLT PET/CT uptake from 
the baseline scan to the post-neoadjuvant scan will be 
greater in pCR versus non-pCR subsets, among patients 
with clinically resectable or radiographically-detected stage 
IIIB/C/D melanoma being treated with the neoadjuvant 
combination of encorafenib (a selective BRAF inhibitor) 
and binimetinib (a MEK inhibitor). 
Distributional summaries of the continuous percent change 
in 18F-FLT PET/CT SUVmax will be reported, where 
percent change is defined as (baseline SUVmax – post-
neoadjuvant SUVmax)/(baseline SUVmax)*100%. The 
comparison of percent change in SUVmax between pCR 
and non-pCR patients will be performed using a one-sided 
nonparametric Wilcoxon rank sum test with an alpha level 
of 0.05. 
Of the 42 accrued patients, we assume that 34 (81%) will 
have interpretable 18F-FLT PET/CT scans at both time 
points. The mean percentage decrease in SUVmax for 
non-pCR versus pCR is assumed to be 30% and 50%, 
respectively, and the standard deviation is assumed to be 
20% for both groups. Given that melanoma is expected, on 
average, to be more proliferative than the breast cancers 
studied in ACRIN 6688, positing an expected 20% 
difference in mean percentage decrease in uptake seems 
justified (55). With a pCR rate of 57%, a sample size of 34 
analyzable cases will yield 86% power with a one-sided 
type I error rate of 0.05 based on the Mann-Whitney 
Wilcoxon test using Monte Carlo simulation (n=100,000) 
from appropriate null and alternative normal distributions 
(PASS 2019); however, the power of this comparison 
varies depending on the pCR rate. For example, it is 84% 
with a pCR rate as low as 35%, and 83% with a pCR rate 
as high as 65%. 


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For the sake of completeness, we will also report 
distributional summaries and comparisons for percent 
change in 18F-FLT PET/CT SUVpeak; however, the 
prespecified primary comparison will be based on 18F-FLT 
PET/CT SUVmax. 
9.7.3.2 
Secondary imaging aims 
Secondary imaging aim #1: To compare post-
neoadjuvant 18F-FLT PET/CT uptake among patients 
with and without pathologic complete response. 
This secondary imaging aim will be analyzed in a similar 
manner to the primary imaging aim, but using post-
neoadjuvant 18F-FLT PET/CT SUVmax, as opposed to 
percent change 18F-FLT PET/CT SUVmax. 
Again, for completeness, we will also report distributional 
summaries and comparisons for post-neoadjuvant 18F-FLT 
PET/CT SUVpeak. 
Secondary imaging aim #2: To estimate an optimal 
threshold for prediction of pathologic complete 
response using i. change in 18F-FLT PET/CT uptake, 
and ii. post-neoadjuvant 18F-FLT PET/CT uptake. 
This secondary imaging aim consists of evaluating the 
diagnostic performance of 18F-FLT PET/CT uptake as a 
marker of pathologic complete response (pCR), and of 
estimating the optimal threshold (binary cutpoint) and 
associated sensitivity/specificity. 
Diagnostic performance of percent change in 18F-FLT 
PET/CT SUVmax (from the baseline scan to the post-
neoadjuvant scan) as a marker for pCR status will be 
assessed using receiver operating characteristic curve 
(ROC) analysis. In particular, the empirical area under the 
receiver operating characteristic curve (ROC AUC) will be 
reported, along with corresponding 95% confidence 
interval. In addition, we will formally test if the ROC AUC 
exceeds 0.5 using a one-sided test as suggested by 
DeLong et al (56) with an alpha level of 0.05. Finally, the 
optimal threshold (binary cutpoint) of continuous percent 
change in SUVmax will be estimated by means of the 
Youden index (57). In order to properly reflect sampling 
variability, a 95% confidence interval for the optimal 
threshold will be estimated using the bootstrap technique 
(58). 
The corresponding performance of the optimal threshold 
(measured via sensitivity and specificity) will be estimated 
using cross-validation. In particular, we will randomly divide 
the cohort into 5 folds. Using 4 folds, the ROC curve will be 
fit and optimal threshold (Youden index) obtained. This 
threshold derived from the 4 folds will then be applied to 
the subjects in the remaining holdout fold, in order to 


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define each holdout subject as test positive (> threshold) 
vs. test negative (≤ threshold). This step will be repeated 
until every subject has been a holdout and has test result 
(positive/negative) defined. Sensitivity and specificity will 
then be calculated and reported, using the test result for 
each subject defined during holdout. 
The proposed sample size of 42 patients (34 analyzable), 
assuming a pCR rate of 57%, yields a minimum of 81% 
power to reject the null hypothesis of an uninformative 
marker (ROC AUC=0.5) based on a one-sided test with 
type I error rate of 0.05, assuming the true ROC AUC is 
0.74 or higher (PASS 2019). 
In addition, estimates of diagnostic performance will be 
reported for percent change in 18F-FLT PET/CT SUVpeak. 
This analysis will be repeated separately for post-
neoadjuvant 18F-FLT PET/CT uptake. 
Secondary imaging aim #3: To assess the correlation 
between change in 18F-FLT PET/CT uptake and change 
in Ki-67. 
This secondary imaging aim consists of assessing the 
correlation between the anticipated decrease in 18F-FLT 
PET/CT (from the baseline scan to the post-neoadjuvant 
scan) and the change in tumor cell Ki-67 (from baseline to 
post-neoadjuvant therapy). 
The correlation between percent change in continuous 
SUVmax and percent change in the continuous Ki67 score 
will be estimated using the Spearman correlation 
coefficient. A one-sided correlation test with null hypothesis 
of zero correlation will be conducted at alpha level of 0.05. 
The corresponding confidence interval for the estimated 
Spearman correlation coefficient will also be reported. 
The proposed sample size of 42 patients (34 analyzable) 
yields a minimum of 83% power to detect a nonzero 
correlation, assuming that the true correlation is 0.5 or 
higher. A two-sided Spearman correlation test with a type I 
error rate of 0.05 was used for this computation based 
Monte Carlo simulation (n=100,000) from a bivariate 
normal distribution (PASS 2019). 
Correlation between change in 18F-FLT PET/CT and the 
early change in tumor cell Ki-67 (from baseline to the week 
2 interim biopsy) will also be separately estimated; 
however, as the week 2 interim biopsy is not mandatory, 
we expect small numbers of subjects, and thus this 
analysis will be exploratory. The corresponding correlation 
with percent change in 18F-FLT PET/CT SUVpeak will also 
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10. 
Specimen Submissions 
Representative tumor tissue from the involved lymph node (not a primary melanoma) 
(block preferred) and related pathology reports from a procedure performed within two 
(2) months prior to the performance of imaging and from the surgical resection after 
eight (8) weeks of treatment must be submitted for central diagnostic review. Additional 
tumor tissue and peripheral blood specimens are to be collected and submitted per 
patient consent. 
• 
Additional tumor tissue from the archived pre-trial biopsy and surgical biopsy 
• 
Tumor tissue from research biopsies performed prior to start of treatment, if 
performed, and after two (2) weeks (+/- 1 week) off treatment 
• 
Peripheral blood specimens for potential future research studies 
All specimens must be clearly labeled with the ECOG-ACRIN protocol number [EA6183], 
the patient’s initials and ECOG-ACRIN patient sequence number, the collection date, 
and specimen type. For pathology materials, it is strongly recommended that full patient 
names be provided. 
It is required that all specimens submitted on this trial be entered and tracked via the 
ECOG-ACRIN Sample Tracking System (STS) (Section 10.4). An STS shipping manifest 
form is to be included with every submission. 
If you have any questions concerning tumor tissue and peripheral blood submissions or 
need information regarding potential alternative submission requirements, please 
contact the ECOG-ACRIN CBPF at (844) 744-2420 or eacbpf@mdanderson.org. 
10.1 
Submissions to ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF) 
The submission of baseline diagnostic and surgical tumor tissue is required for 
central diagnostic review and pathologic response assessment. Additional tumor 
tissue from these procedures and from biopsies performed for research from 
patients who agree to participate in the laboratory research studies are also 
requested. Tumor tissue is to be submitted within one month of registration or 
collection. 
The tumor tissue specimens are to be labeled with the institution’s assigned 
pathology ID# as well as the information above. If only slides are submitted, 
slides are to be adequately labeled and numbered in the order sectioned from 
the block. 
Submitting pathologist and clinical research associate may refer to Appendix I 
which outlines the Pathology Submission Guidelines. 
10.1.1 
Form Submission Requirements 
The following forms must be submitted with all pathology 
submissions. 
• 
STS generated shipping manifest form 
• 
Copy of the institutional diagnostic and surgical pathology 
reports 
• 
Immunological study reports, if available 


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10.1.2 
MANDATORY Tumor Tissue Submissions 
Representative formalin-fixed paraffin-embedded (FFPE) tumor tissue 
blocks: 
A. Baseline Diagnostic Tumor Tissue 
Submit the following: 
• 
all available tumor tissue blocks, OR 
• 
two (2) representative unstained FFPE slides per 
block, OR 
• 
one (1) representative H&E slide and one (1) 
representative unstained slide per block. 
NOTE: 
If the patient has consented to undergo a research 
biopsy to obtain tumor tissue for laboratory research 
studies, material captured prior to start of treatment may 
be submitted as outlined below in leiu of archived FFPE. 
If a research biopsy from consenting patients is 
submitted for the mandatory baseline diagnostic 
submission, an FFPE block must be submitted. 
B. Post Neo-adjuvant Surgical Resection Tumor Tissue 
Submit the following from the surgically resected specimen: 
• 
all available tumor tissue blocks, OR 
• 
two (2) representative unstained FFPE slides per 
block, OR 
• 
one (1) representative H&E slide and one (1) 
representative unstained slide per block. 
NOTE: 
A three-dimensional macroscopic measurement of the 
largest grossly positive identified lymph node should be 
provided in the gross description accompanying the 
specimen. If the largest grossly positive lymph node 
measures < 5 cm in greatest dimension, then each 
grossly positive lymph node should be submitted 
entirely at 2 mm serially sectioned intervals. For any 
grossly positive lymph node measuring > 5 cm in 
greatest dimension, representative sections of the 
largest lymph nodes may be utilized to avoid 
oversampling. Following serial sectioning of each lymph 
node, for those nodes > 5 cm, sections representing a 
complete cross section of the entire surface area should 
be submitted per 1 cm of each grossly positive lymph 
node. Sections submitted should include grossly 
obvious tumor. All grossly positive lymph nodes < 5 cm 
in specimens (where the largest node(s) exceeds 5 cm) 
should be submitted entirely. 


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10.1.3 
Tumor Tissue Submissions per Patient Consent 
10.1.3.1 
Additional Baseline Archive and Surgical FFPE Tumor 
Tissue 
If only slides are submitted for the mandatory central 
diagnostic review, additional tumor tissue is requested to 
be submitted for laboratory research studies from patients 
who answer “Yes” to “My leftover tissue samples and 
related information may be kept in a Biobank for use in 
future health research” or “I agree to have my tissue 
samples collected from procedures performed as part of 
my standard of care and I agree that my tissue samples 
and related health information may be used for the 
laboratory research studies described above.” 
• 
Twenty (20) 5 µm and five (5) 4 µm unstained, 
positively charged, air-dried plus slides from the 
thickest part of the tumor 
• 
Also requested: One (1) or more core punches 
(minimum of 4mm diameter). If core punch tool is 
unavailable, request core punch kit from the ECOG-
ACRIN CBPF (844) 744-2420. Adequately label every 
slide and core submitted, with slides numbered 
sequentially in the order cut. 
10.1.3.2 
Research Biopsies 
From patients who consent “Yes” to “I agree to have one or 
two research biopsies to collect tissue for known laboratory 
research studies.” 
Tumor tissue blocks from biopsies performed to obtain 
research specimens are to be submitted within one (1) 
month of the procedure. Biopsies are done only if they can 
be performed at minimal risk (no more than 2% risk of 
serious complication requiring hospitalization) and are 
requested at: 
• 
Baseline, following step 1 registration prior to 
treatment. If a baseline biopsy is performed after study 
registration, the baseline FLT-PET/ CT scan should be 
completed prior to biopsy (can be done same day). 
This biopsy is requested only if there is no material 
available from a prior procedure performed within two 
(2) months of imaging. 
• 
Two (2) weeks (+/- 1 week) post treatment. 
Tumor tissue specimens will be obtained from the target 
lymph node metastasis, with or without image guidance. 
Types of biopsies are to include: 3-4 (1-2 cm in length), 14-
16 or 18-gauge core biopsies, or small incisional biopsies 
(tumor biopsy at least 4-5 mm in diameter) such that the 
smallest dimension of the residual tumor after initial biopsy 
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would be at least 1cm. It is suggested that core biopsies be 
submitted separately into individual tissue blocks. 
NOTE: 
Reimbursement guidelines for research 
biopsies are outlined in Appendix XI. 
10.1.4 
Shipping Procedures 
Tumor tissue specimens are to be shipped overnight at ambient 
temperature within one (1) month following registration or collection. 
During warm months, it is strongly recommended that tumor tissue 
specimens be shipped with a cool pack to prevent the paraffin from 
melting. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager. 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org. 
An STS Shipping Manifest Form must be generated and shipped with 
all specimen submissions. 
10.2 
Peripheral Blood Submissions: 
10.2.1 
Submissions to the MD Anderson Cancer Center CBPF Life Science 
Plaza 
Submit from patients who answer ‘Yes’ to ‘I agree to provide 
additional blood samples for future health research.’ 
Kits for the collection and shipment of the peripheral blood specimens 
are ordered online from Cenetron Central Laboratories. Instructions 
are provided in Appendix VIII. Questions regarding kits can be 
directed to projectmanagement@cenetron.com or call the Cenetron 
Clinical Trials Group at (512) 439-2000. Kits must be ordered after the 
patient has been registered to the trial and will generally arrive within 
three (3) business days from when the order was placed. 
10.2.2 
Collection Schedule 


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Peripheral blood specimens are to be collected at the following time 
points: 
• 
Prior to Start of Treatment 
• 
After Two Weeks of Therapy 
• 
After Eight Weeks of Therapy 
• 
Weeks: 20, 32, 44, and End of Treatment 
10.2.3 
Sample Preparation Guidelines 
Package and ship at ambient temperature. SST Red Top and Streck 
tubes may be packaged with cool packs during the hot season, but 
the Green Top Heparin tubes are to be shipped ambient only. If a cool 
pack is used, specimens must be packaged to protect them from 
freezing, otherwise just ship ambient. 
1. Red Top SST Tubes 
• 
Draw two (2) 10mL red top SST tubes of whole 
blood at each time point. 
2. Green Top Heparin Tubes 
• 
Draw ten (10) 10mL green top heparin tubes of 
whole blood at each time point.  
3. Streck Cell-Free DNA Tubes 
• 
Draw one (1) 10mL Streck Cell-Free DNA BCT 
tube of whole blood at each time point. Fill each tube 
completely. 
• 
Ensure at least 10mL of blood is drawn in each 
tube. Avoid low volume to minimize agitation during shipping. 
• 
Immediately after collection, gently invert tube 180 
degrees and back 10 times to ensure adequate mixing. 
• 
Maintain blood at room temperature (6ºC to 37ºC) 
until shipping. Do Not place tube in refrigerator. 
10.2.4 
Shipping Procedures 
Peripheral blood specimens in SST Red Top and Streck tubes are to 
be shipped at ambient temperature day of collection Monday through 
Thursday via overnight courier. 
The green top heparin tubes must be shipped the same day they 
are drawn because they must be processed the day after 
collection. 
The laboratory is open Monday through Friday to receive specimens. 
Do not ship on Fridays or Saturdays, or the day before legal holidays. 
Friday shipments are ill advised, similarly shipping before 
holidays is often problematic. The laboratory is closed Saturday, 
Sunday, and holidays. 
Ship using the CBPF’s FedEx account using the FedEx on-line ship 
manager. 
MD Anderson Cancer Center CBPF 
Mike Balco 


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Life Science Plaza - Suite 910 
2130 West Holcombe Boulevard, LSP9.4227 
Houston, TX 77030 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
site needs to have an account created, please contact the ECOG-
ACRIN CBPF by email at eacbpf@mdanderson.org 
An STS Shipping Manifest Form must be generated and shipped with 
all specimen submissions. 
10.3 
Central Laboratory: Processing and Routing 
Pathology materials will be distributed to investigators for central pathology 
review and defined laboratory research studies described in Section 11. 
Specimens submitted will be processed to maximize their utility for current and 
future research projects and may include, but not limited to, extraction of plasma, 
serum, DNA and RNA. 
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies, including residuals from the currently defined 
research studies, will be retained in an ECOG-ACRIN designated central 
repository. For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility. Specimens will be de–identified prior to 
distribution for any approved research projects. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future study. Pathology materials may 
be retained for documentation purposes or returned to the site. All other 
specimens will be destroyed per guidelines of the respective repository. 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all specimens submitted on 
this trial be entered and tracked using the ECOG-ACRIN Sample Tracking 
System (STS). As of June 2007, the software will allow the use of either 1) an 
ECOG-ACRIN username and password previously assigned (for those already 
using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst. 
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated Shipping Manifest must be generated and shipped with all 
specimen submissions. 


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Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
Study Specific Notes 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.5 
Sample Inventory Submission Guidelines 
Inventories of all specimens submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized will be submitted by the investigating 
laboratories to the ECOG-ACRIN Operations Office - Boston on a monthly basis 
in an electronic format defined by the ECOG-ACRIN Operations Office - Boston. 


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11. 
Specimen Analyses: Diagnostic Review and Research Studies 
11.1 
Central Diagnostic Review 
The baseline diagnostic and surgical resection tumor tissue is required for central 
diagnostic review to determine patient evaluability for the trial and for central 
pathologic response assessments. 
11.2 
Ki67 and CD8+ infiltration 
CD8 and Ki67 assays including staining, digital imaging and image analysis will 
be performed at MD Anderson Cancer Center and final result analysis will be 
performed under the direction of Dr. Ari Karunamurthy. 
CD8 will be quantified as an H score as proposed and will include cytoplasmic 
and membranous staining. Focus will be placed on the tumor and peritumoral 
areas if needed and these areas of interest will be designated by the pathologist. 
Ki67 nuclear staining is considered positive and not graded by staining intensity. 
The positively stained cells will be enumerated and the score will be generated 
by assessing both the total number and density of positive cells per square 
millimeter within the tumor/tumor bed area. 
Ki-67 IHC in tumor cells will be graded as a percentage of total number of tumor 
cells with nuclear staining (to the nearest 10%) over 10 high powered fields (at 
20X magnification). 
Ki-67 alone can highlight any proliferating cell so this may overestimate the 
percent of proliferating cells. Focus will be placed on the on tumor cell rich areas 
as designated by pathologist. 
Ki-67 IHC 
Immunohistochemical studies will be performed on a Leica Bond autostainer, 
using the following antibodies: 3,3'-diaminobenzidine chromogen anti-Ki-67 
(clone MIB-1; Dako, Carpinteria, CA; dilution 1:100). 
CD8 IHC 
Immunohistochemical studies will be performed on a Leica Bond autostainer, 
using the following antibodies 3,3'-diaminobenzidine chromogen anti-CD8 (Life 
Sciences Technologies MS457s; 1:25). 
Image Analysis 
Slides will be scanned at 20x magnification (Aperio Scanscope AT Turbo; Leica 
Biosystems). Image analysis software (Aperio ImageScope) measures the 
number of positive cells within designated areas. A Nuclear v9 algorithm is 
applied to determine Ki67 positivity. Also, given the relatively small size of 
immune cells, a modified version of the Nuclear v9 algorithm will be applied as a 
basis for CD8 immune marker positivity, with the intensity thresholds adjusted 
manually to remove background artifacts and to account for variable differences 
in cell size. 
For each region of interest designated, the numbers of positive cells will be 
tabulated, and the total number of positive cells will be divided by the total area 
(mm2) in which cells will be counted. The result will be reported as number of 
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Specimens will be examined with a minimum of 4 quadrant sections of viable 
tumor to be submitted for pathological examination. The whole specimen will be 
evaluated and each slide divided into 4 quadrants. At 20x, intratumoral, 
peritumoral and perivascular mononuclear cell infiltrates will be enumerated, per 
published protocols [Tarhini,et al, PLOS One 9(2):1-8. 
11.3 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the Investigator. 


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12. 
Electronic Data Capture 
Please refer to the EA6183 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
NOTE: 
Serious adverse events must be submitted via CTEP-AERS per protocol 
guidelines. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
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trametinib versus standard of care in patients with high-risk, surgically resectable 
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2. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade 
in high risk resectable melanoma. Nautre Medicine 2018. 
3. Ascierto PA, Del Vecchio M, Mandala M, et al. Adjuvant nivolumab versus 
ipilimumab in resected stage IIIB-C and stage IV melanoma (Checkmate 238): 4-
year results from a multicenter, double-blind, randomized, controlled, phase 3 trial. 
Lancet Oncol, 2020 Nov;21(11);1465-1477. 
4. Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab 
plus nivolumab in macroscopic stage III melanoma. Nature Medicine 2018.  
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8. Chen PL, Roh W, Reuben A, et al. Analysis of immune signatures in longitudinal 
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9. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. 
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10. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or 
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23. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced 
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27. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 
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21, 2012 
29. Huang AC, Xu X, Orlowski R, et al. Safety, activity, and biomarkers for neoadjuvant 
anti-PD-1 therapy in melanoma. AACR 2018 (abstract CT181) 
30. Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade 
predicts clinical outcomes in resectable melanoma. Nat Med. 2019 Feb 25. doi: 
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31. Kenny L, Coombes RC, Vigushin DM, et al. Imaging early changes in proliferation at 
1 week post chemotherapy: a pilot study in breast cancer patients with 3'-deoxy-3'-
[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol 
Imaging. 2007 Sep;34(9):1339-47. Epub 2007 Mar 2. 
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Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to 
Neoadjuvant Chemotherapy: Results from ACRIN 6688. J Nucl Med. 2015 
Nov;56(11):1681-9. doi: 10.2967/jnumed.115.160663. Epub 2015 Sep 10. 
33. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in 
BRAF-mutated melanoma. NEJM 2014 Nov 13;371(20):1867-76. 
34. Leyton J, Smith G, Lees M, et al. Noninvasive imaging of cell proliferation following 
mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer 
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melanoma tissue before treatment, early during treatment, and on progression. 
Pigment Cell & Melanoma Research, 2013. 26(4), 499–508. 
36. Long G, Stroyakovsky D, Gogas H, et al. Combined BRAF and MEK inhibition versus 
BRAF inhibition alone in melanoma. NEJM 2014 Nov 13;371(20):1877-88. 
37. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in 
stage III BRAF-mutated melanoma. NEJM 2017; 377:1813-23 
38. Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib combinated with trametinib 
for resectable, stage IIIB-C, BRAFv600 mutation-positive melanoma (NeoCombi): a 
single arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019. Jun 3. pii: 
S1470-2045(19)30331-6 
39. Ma WW, Jacene H, Song D, et al. [18F]fluorodeoxyglucose positron emission 
tomography correlates with Akt pathway activity but is not predictive of clinical 
outcome during mTOR inhibitor therapy. J Clin Oncol. 2009 Jun 1;27(16):2697-704. 
40. McArthur GA, Puzanov I, Amaravadi R, et al. Marked, homogeneous, and early 
[18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in 
BRAF-mutant advanced melanoma. J Clin Oncol. 2012 May 10;30(14):1628-34. doi: 
10.1200/JCO.2011.39.1938. Epub 2012 Mar 26.  
41. McArthur, G., Ribas, A., Chapman, P.B., Flaherty, K.T., Kim, K.B., Puzanov, I., et al. 
Molecular analyses from a phase 1 trial of vemurafenib to study mechanism of action 


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melanoma patients. J Clin Oncol, 2011; 29(Suppl.): abstract 8502. 
42. McKinley ET, Smith RA, Zhao P, et al. 3'-Deoxy-3'-18F-fluorothymidine PET predicts 
response to (V600E)BRAF-targeted therapy in preclinical models of colorectal 
cancer. J Nucl Med. 2013 Mar;54(3):424-30. doi: 10.2967/jnumed.112.108456. Epub 
2013 Jan 22 
43. Menzies AM, Rozeman EA, Rodabe AN et al. Pathological response and survival 
with neoadjuvant therapy in melanoma: A pooled analysis from the International 
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44. Menzies AM, Gonzalez M, Guminski A, et al. Phase 2 study of neoadjuvant 
dabrafenib + trametinib (D+T) for resectable stage IIIB/C BRAF V600 mutant 
melanoma. Ann Oncol 2017; 28, sup 5 (abst 1220PD). 
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patients with high-risk melanoma: a systematic review and meta-analysis. J Natl 
Cancer Inst. 2010 Aprr 7;102(7):493-501 
46. Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage 
IIIB melanoma with high dose interferon alfa-2b induced objective tumor regression 
in association with modulation of tumor infiltrating host cellular immune responses. J 
Clin Oncol 2006: 24(19):3164-71. 
47. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma 
with combined dabrafenib and trametinib. NEJM 2015 Jan 1;372(1):30-9. 
48. Rozeman EA, Menzies AM, van de Wiel BA, et al. OpACIN-neo-A multicenter phase 
2 study to identify optimal neo-adjuvant combination scheme of ipilimumab and 
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49. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal 
combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in 
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the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III 
melanoma. Nat Med 2021. 27:256-263 
51. Saw R, Menzies A, Guminski A, et al. Phase 2 study of neoadjuvant dabrafenib + 
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2016) 9583-9583. 
52. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 
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53. Sloot S et al.. BRAF inhibition for advanced locoregional BRAF V600E 
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54. Sohn HJ, Yang YJ, Ryu JS, et al. [18F]Fluorothymidine positron emission 
tomography before and 7 days after gefitinib treatment predicts response in patients 
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55. Solit DB, Santos E, Pratilas CA, et al. 3'-deoxy-3'-[18F]fluorothymidine positron 
emission tomography is a sensitive method for imaging the response of BRAF-
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56. Sullivan R et al. A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) 
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to BRAFi treatment. J Clin Oncol 33, 2015 (suppl; abstr 9007). 
57. Tarhini AA, Edington H, Butterfield LH, et al. Neoadjuvant ipilimumab in 
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58. Tarhini A, et al. Neoadjuvant combination immunotherapy with pembrolizumab and 
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59. Tarhini AA, Edington H, Butterfield LH, et al. Immune monitoring of the circulation 
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63. Wargo JA, et al. Relapse-free survival and target identification to enhance response 
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69. Youden WJ. Index for rating diagnostic tests. Cancer. 1950; 3:32-35.  
 


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A Phase II Neoadjuvant Study of Encorafenib With Binimetinib in Patients With 
Resectable Locoregional Metastases From Cutaneous or Unknown Primary Melanoma 
(Stages III N1B/C/D) 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. List of Required Materials for EA6183 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981v3) 
 


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Guidelines for Submission of Pathology Materials 
The following pathology materials are to be submitted within one (1) month of 
registration or collection. If these criteria cannot be met, please contact the ECOG-
ACRIN CBPF (eacbpf@mdanderson.org) to obtain alternative submission requirements. 
Adequate patient identifying information must be included with every submission to 
retain chain of custody. It is strongly recommended that full patient names be provided. 
The information will be used only to identify patient materials, and will expedite any 
required communications with the institution (including site pathologists). 
Pathology Submissions: 
Mandatory: 
• 
Representative formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks 
from the baseline diagnostic biopsy 
Submit the following: 
• 
all available tumor tissue blocks, OR 
• 
two (2) representative unstained FFPE slides per block, OR 
• 
one (1) representative H&E slide and one (1) representative unstained slide per 
block. 
NOTE: 
If the patient has consented to undergo a research biopsy to obtain tumor 
tissue for laboratory research studies, material captured prior to start of 
treatment may be submitted as outlined below in leiu of archived FFPE. If 
a research biopsy from consenting patients is submitted for the 
mandatory baseline diagnostic submission, an FFPE block must be 
submitted. 
• 
Representative formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks 
from the surgical resection biopsy 
Submit the following: 
• 
all available tumor tissue blocks, OR 
• 
two (2) representative unstained FFPE slides per block, OR 
• 
one (1) representative H&E slide and one (1) representative unstained slide per 
block. 
NOTE: 
A three-dimensional macroscopic measurement of the largest grossly 
positive identified lymph node should be provided in the gross description 
accompanying the specimen. If the largest grossly positive lymph node 
measures < 5 cm in greatest dimension, then each grossly positive lymph 
node should be submitted entirely at 2 mm serially sectioned intervals. 
For any grossly positive lymph node measuring > 5 cm in greatest 
dimension, representative sections of the largest lymph nodes may be 
utilized to avoid oversampling. Following serial sectioning of each lymph 
node, for those nodes > 5 cm, sections representing a complete cross 
section of the entire surface area should be submitted per 1 cm of each 
grossly positive lymph node. Sections submitted should include grossly 
obvious tumor. All grossly positive lymph nodes < 5 cm in specimens 
(where the largest node(s) exceeds 5 cm) should be submitted entirely. 


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From Consenting Patients: 
Research Biopsies 
• 
Representative formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks 
from baseline following step 1 registration (prior to treatment) and two weeks post 
treatment biopsy. 
NOTE: 
This baseline research biopsy is requested only if there is no material 
available from a prior procedure performed within two (2) months of imaging. 
Biopsies to obtain specimens for research must be determined to be minimal risk prior to 
performance. Tumor tissue specimens are to be obtained from the target lymph node 
metastases, with or without image guidance. Types of biopsies are to include: 3-4 (1-2 
cm in length), 14-16 or 18-gauge core biopsies, or small incisional biopsies (tumor 
biopsy at least 4-5 mm in diameter) such that the smallest dimension of the residual 
tumor after initial biopsy would be at least 1 cm [minimal size of single tumor is at least 2 
cm in smallest dimension]. It is suggested that core biopsies be submitted separately 
into individual tissue blocks. 
NOTE: 
Reimbursement guidelines for research biopsies are outlined in Appendix XI. 
Forms and Reports: 
The following items are to be included with the pathology materials: 
• 
Institutional Diagnostic and Surgical Pathology Report 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981v3) [if STS is 
unavailable] 
• 
Sample Tracking System (STS) Shipping Manifest Form 
• 
Immunological study reports, if available 
Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center  
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions, contact the pathology 
coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by 
telephone: (844) 744-2420 or email: eacbpf@mdanderson.org 


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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA6183: A Phase II 
Neoadjuvant Study of Encorafenib with Binimetinib in Patients with 
Resectable Locoregional Metastases from Cutaneous or Unknown 
Primary Melanoma (Stages III N1B/C/D)  
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for central pathology review and 
defined laboratory research studies. 
Please return the diagnostic and surgical pathology reports, the slides and/or blocks and 
any other required materials to the Clinical Research Associate (CRA). The CRA will 
forward all required pathology materials to the ECOG-ACRIN Central Biorepository and 
Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Biorepository and Pathology Facility for undefined future research studies. 
Paraffin blocks will be returned upon written request for purposes of patient 
management. 
NOTE: Since blocks are being used for laboratory research studies, in some cases the 
material may be depleted and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility at (844) 744-2420 (713-745-4440 Local or 
International Sites) or email: eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
Thank you. 
 


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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 


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(Stages III N1B/C/D) 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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A Phase II Neoadjuvant Study of Encorafenib With Binimetinib in Patients With 
Resectable Locoregional Metastases From Cutaneous or Unknown Primary Melanoma 
(Stages III N1B/C/D) 
Appendix III 
 
Patient Pill Calendar 
NOTE TO SITES: Local study teams may use a different calendar format as long as all 
drug/ dates/ doses are recorded for study reporting/ data completion. These should be 
shared with the Site Principal Investigator and approved by local IRBs per local guidelines, 
prior to use.  
 
Pill Calendar Directions 
1. Take your scheduled dose of each pill. 
2. If you forget, the missed pills will not be taken later. 
3. Please bring the empty bottle or any leftover tablets and your  
pill calendar to your next clinic visit. 
 
 


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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take each day 
for Encorafenib and Binimetinib. You should take your scheduled dose of each pill. Note the 
times and the number of tablets that you take each day. If you develop any side effects, 
please record them and anything you would like to tell the doctor in the space provided. Bring 
any unused tablets and your completed pill calendar to your doctor’s visits. 
Instructions:  
 
Encorafenib:   
Take by mouth once daily 
Pills should be swallowed whole and may be taken with or without food. 
Dose of each pill: 75 mg 
Number of pills to take at each dose: _____ capsules  
Total dose to take each day: ____mg 
 
Binimetinib:  
 
Take by mouth twice daily  
Pills should be swallowed whole and may be taken with or without food. 
Dose of each pill: 15 mg 
Number of pills to take at each dose: ____ tablets  
Total dose to take at each dose: ____mg  
• 
Doses of Binimetinib that are missed should not be taken within 6 hours prior to 
the next scheduled dose. 
• 
Doses of Encorafenib that are missed should not be taken within 12 hours prior 
to the next scheduled dose. 
• 
If vomiting occurs after taking either medication, the dose should not be repeated 
CYCLE 
DAY 
Date 
 
 
 
Encorafenib  
 
 
 
Binimetinib 
 
 
 
Use the space below to 
make notes about things 
you would like to tell the 
doctor (including unusual 
symptoms you experience, 
other medicine you have 
taken and anything else 
you think would be of 
interest.) 
(Month/ Day/ Year) 
# 
Capsules 
Time 
taken 
# 
Tablets 
Time 
Taken 
AM 
Time 
Taken 
PM 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
Rev Add2 


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CYCLE 
DAY 
Date 
 
 
 
Encorafenib  
 
 
 
Binimetinib 
 
 
 
Use the space below to 
make notes about things 
you would like to tell the 
doctor (including unusual 
symptoms you experience, 
other medicine you have 
taken and anything else 
you think would be of 
interest.) 
(Month/ Day/ Year) 
# 
Capsules 
Time 
taken 
# 
Tablets 
Time 
Taken 
AM 
Time 
Taken 
PM 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
Signature of staff 
(End of cycle) 
 
Date 
 
 


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(Stages III N1B/C/D) 
Appendix IV 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


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(Stages III N1B/C/D) 
Appendix V 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on encorafenib and 
binimetinib or 18F-FLT within 28 days of the female patient’s last dose of encorafenib, 
binimetinib or 18F-FLT must be reported in an expeditious manner. The outcome of the 
pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy (including a positive or inconclusive pregnancy test) 
must be reported via CTEP’s Adverse Event Reporting System (CTEP-AERs). 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 
24-hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event. 
• 
The start date of the pregnancy should be reported as the calculated date of conception. 
• 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of 
the CTEP-AERs report. 
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status via CTEP-AERS. 
• 
The decision on whether an individual female patient can continue protocol treatment 
will be made by the site physician in collaboration with the study chair and ECOG-
ACRIN Operations Office – Boston. Please contact the ECOG-ACRIN Operations Office 
– Boston to ask for a conference call to be set up with the appropriate individuals. 
• 
It is recommended the female patient be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling. 


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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-
AERs report if the outcome occurs on the same cycle of treatment as the pregnancy itself. 
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new and 
separate CTEP-AERs report should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects. For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis. 
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
It must be reported via CTEP-AERS as a Grade 4 “Pregnancy Loss” under the System 
Organ Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A pregnancy loss should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A death occurring during the first 28 days after 
birth” that is felt by the investigator to be at least possibly due to the investigational 
agent/intervention. However, for this protocol, any neonatal death that occurs within 28 days 
of birth, without regard to causality AND any infant death after 28 days that is suspected of 
being related to the in utero exposure to encorafenib, binimetinib or 18F-FLT must also be 
reported via CTEP-AERS. It must be reported via CTEP-AERS as a Grade 4 “Death 
neonatal” under the System Organ Class (SOC) “General disorder and administration site 
conditions”. 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
Form.pdf) 


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(Stages III N1B/C/D) 
Appendix VI 
 
Contraception Guidance 
Patients of Childbearing Potential 
A patient 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. 
Patients in the following categories are not considered of child-bearing potential 
1. Premenarchal 
2. Premenopausal patient with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
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 patient’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal patient 
• 
A postmenopausal state is defined as no menses for 24 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 patients not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
24 months of amenorrhea, confirmation with more than one FSH measurement is 
required.  
• 
Patients 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. 
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 patients 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). Patients must agree to use highly effective methods of 


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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: 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
Oral 
• 
Injectable 
• 
Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner (considered highly effective provided the vasectomized 
partner has received medical assessment of surgical success and that the partner is a 
female participant’s sole sexual partner) 
Acceptable birth control methods characterized as having a failure rate of more than 1% per 
year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide


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(Stages III N1B/C/D) 
Appendix VII 
 
EA6183 Binimetinib and Encorafenib Study Drug Request Form Download Instructions 
Downloading the EA6183 Binimetinib and Encorafenib Study Drug Request Form: The 
form is available for download from the EA6183 protocol page located on the CTSU 
members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA6183 
• 
Click on Documents tab, select the Pharmacy tab, and download and complete 
the forms provided. 


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(Stages III N1B/C/D) 
Appendix VIII 
 
EA6183 Collection and Shipping Kit Order Instructions 
 
Specimen Collection/Shipping Kits are being provided by CENETRON CENTRAL 
LABORATORIES and are to be ordered ONLINE. 
Starter kits are not available. Kit requests are to be made after patient registration. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call the 
Cenetron Clinical Trials Group at (512) 439-2000. 
Ordering Process: 
• 
Following registration of the patient to the trial, go to the website 
www.cenetron.com and click on the ‘Order Kits’ button at the top right. It is recommended 
that kits be ordered same day as patient registration. 
• 
The order form is not study specific and can be used for any study. Complete the 
online form as follows: 
• 
Sponsor (REQUIRED): ECOG-ACRIN 
• 
Contact Name (REQUIRED): Name of the institution kit contact.  
• 
Protocol Number (REQUIRED): EA6183 
• 
Phone Number (REQUIRED): Phone number of the kit contact. Please 
ensure that this is a number that can be reached from an external caller 
• 
FAX Number: Fax number of the kit contact 
• 
Investigator: Last name of the kit contact is adequate 
• 
Email (REQUIRED): Email of the institution kit contact. Must be entered 
twice to confirm 
• 
Date Supplies Needed (REQUIRED): Add three (3) business days or 
more to order date. (Reminder that weekends and holidays must also be considered in 
this timeline) 
• 
KIT NAME (REQUIRED): Type in the kit type needed 
• 
EA6183 Collection Kit 
• 
Quantity: 1 
• 
Comments: Provide EA6183 Patient Case ID# and full shipping address 
• 
Patient Case ID =’ ##### 
• 
‘Ship Kit to’ name of the individual to whom the kit is being 
shipped. (May be different than the kit contact provided above) 
• 
Full street address, town, state and zip code 
• 
Answer the security question 
Please complete this form correctly, including the valid ECOG-ACRIN patient case 
number and complete shipping address. If information is missing the kit processing will 
be delayed. 


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(Stages III N1B/C/D) 
Appendix IX 
 
Clinical Trial Wallet Card 
Patients will be given a clinical trial wallet card.  The wallet card is to inform other healthcare 
providers that the patient is participating in a clinical trial.  The card also contains the 
investigator contact information and the investigational drug names.  The sites are to complete 
the wallet card information before providing the Clinical Trial Wallet Card to study patient. 
 
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 #:  EA6183 
Study Drug(S):  Encorafenib, Binimetinib, 
and 18F-FLT 
 
 
 
Version July 2019 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 


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Appendix X 
 
CYP3A4 Inducers and Inhibitors 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as Facts and Comparisons or Lexicomp; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information.  The Principal Investigator should be alerted if the subject is taking any 
agent on these lists. 
List of moderate/ strong CYP3A4 Inducing Agents: 
Carbamazepine 
Phenytoin 
Dexamethasone 
Primidone 
Ethosuximide 
Progesterone 
Glucocorticoids 
Rifabutin 
Griseofulvin 
Rifampin 
Modafinil 
Rifapentine 
Naficillin 
Rofecoxib 
Nelfinavir 
St. John’s Wort 
Nevirapine 
Sulfadimidine 
Oxcarbazepine 
Sulfinpyrazone 
Phenobarbitol 
Tipranavir 
Phenylbutazone 
Troglitazone 
Enzalutamide 
Etravirine 
Mitotane 
Efavirenz 
Bosentan 
List of strong CYP3A4 Inhibitors: 
Amiodarone 
 
Mifepristone 
Cimetidine 
 
Nefazodone 
Ciprofloxacin 
 
Nelfinavir 
Clarithromycin 
 
Norfloxacin 
Delavirdine 
 
Norfluoxetine 
Diethyl-dithiocarbamate 
 
Ritonavir (any ritonavir containing regimen) 
Diltiazem 
 
Roxithromycin 
Erythromycin 
 
Saquinavir 
Fluconazole 
 
Troleandomycin 
Fluvoxamine 
 
Voriconazole 
Gestodene 
 
Warfarin 
Grapefruit or Grapefruit juice 
 
Amprenavir 
Indanvir 
 
Atazanavir 
Itraconazole 
 
Miconazole 
Ketoconazole 
 
Telithromycin 
Mibefradil 
 
Verapamil 
Boceprevir 
 
Idealisib 
Posaconazole 
Cobicistat 
 
Telaprevir 
Conivaptan 


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Appendix XI 
 
Tumor Tissue Biopsy Reimbursement Instructions 
Biopsies performed to obtain research specimens from patients who answer “Yes” to “I agree to 
have one or two research biopsies to collect tissue for known laboratory research studies.” at 
baseline and/or two (2) weeks after treatment are reimbursable at the following research rates 
per biopsy: 
• 
Lymph Node Biopsy with CT Guidance = $1,743.42 
• 
Lymph Node Biopsy with US Guidance = $1,550.20 
• 
Skin Lesion Biopsy with US Guidance = $494.44 
Biopsies that are performed as part of the patient’s standard of care are not eligible for 
reimbursement. 
All sites are eligible for the reimbursement for applicable biopsies regardless of cooperative 
group. 
Prior to performing the research biopsies, the following conditions must be met: 
a. The research rates outlined above are deemed acceptable by the institution’s central 
research office. Costs above these reimbursement rates are not to be billed to the patient or 
patient’s insurance. 
b. The research rate is reported to the institution’s financial office and an account established 
under the designated Investigator’s name. 
Reminder that the site must set up the mechanism for the ‘billing’ of these research 
biopsies. ECOG-ACRIN recommends billing the cooperative group Principal Investigator (PI) 
of the site. Contact your coordinating group’s operations office and ask to whom this 
account should be named 
Expenses for biopsies will be paid only to participating institutions, not to any other persons or 
entities, at the above stated research rates. 
Distribution of the reimbursements requires: 
• 
Submission and receipt of the biopsies via the ECOG-ACRIN Sample Tracking 
System (STS) 
• 
Completion and submission of the EA6183 Biopsy Reimbursement Form 
(Appendix XI, page 2) to the ECOG-ACRIN Operations Office - Boston. 
• 
Supporting documentation, if requested. 
 
 
 
Rev Add2 


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EA6183 Biopsy Reimbursement Form 
This form is to be used to request reimbursements for the performance and submission of the tumor 
tissue biopsies at baseline and two weeks post therapy as outlined in Section 12. Reimbursements are 
NOT applicable for biopsies performed as part of standard of care, and thus billed to patients or their 
insurance. 
If you have questions about the reimbursement 
process, please contact the EA funding team at 
ea.fundingsheet@jimmy.harvard.edu. 
Please fax the completed form to the  
ECOG-ACRIN Translational Science Team (TST),  
FAX: (617) 589-0914 
 
Payee Address 
 
 Payee/W-9 Name: 
      
 
 
Payee Tax ID #: 
      
Attention To: 
      
 
 
 
Institution CTEP ID: 
      
Street Address: 
      
 
Name of Investigator: 
      
 City, State, Zip: 
      
 
NCI Investigator ID #: 
      
 Any Requested Reference on 
Payment (i.e. Invoice #): 
      
 
 
 
ECOG-ACRIN 
Case ID 
Date of 
Service 
Time  
point 
Indicate Service Performed 
Amount 
Requested 
#1 
 
 
Baseline 
 
Lymph Node CT Guidance 
$1743.42 
 
Lymph Node US Guidance 
$1550.20 
 
Skin Lesion US Guidance 
$494.44 
#2 
 
 
Week Two 
 
Lymph Node CT Guidance 
$1743.42 
 
Lymph Node US Guidance 
$1550.20 
 
Skin Lesion US Guidance 
$494.44 
 
I confirm that these patients are registered to the protocol referenced above, the patient numbers and 
procedure dates are correct, and the biopsies were performed for the purposes of the trial only, following 
registration of the patient to the lowest step of the trial, and that the biopsy was NOT standard of care and 
was NOT billed to insurance or the patient 
Signature: ___________________________________________________ Date: _________ 
 
 
 
 
 


ECOG-ACRIN 
EA6183 
Cancer Research Group 
Version Date: August 2, 2021 
131 
 
If there are problems with this invoice, please contact:  
 
Name 
 
Phone 
 
Fax 
 
Email 
 
      
      
      
      
 
ECOG-Operations Office Use Only:      TST Reviewer: ____________________  Date: _____________ 
Patient 
#1 
#2 
Date of Registration to Step 1 
 
 
Registering Institution 
 
 
Data in STS indicates “Not billed to insurance” 
 
 
Performed after patient registered to the trial and time point is consistent 
with protocol. 
 
 
Sample indicated as received by the receiving laboratory in STS 
 
 
Approved 
 
 


ECOG-ACRIN 
EA6183 
Cancer Research Group 
Version Date: August 2, 2021 
132 
A Phase II Neoadjuvant Study of Encorafenib With Binimetinib in Patients With 
Resectable Locoregional Metastases From Cutaneous or Unknown Primary Melanoma 
(Stages III N1B/C/D) 
Appendix XII 
 
Guidelines for Radiopharmaceutical Production Facilities Shipping 18F-FLT to Sites 
1. An existing agreement is required between the Radiopharmaceutical Production Facility 
(RPF) and receiving site. This agreement shall include, at minimum, the RFP’s 
agreement to comply with all existing and applicable Federal, State and local regulations 
for radiopharmaceuticals. 
2. PET drug products leaving the manufacturing site to be shipped to another site, will meet 
all Federal, State and local regulations including but not limited to DOT certified 
radioactive materials shipment regulations. 
3. Passing results for all quality control tests (excluding sterility) and final release 
acceptance criteria will be obtained at the production/shipping site and provided to 
receiving site prior to injection of the radiopharmaceutical.  
4. The receiving site will notify the production/shipping site upon receipt of drug. Expiration 
time will be listed on the drug in compliance with FDA regulations - injection will take 
place prior to expiry. Expiration is specific to each production/shipping site as validated 
in stability testing provided to FDA for review in site specific IND. 
5. In the event that the QC testing and release are performed when the shipment is in 
route, a release form must be received by the study site before the injection can take 
place. In the event that a release form cannot be obtained, either by test failure or other 
factors, the injection must not take place. The radioactive material should be disposed 
following the institutional regulation. 
Rev Add2