A Phase II Study of Binimetinib in Children and Adults With NF1 Associated Plexiform Neurofibromas (PNOC010)
Phase: PHASE2
Conditions: Neurofibromatosis Type 1, Plexiform Neurofibroma
Sponsor: University of Alabama at Birmingham

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Neurofibromatosis (NF) Consortium 
 
 
 
NF PROTOCOL 108 
A Phase II Study of Binimetinib in Children and Adults with NF1 associated 
Plexiform Neurofibromas (PNOC010) 
 
 
 
Sponsored by: 
Department of Defense 
USAMRMC 
And the 
Office of the Congressionally Directed Medical Research Programs (CDMRP)  
 
Supported by: 
Array BioPharma Inc, a wholly owned subsidiary of Pfizer Inc. 
Pacific Pediatric Neuro-Oncology Consortium 
 
 
 
 
 
 
 
 
 
Protocol Chairs 
Sabine Mueller, Chair 
Michael Fisher, Co-Chair 
Alyssa Reddy, Co-Chair 
 
Research Monitor 
Julia Glade Bender, MD 
 
 
 

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PROTOCOL ROSTER 
Study Chair 
Sabine Mueller, MD, PhD, MAS 
University of California, San 
Francisco 
675 Nelson Rising Lane 
Room 402 
San Francisco, CA 94158 
415-476-3831 Phone 
sabine.mueller@ucsf.edu 
Study Co-Chairs 
Michael Fisher, MD 
Children’s Hospital of Philadelphia 
3501 Civic Center Blvd 
Philadelphia, PA 19104 
215-590-2800 Phone 
215-590-4183 Fax 
fisherm@email.chop.edu 
 
Alyssa Reddy, MD 
University of California, San 
Francisco 
550 16th Street 
UC Box 0137 
San Francisco, CA 94758 
415-353-2657 Phone 
Alyssa.Reddy@ucsf.edu 
 Co-Investigators 
Eva Dombi, MD 
National Cancer Institute 
10 Center Drive 
Bldg 10-CRC, 
Rm 1-5750 
Bethesda, MD 20892 
301-451-7023 Phone 
301-402-1734 Fax 
dombie@mail.nih.gov 
NFCTC Operations Ctr PI 
Bruce Korf, MD, PhD 
University of Alabama at 
Birmingham 
1720 2nd Ave So-  KAUL 230 
Birmingham, Alabama  35294 
205-934-9411 Phone 
bkorf@uabmc.edu 
Study Statistician/NFCTC Co-PI 
(Data)  
Gary Cutter, PhD 
Department of Biostatistics 
U. of Alabama at Birmingham 
1667 Univ Blvd - Ryals 410 
Birmingham AL  35243 
205-975-5048 Phone 
cutterg@uab.edu 
 Study Statistician/NFCTC Co-PI 
(Data)  
Lloyd Edwards, PhD 
Department of Biostatistics 
University of Alabama at Birmingham 
1665 Univ Blvd - Ryals 309C 
Birmingham AL  35243 
205-975-0687 Phone 
ljedward@uab.edu 
 
 
Program Director 
Karen A. Cole-Plourde, BS 
University of Alabama at 
Birmingham – Kaul 230 
Birmingham, AL 35294-0024 
205-934-5150 Phone 
kplourde@uab.edu 
Research Compliance Specialist 
Juliette Southworth, BS, CCRP 
The University of Alabama at 
Birmingham – Kaul 230 
Birmingham, AL 35294-0024 
205-975-4075 Phone  
jsouthworth@uab.edu 
Clinical Nurse Manager  
Lynn Merritt, RN 
University of Alabama at Birmingham 
1530 3rd Avenue South – Kaul 230 
Birmingham, AL  35294-0024 
205-934-5376 Phone 
jlynnrn@uab.edu 
Department of Defense 
Kimberly Boelte Pope, PhD 
Science Officer 
General Dynamics Information 
Technology (GDIT) Supporting 
Congressionally Directed Medical 
Research (CDMRP) 
301-619-4006 Phone 
kimberly.b.pope2.ctr@mail.mil 
Research Monitor 
Julia Glade Bender, MD 
Vice Chair for Clinical Research 
Department of Pediatrics 
Memorial Sloan Kettering Cancer 
Center 
1275 York Avenue, New York, NY 
10065 
212-639-6729 Phone 
929-321-7101 e-
Faxgladej@mskcc.org 
 
QOL Chair 
Karin S. Walsh, Psy.D. 
Division of Pediatric Neuropsychology 
| Children's National Medical Center 
Gilbert Neurofibromatosis Institute | 
Brain Tumor Institute 
Associate Professor | Depts of 
Pediatrics and Psychiatry 
The George Washington University 
Medical Center 
111 Michigan Avenue NW WP1066 | 
Washington, DC 20010 
202-476-3923 Phone  
kwalsh@ChildrensNational.org  

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Data Manager – UAB  
Steve Powell, PhD 
Biostatistician NFCTC  
Ryals Public Health 514F 
University of Alabama at 
Birmingham  
1720 2nd Avenue South  
Birmingham, AL 25294 
205-934-9463 Phone  
powells@uab.edu 
Data Manager – UAB  
Coretta Thomas, MPH 
Ryals Public Health 507F 
University of Alabama at Birmingham  
1720 2nd Avenue South  
Birmingham, AL 25294 
205-934-8629 Phone 
coretta@uab.edu 
 
 
Participating Sites: 
 
Bruce Korf, MD, PhD 
University of Alabama at Birmingham 
1720 2nd Ave So-  KAUL 230 
Birmingham, Alabama  35294-0024 
Phone:  205-934-9411/Fax: 205-934-9488 
bkorf@uabmc.edu 
 
 
*Michael Fisher, MD 
Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard 
Philadelphia, PA 19096 
Phone:  215-590-2800 
fisherm@email.chop.edu 
 
 
*Roger Packer, MD 
Children’s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone:  202-884-2120 
rpacker@cnmc.org 
 
Wade Clapp, MD 
Indiana University  
1044 West Walnut Street  
Cancer Center, Room 402A  
Indianapolis, IN  46202 
Phone: 317-278-9290 
dclapp@iu.edu 
 

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*Tena Rosser, MD 
Children’s Hospital Los Angeles 
300 Medical Plaza Box 696824 
Los Angeles, CA  90095 
Phone: 323-361-2471 
trosser@chla.usc.edu 
 
 
Elizabeth Schorry, MD  
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue - ML 4006 
Cincinnati, OH  45229 
Phone:  513-636-4760 
elizabeth.schorry@cchmc.org 
 
James Tonsgard, MD 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488 
tonsgard@midway.uchicago.edu 
 
*David Viskochil, MD, PhD 
University of Utah 
50 North Medical Drive – 2C412 SOM 
Salt Lake City, UT  84132 
Phone:  801-581-8943 
dave.viskochil@hsc.utah.edu 
 
 
 
*Amy Armstrong, MD 
Washington University School of Medicine 
660 South Euclid Avenue – Box 811 
St. Louis, MO  63110 
Phone: 314-362-7379  
gutmannd@neuro.wustl.edu 
 
Jeffrey Allen, MD 
New York Univ. Pediatrics 
160 E. 32nd Street – 2nd Floor 
Hassenfeld Children’s Center 
New York, NY 10016 
Phone: 212-263-9907 
Jeffrey.Allen@nyumc.org  
 
 
 

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Nicole Ullrich, MD, PhD 
Children’s Hospital Boston – Dept. of Neurology 
300 Ongwood Avenue – Fegan 11 
Boston, MA  02115 
Phone: 617-355-2066 
Nicole.Ullrich@childrens.harvard.edu 
 
Brigitte Widemann, MD 
National Institutes of Health – NCI  
10 Center Drive; Building 10-CRC: Room 1-5750 
MSC 
Bethesda, MD  20892 
Phone: 301-496-7387Widemanb@mail.nih.gov 
 
 
 
Affiliate NF Consortium Sites 
*Massachusetts General Hospital (Ullrich; Plotkin) 
*Dana Farber Cancer Institute (Ullrich) 
UCLA (Rosser; Silva) 
*Johns Hopkins (Packer; Blakeley) 
*Ohio State University (Schorry) 
*Lurie Children's Hospital of Chicago (Tonsgard; Listernick, Goldman and Wannders) 
 
Affiliate Study Sites 
PNOC Site: University of California, San Francisco (Mueller) 
PNOC Site: University of Washington/Seattle Children’s Hospital (Leary) 
PNOC Site: University of California, San Diego/Rady Children’s Hospital (Crawford) 
PNOC Site: Nationwide Children’s Hospital (AbdelBaki) 
PNOC Site: Oregon Healthy and Sciences University (Nazemi) 
 
* PNOC Site as well 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study DSMB 
Amy A. Smith, MD - Chair 
Orlando Health 
Amy.Smith@orlandohealth.com  
 
Adam Levy, MD 
Professor of Pediatrics 
Montefiore Medical Center 
Albert Einstein College of Medicine 
ADLEVY@montefiore.org  
 
John M. Kittelson PhD 
Professor of Biostatistics 
Colorado School of Public Health 
John.Kittelson@ucdenver.edu   
 
  
 
ROLES AND RESPONSIBILITY OF STUDY PERSONNEL 
 
Sabine Mueller, MD PhD MAS:  Study PI, Protocol Chair 
Michael Fisher, MD:  Protocol Co-Chair 
Alyssa Reddy, MD: Protocol Co-Chair  
Roger Packer, MD: Executive Director of NF Consortium, oversight of trial coordination  
Bruce Korf, MD, PhD:  NF Consortium PI 
Gary Cutter, PhD: Biostatistician & Co-PI NF Operations Center 
Lloyd Edwards, PhD: Biostatistician & Co-PI NF Operations Center 
Julia Glade Bender, MD: Research Monitor 
Eva Dombi, MD: Volumetric MRI analysis of plexiform neurofibromas on protocol 
Karin Walsh, PsyD: Quality of life and pain surveys 
Lynn Merritt, RN:  Clinical Coordinator – NF Operations Center 
Karen Cole-Plourde, BS:  Program Director – NF Operations Center 
Juliette Southworth, BS, CCRP:  Research Compliance Manger – NF Operations Center  
Steve Powell, PhD:  Biostatistician - NF Operations Center  
Coretta Thomas Robinson, BA, MPH: Data Manager – NF Operations Center 

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Table of Contents 
Protocol Roster.............................................................................................................................................. 2 
Roles and Responsibility of Study Personnel ............................................................................................... 6 
Experimental Design Schema ..................................................................................................................... 11 
1.0 
Goals and Objectives (Scientific Aims) ......................................................................................... 12 
1.1 
Primary Aim ...................................................................................................................................... 12 
1.2 
Secondary Aims ............................................................................................................................... 12 
1.3 
Exploratory Aims ............................................................................................................................ 12 
2.0 
Background and Rationale ............................................................................................................. 12 
2.1 
Neurofibromatosis Type 1 and Plexiform Neurofibromas ............................................. 12 
2.2 
Binimetinib ........................................................................................................................................ 13 
2.3 
Pharmacokinetics and Dosing of binimetinib ...................................................................... 14 
2.4 
Patient Reported Outcomes ........................................................................................................ 15 
2.5 
Cytokine and Plexiform Neurofibroma .................................................................................. 15 
2.6 
Volumetric Assessment of Plexiform Neurofibroma Size ............................................... 16 
2.7 
Overview of Proposed Study ...................................................................................................... 17 
3.0 
Screening and Study Enrollment Procedures ................................................................................. 17 
3.1 
Informed Consent/Assent ........................................................................................................... 17 
3.2 
Screening Procedures .................................................................................................................... 18 
3.3 
Study Enrollment ............................................................................................................................ 18 
4.0 
Patient Eligibility ........................................................................................................................... 18 
4.1 
Inclusion Criteria for all subjects: ............................................................................................. 18 
4.2 
Exclusion Criteria ............................................................................................................................ 21 
5.0 
Required Data ................................................................................................................................ 23 
5.1 
Tests and Observations ................................................................................................................ 25 
5.2 
Records to be Kept.......................................................................................................................... 25 
5.3 
Role of Data Management ............................................................................................................ 26 
6.0 
Treatment Program ........................................................................................................................ 26 
6.1 
Agent Information/ binimetinib ............................................................................................... 26 
6.2 
Treatment Overview ...................................................................................................................... 29 
6.3 
Criteria for Starting Subsequent Courses .............................................................................. 30 
7.0 
Supportive Care and Other Concomitant Therapy ......................................................................... 30 
7.1 
Supportive Care ............................................................................................................................... 30 
7.2 
Growth Factors ................................................................................................................................ 30 
7.3 
Surgery ................................................................................................................................................ 31 
7.4 
Management of Hypertension, Skin Toxicity, and Nausea and Vomiting ................. 31 
7.5 
Concomitant Medications ............................................................................................................ 32 
8.0 
Modifications for Adverse Events ................................................................................................. 32 
8.1 
Grading of common adverse events for MEK inhibitors .................................................. 33 
8.2 
Binimetinib dose modification guidelines............................................................................. 35 
8.3 
Criteria for dose-modification in case of suspected binimetinib toxicity and re-
initiation of treatment ................................................................................................................................. 37 
8.4 
Toxicities Requiring Removal from Protocol Therapy ..................................................... 40 
9.0 
Evaluations/Material and Data to be Accessioned ......................................................................... 40 
9.1 
Required Clinical, Laboratory and Disease Evaluation .................................................... 40 
9.2 
History and physical examination and vital signs .............................................................. 41 

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9.3 
Ophthalmological Toxicity Exam .............................................................................................. 41 
9.4 
Hematology ....................................................................................................................................... 42 
9.5 
Blood chemistry ............................................................................................................................... 42 
9.6 
Serum or Urine Pregnancy Test ................................................................................................ 43 
9.7 
ECHO (or MUGA) and ECG ........................................................................................................... 43 
9.8 
MRI for volumetric analysis of plexiform neurofibroma (Appendix IV) ................... 43 
9.9 
Photographs and Functional Evaluations (Appendix XVI) ............................................. 44 
9.10 
Plexiform Neurofibroma Clinician Morbidity Assessment (Appendix XI) ............... 44 
9.11 
Binimetinib diary (Appendix V) ................................................................................................ 44 
9.12 
Plasma Cytokines and Growth Factors (Optional) (Appendix VII).............................. 45 
9.13 
Biological Specimens for banking (Appendix XXI) ............................................................ 45 
9.14 
Baseline PN location and morbidity form (Appendix X) ................................................. 46 
9.15 
Symptom checklist completed by subject or their guardian (Appendix IX) ............ 46 
9.16 
Patient-reported Outcomes (PROs): Quality of Life (QOL) and Pain Evaluations 
(Required) ........................................................................................................................................................ 46 
10.0 
Adverse Reporting Requirements .................................................................................................. 48 
10.1 
Definitions.......................................................................................................................................... 48 
10.2 
Common Terminology Criteria for Adverse Events (CTCAE) V.4.03 .......................... 48 
10.3 
Attribution: Definitions of relationship to study medication are as follows: .......... 48 
10.4 
Reporting Procedures for All Adverse Events ..................................................................... 49 
10.5 
Expedited Reporting Guidelines ............................................................................................... 49 
10.6 
Reporting of Protocol Violations/Deviations and Unanticipated Problems ............ 51 
11.0 
Criteria for Removal From Protocol Therapy and Off Study Criteria ........................................... 52 
11.1 
Criteria for Removal from Protocol Therapy ....................................................................... 52 
11.2 
Off Study Criteria ............................................................................................................................. 52 
12.0 
Statistical and Ethical Considerations ............................................................................................ 53 
12.1 
Subject Accrual ................................................................................................................................. 53 
12.2 
Statistics and Feasibility ............................................................................................................... 53 
12.3 
Statistical Analysis Plan ................................................................................................................ 53 
12.4 
Definitions of Evaluable................................................................................................................ 56 
13.0 
Response Criteria ........................................................................................................................... 56 
14.0 
Human Subjects Protection & Data Safety Monitoring Plan ......................................................... 57 
15.0 
References ...................................................................................................................................... 60 
Appendix I: Schedule of Evaluations .......................................................................................................... 62 
Appendix II: Performance Status Scales/Scores ......................................................................................... 64 
Appendix III:  NIH Consensus clinical Defintion of Neurofibromatosis ................................................... 65 
Appendix IV:  Protocol for Required Pre-Study and On-Study MRI Studies ............................................ 66 
Appendix IVa:  MRI eligibility form .......................................................................................................... 69 
Appendix V: Subject Diary On binimetinib Protocol ................................................................................. 70 
Appendix VI: Information on possible drug interactions ........................................................................... 74 
Appendix VII: Pharmacodynamic Studies .................................................................................................. 77 
Appendix VIII:  Consortium QOL and Pain Measures ............................................................................... 78 
Appendix IX: Plexiform Neurofibroma Symptom Checklist ..................................................................... 86 
Appendix X:  PN Location and Associated Morbidities ............................................................................. 89 
Appendix XI: Plexiform Neurofibroma Clinician Morbidity Assessment ................................................. 91 
Appendix XII: Functional Ophthalmology Evaluation for Orbital PN ....................................................... 93 
Appendix XIII: Motor/Strength Evaluations .............................................................................................. 95 
Endurance Evaluation ............................................................................................................................... 95 

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Range of Motion Evaluation ................................................................................................................... 98 
Leg Length Evaluation............................................................................................................................ 100 
Grooved Pegboard Test .......................................................................................................................... 101 
Appendix XIV: Bladder and Bowel Patient Questionnarie ...................................................................... 103 
Appendix XV: Functional hearing Evaluation for PN that compress the ear canal, cause hearing loss, or 
potentially can cause hearing loss ............................................................................................................. 105 
Appendix XVI: Photography of Visible PN ............................................................................................. 107 
Appendix XVII: Blood Pressure Norms for Subjects < 18 Years of Age ................................................ 108 
Appendix XVIII: Instructions for preparation of MEK162 (binimetinib) Oral Suspension ..................... 110 
Appendix XIX: Pediatric dosage of binimetinib (MEK162) for liquid suspension .................................. 113 
Appendix XX: Pediatric dosage of binimetinib (MEK162) for tablets .................................................... 114 
Appendix XXI:  Biological Specimen for Banking  – Collection and Shipping ...................................... 115 
 
 
 

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ABSTRACT/SCHEMA 
 
Background 
 
• 
Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the 
peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath 
tumors that are among the most debilitating complications of NF1. There are no standard treatment 
options for PN other than surgery, which is often difficult due to the extensive growth and invasion 
of surrounding tissues.  
• 
The Mitogen-activated Protein Kinase (MAPK) pathway is important for plexiform neurofibroma 
growth. 
• 
Phosphorylated Extracellular signal-regulated protein kinase (p-ERK) is detected in human 
plexiform neurofibromas at higher levels than normal human nerve. 
• 
The Dhh-Cre;Nf1fl/fl mouse model develops plexiform neurofibromas, and these tumors 
histologically mimic those of human plexiform neurofibromas [1]. 
• 
Elevated phosphorylated (p)-ERK1,2 was detected in Nf1fl/fl;Dhh-cre mouse neurofibromas 
relative to Nf1fl/fl;Dhh-cre or wild type mouse nerve. 
• 
Binimetinib is an ATP-uncompetitive inhibitor of MEK1/2 currently in clinical cancer trials that 
blocks MAPK signaling.  
 
Primary Objective 
• 
To determine the proportion of children and adults with NF1 associated plexiform neurofibromas 
who will have an objective response to binimetinib defined as a 20% or greater decrease in tumor 
volume reduction by 12 courses.   
Secondary Objectives 
• 
To evaluate the feasibility and toxicity of protracted binimetinib administration in this patient 
population. 
 
Exploratory Aims 
• 
To evaluate the effect of binimetinib on quality of life and pain.  
• 
To validate the NRS-11, which has been adapted to assess pain intensity in individuals with NF1 
and plexiform neurofibromas, for use in this patient population 
• 
To characterize the effect of binimetinib on plasma cytokines and growth factors 
• 
To determine whether subjects who respond will maintain that response for 1 year once they come 
off therapy. 
• 
To estimate the objective response rate of up to 2 non-target plexiform neurofibromas to 
binimetinib by MRI. 
• 
To evaluate the effect of binimetinib on functional outcomes depending on PN location, such as 
vision, motor, disfigurement, bowel/bladder 
• 
To obtain blood and tumor tissue to be stored for future PN biological studies 
• 
To compare the volumetric assessment of plexiform neurofibroma response to therapy performed 
by two independent analysts using different volumetric analysis methods. 
• 
To evaluate the likelihood of response and prolonged disease stabilization rate to binimetinib in 
participants with recurrent, progressive PN who previously responded to binimetinib.   
 
Eligibility 
• 
Patients >1 year of age with NF1 and PN(s) that are progressive by serial imaging OR causing 
significant morbidity, and that can be analyzed by volumetric MRI.  

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Design 
• 
Binimetinib starting dose was initially 45 mg per dose (the adult RP2D) orally twice daily in the 
adult stratum (Stratum A) but was reduced (since protocol version 2.0) to 30 mg per dose twice 
daily.  The starting dose in the pediatric stratum (Stratum B) is 32 mg/m2 per dose (maximum 
45mg per dose), which has been established as the pediatric RP2D by NCT02285439 (PI: 
Robison). Dosing will be continuous, with 28 days defined as a course, and will continue for a 
total of 24 courses or until one of the Off Treatment or Off Study criteria are met. 
• 
Subjects will undergo volumetric assays of their target PN using MRI after every 4 courses for 
the first year and then every 6 courses. Review of the volumetric analysis will occur centrally at 
the NCI under the guidance of Dr. Dombi. 
• 
Treatment beyond course 12 will only be given to those subjects who achieve a response (≥ 20% 
tumor shrinkage by volumetric analysis) by the end of course 12, and will be continued for a 
maximum of 24 total courses. Subjects will be removed for significant toxicity, treatment delay ≥ 
28 days, or objective progression (≥ 20% tumor growth by volumetric analysis) at any time. 
 
 
EXPERIMENTAL DESIGN SCHEMA 
 
 
 

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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim 
• 
To determine the proportion of children and adults with NF1 associated plexiform neurofibromas 
who will have an objective response to binimetinib defined as a 20% or greater decrease in tumor 
volume reduction by 12 courses. 
 
1.2 
Secondary Aims 
• 
To evaluate the feasibility and toxicity of protracted binimetinib administration in this patient 
population. 
 
1.3 
Exploratory Aims 
• 
To evaluate the effect of binimetinib on quality of life and pain.  
• 
To validate the NRS-11, which has been adapted to assess pain intensity in individuals with NF1 
and plexiform neurofibromas, for use in this patient population 
• 
To characterize the activity of binimetinib on plasma cytokines and growth factors 
• 
To determine whether subjects who respond will maintain that response for 1 year once they 
come off therapy. 
• 
To estimate the objective response rate of up to 2 non-target plexiform neurofibromas to 
binimetinib by MRI. 
• 
To evaluate the effect of binimetinib on functional outcomes depending on PN location, such as 
vision, motor, disfigurement, bowel/bladder. 
• 
To obtain blood and tumor tissue to be stored for future PN biological studies. 
• 
To compare the volumetric assessment of PN response to therapy performed by two independent 
analysts using different volumetric analysis methods 
 
• 
To evaluate the likelihood of response and prolonged disease stabilization rate to binimetinib in 
participants with recurrent, progressive PN who previously responded to binimetinib.   
 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Neurofibromatosis Type 1 and Plexiform Neurofibromas 
Neurofibromatosis type 1 (NF1) is a common autosomal dominant, genetic disorder with an incidence of 
1:3000.  NF1 is caused by a mutation in the NF1 tumor suppressor gene. NF1 is characterized by diverse, 
progressive cutaneous, neurological, skeletal, and neoplastic manifestations. Patients with NF1 have an 
increased risk of developing tumors of the central and peripheral nervous system including plexiform 
neurofibromas, which are benign peripheral nerve tumors. These tumors may cause significant morbidity 
including disfigurement and pain and may be life-threatening when they compress vital structures such as 
the spinal cord, trachea, and great vessels. 
The only proven treatment for plexiform neurofibromas is surgical removal; however, this is rarely 
achieved because of the infiltrative nature of the tumor and the high-risk of neurological morbidity. There 
is no currently accepted effective drug therapy for plexiform neurofibromas. A number of medical 
treatments including thalidomide 9, cis-retinoic acid, interferon alpha 2b [2, 3], methotrexate and 
vinblastine, PEG interferon alpha-2b [4], the farnesyltransferase inhibitor tipifarnib (R115777) [5, 6], the 
antifibrotic agent pirfenidone [7, 8], the RAF kinase inhibitor Sorafenib [9], the cKIT inhibitor Gleevec 
[10], and the mTOR inhibitor Sirolimus have been evaluated but to date no medical treatment has reliably 
resulted in objective radiographic response of plexiform neurofibromas. 

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NF1 encodes the tumor suppressor neurofibromin, a Ras-GTPase activating protein that converts active 
Ras-GTP to inactive Ras-GDP [11, 12]. In benign and malignant peripheral nerve tumors, cells acquire 
somatic inactivation of a second NF1 allele, with loss of neurofibromin function resulting in elevated 
levels of active Ras-GTP [13]. Aberrant Ras signaling promotes tumor cell proliferation and survival [14].  
Research focused on the biology of NF1 and pathogenesis of plexiform neurofibroma has identified 
potential therapeutic targets including Ras itself, Ras effectors, tumor microenvironment, and 
angiogenesis.  
 
The PI3K/AKT/mTOR pathway, known to regulate cellular proliferation and survival, has been 
implicated in NF1 tumorigenesis [15]. However, preclinical studies in Nf1fl/fl;Dhh-Cre mice with PN 
treated with the rapamycin analog everolimus failed to block tumor growth, and the multikinase inhibitor 
sorafenib affected only 5 of 9 (56%) mice [9]. A Phase I trial of sorafenib failed due to dose limiting 
toxicities of pain and mood changes in NF1 patients with PN [16], and a phase II trial of rapamycin in 
plexiform neurofibromas was not effective in shrinking non-progressive plexiforms [17], and modestly 
prolonged the time to progression of progressive PN. 
 
To date, no chemotherapeutic approach blocking any molecular target, including tyrosine kinases 
upstream of Ras, Ras itself, or Ras effectors has consistently prevented or arrested neurofibroma 
formation [18] . 
 
A recent preclinical study by Jessen and colleagues represents the most dramatic result described to date 
for treatment of neurofibroma bearing mice [19]. In this study, cross-species transcriptome analyses of 
mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate 
Ras-Raf-MEK-ERK signaling in both species. Nonetheless, activation of ERK was sustained in mouse 
and human neurofibromas. PD0325901, a highly selective pharmacological inhibitor of MEK, was used 
to test whether sustained Ras-Raf-MEK-ERK signaling contributed to neurofibroma growth in the 
Nf1fl/fl;Dhh-cre mouse model [19]. PD0325901 demonstrated remarkable effect, with reduction of 
aberrantly proliferating cells in neurofibromas and shrinkage of neurofibroma tumors in 39/49 (>80%) of 
mice tested. PD0325901 also caused effects on tumor vasculature. Similarly, dramatic responses to 
PD0325901 were seen in a murine model of juvenile myelomonocytic leukemia (JMML) characterized by 
homozygous Nf1 inactivation [19]. Together, these data provide a strong rationale for targeting MEK in 
the treatment of NF1-associated neoplasms in patients. 
 
Indeed, results from a recent Phase I trial of MEK inhibitor AZD6244 in children with plexiform 
neurofibromas demonstrates an early efficacy signal in this population with partial responses (PN volume 
decrease of ≥ 20%) in 71% of evaluable subjects [20]. A Phase II trial is currently ongoing that also 
includes functional outcome measures as part of the overall benefit analysis of this therapeutic approach 
(NCT02407405).  
 
2.2 
Binimetinib 
 
Binimetinib (also known as MEK162 or ARRY-438162) is a potent, selective, allosteric small-molecule 
inhibitor of MEK that is uncompetitive with adenosine triphosphate (ATP). Binimetinib is currently being 
evaluated clinically in healthy subjects and in cancer patients.  
 
In cell-free systems, binimetinib inhibits MEK1/2 with an IC50 of 12 nM. In vitro, binimetinib potently 
inhibits MEK dependent phosphorylation of ERK in human BRAF-mutant melanoma cell lines, including 
A375, IGR-1, IGR-39, Colo-800, MDA-MB-435S, RPMI-7951, UACC-62, and WM-115, as well as 
NRAS-mutant melanoma lines, such as IPC-298, Hs944.T, MEL-JUSO, SK-MEL-2, and SK-MEL-30. In 
vivo, binimetinib treatment results in dose- and time-dependent inhibition of phosphorylation of ERK in 

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the HT-29 human colorectal carcinoma xenograft. Similarly, levels of both pERK and DUSP6 mRNA (a 
target gene of phosphorylated ERK) are reduced in the A375 melanoma xenograft. Lastly, in ex vivo 
experiments, binimetinib reduces pERK levels in human whole blood cells (Investigator Brochure (IB) 
version 12.1). 
2.3 
Pharmacokinetics and Dosing of binimetinib 
The oral bioavailability (F) in rat and monkey absorption, distribution, metabolism and excretion 
(ADME) studies is moderate (48%) and similar to the fraction absorbed (based on radioactivity excreted) 
suggesting a minimal first pass effect. Binimetinib shows a low total systemic plasma clearance and 
volume of distribution at steady state after intravenous (IV) administration. Mean plasma terminal half-
life (T1/2) ranges from 2 to 9 hours in preclinical species. 
In vitro experiments indicate that binimetinib has moderate to high membrane permeability and is a 
substrate of P-gp and BCRP. 
Binimetinib is highly bound to plasma proteins (humans: 97.2%). 
Binimetinib is more distributed in plasma than blood. The blood-to-plasma concentration ratios of 
binimetinib ranges from 0.652 to 0.994 in the species tested. In humans, the blood-to-plasma ratio is 
0.718. 
[14C]-binimetinib-derived radioactivity is absorbed and widely distributed to tissues in both pigmented 
rats and albino rats following a single oral (PO) dose. 
With multiple routes of metabolism, binimetinib is metabolized primarily by glucuronidation pathways 
(mainly via UGT1A1, 1A3 and 1A9) and to a lesser extent by oxidation pathways (mainly via CYP1A2 
and 2C19). UGT1A1 was shown to be the major contributor (90%) to the formation of the direct 
glucuronide. 
Following IV dosing in the rat, fecal and urinary excretion accounts for 46% and 45% of total 
radioactivity, respectively. Approximately 15% of binimetinib is excreted unchanged in urine and 16 % in 
feces. Total recovery of radioactivity in the excreta of monkey is 99% and 85% following PO and IV 
dosing, respectively. The most abundant drug-related components in monkey excreta included 
binimetinib, the 2 glucuronides and the amide. 
In vitro, binimetinib reversibly inhibits CYP2B6 and is a weak reversible inhibitor of CYP1A2 and 
CYP2C9. Binimetinib is not considered a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or 
CYP3A4/5. Binimetinib induces CYP3A, but this was not confirmed in a human DDI study (please see 
Investigator’s Brochure). 
Preliminary findings from a phase I portion of a phase I/II study of Binimetinib for children with low 
grade glioma (NCT02285439) are as follows: 19 children were enrolled on the phase I study, 18 of whom 
were DLT-evaluable. Three DLT-evaluable participants were enrolled and treated at each dose level from 
1 through 4, and 6 DLT-evaluable participants at dose level 5 (32mg/m2/dose bid). No DLTs were 
observed during the DLT evaluation period in any participant. Preliminary analysis of initial 
pharmacokinetic data showed that the pediatric AUC and Cmax values at 32mg/m2/dose were similar to 
corresponding values in adult patients at the adult RP2D of 45 mg/dose bid. Based on these findings, the 
convened study committee determined 32mg/m2/dose bid to be the pediatric RP2D for the phase II 
portion of the low-grade glioma study. 

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2.4 
Patient Reported Outcomes 
 
Although PN growth can be variable and unpredictable, we know that early adolescence through young 
adulthood is a critical period for the accelerated growth of neurofibromas [4, 21]. In fact, neurofibromas 
can continue to grow into later adulthood and continue to significantly impact health-related quality of 
life (HRQOL) of individuals with NF1. Participants of NF1 clinical trials traditionally undergo objective 
imaging and examination follow up to monitor changes in clinical symptoms. Volumetric MRI has 
become a standard imaging modality to measure tumor response. However, defining response solely from 
imaging of tumor size is difficult, as neurofibromas have irregular shapes and may be fibrotic; thus, with 
treatment, imaging may not always show a significant decrease in tumor size despite a clinically 
significant improvement in symptoms. Patients with little tumor shrinkage have reported large 
improvements in functioning and well-being that could be measured with a NF1-specific HRQOL 
instrument [21, 22]. As such, NF1-specific HRQOL instruments have been incorporated in all NF 
Consortium plexiform neurofibroma trials. With the above logic in mind, we include adults in this clinical 
trial, with complementary endpoints of imaging response measured via volumetric MRI and validated 
NF1-specific HRQOL assessments (including pain assessments) as well as functional assessments of 
vision and motor function to enhance our ability to assess the utility of this new therapy paradigm.  
 
2.5 
Cytokine and Plexiform Neurofibroma  
 
Neurofibromas are complex tumors, containing 
not only Schwann cells and vasculature, but 
also hematopoietic cells including mast cells 
and macrophages. Recent data from the Ratner 
lab [23] indicate that roughly 30% of 
neurofibroma cells are macrophages. Based on 
this finding, we hypothesized that patient 
plasma contains growth factors/cytokines that 
attract these hematopoietic cells to 
neurofibromas. Such factors could be 
biomarkers of tumor burden and/or play roles 
in tumor growth, or response to therapy. 
Figure 1. Iba1+ macrophages in nerve and 
neurofibroma. (A) Staining of paraffin sections 
with anti-Iba1 (brown) to mark macrophages. 
GEM genetically engineered mouse model. (B) 
Quantification of Iba1+ macrophages per high-
powered field (hfp) (*p=0.001). Averages from 
individual mice are shown as individual dots. 
(C) Staining of Dhh-Cre; Nf1fl/fl sciatic nerve 
sections with anti-Iba1 to mark macrophages 
(red) and with anti-GFP to mark Schwann cells 
(green). (D) M2 macrophages are rare in Nf1- 
deficient nerves and tumors. Iba1 (brown) and 
CD163 (purple) in paraffin sections. Green 
arrowheads show rare double-labeled cells. In 
all other cases, cells are single labeled. (E) Staining of human plexiform neurofibroma (PNF) and 
malignant peripheral nerve sheath tumor (MPNST) paraffin sections with anti-Iba1 (brown) to mark 
macrophages. (F) Average numbers of Iba1+ cells in human neurofibroma and MPNST. (G) FACS 

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shows populations of CD11b cells (macrophages) isolated from human neurofibromas after in vitro 
culture; table presents quantification. Scale bar in Fig. 1. 
Cytokines, chemokines, 
and growth factors mediate 
and regulate immunity and 
inflammation, which are 
an important component of 
the tumor 
microenvironment 
contributing to tumor 
initiation and growth. 
These factors may also be 
useful as biomarkers tumor 
response. The literature shows that multiple cytokines/growth factors are altered in subjects with 
plexiform neurofibromas. In our mouse model of NF1, our unpublished filter-based multiplex detection 
data shows that the cytokine levels are associated with tumor progression and responsiveness to MEK 
inhibition (not shown) and PEG-Interferon therapy in mice (Choi et al., submitted; Figure 2). Pro-
inflammatory cytokines in Neurofibroma (a) Left panel: Pro-inflammatory cytokines are at low levels 
in wild-type nerve (top), show increased protein levels in neurofibroma (middle), and are reduced after 
treatment of neurofibroma with PEGylated IFN-2b (bottom). Right panel: Relative intensity, reflecting 
comparative levels of expression for each protein, after the intensity of pixels was averaged and plotted. 
Multiplex analysis permits the characterization of groups of cytokines/chemokines/growth factors in a 
single sample. Because cytokines operate in integrated networks, a more complete understanding will be 
gained as multiple cytokines can be examined for patterns of response associated with response to 
therapy. 
 
The Luminex is a high throughput multiplexing suspension array system. It enables the simultaneous 
quantitation of groups of cytokines and mediators in a single human, sample (i.e. serum/plasma), using 
magnetic beads that are coupled to antibodies. This assay is particularly useful for measurement of 
mediators/cytokines in small samples.  
 
This Plasma biomarker panel (cytokine/chemokine/growth factor) simultaneously quantifies thirty soluble 
cytokines and growth factors including: VEGF, TGF-β, PDGF-AB/BB, MCP-1, MIP1α, MIP1β, TNFα, 
GM-CSF, EGF, IL-13, IL-1rα, IL-10, IL-4, IL6, FGF-2, and RANTES. The assay has large a dynamic 
range of 0.2 -10,000 pg. The multiplex assay will be performed according to the manufacturer’s protocol 
(Millipore Milliplex, Billerica, MA) and analyzed on a Luminex 100 cytometer with StarStation software 
(Luminex Corp, Austin, TX).  
2.6 
Volumetric Assessment of Plexiform Neurofibroma Size 
PNs are complex-shaped and slow-growing peripheral nerve sheath tumors that are challenging to 
measure by simple linear measurements. Automated volumetric MRI analysis can sensitively and 
reproducibly detect small changes in PN size, and it has become the measurement method of choice to 
determine tumor response and time to disease progression in recent clinical trials. There are two volume 
segmentation methods optimized for PN measurement, MEDx developed at the National Cancer Institute 
(NCI) and 3DQI used by the Tumor Imaging Metrics Core at Massachusetts General Hospital (MGH). 
The NF Clinical Trials Consortium has utilized MEDx in all its PN trials. In a small, retrospective study 
volume measurements and volume changes over time were compared using these two different methods 
and found good agreement. The goal is to prospectively evaluate a larger cohort of clinical trial 

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participants to further define the level of agreement in volume measurements, disease status 
classifications, and objective response rates between MEDx and 3DQI. 
2.7 
Overview of Proposed Study 
 
This phase II open label study will evaluate children ≥ 1 year of age and adults with neurofibromatosis 
type-1 (NF1) and plexiform neurofibromas treated with the MEK inhibitor binimetinib. The primary aim 
of the study will be to assess quantitative radiographic response in a target lesion. Initially, adult subjects 
(Stratum A) received binimetinib by mouth on a BID dosing schedule of 45mg/dose (the established adult 
RP2D). Because 4 of the first 11 enrolled subjects chose to remove themselves from study for 
“intolerable” skin adverse events (AE’s) at the 45 mg BID dosing, the starting dose for the adult stratum 
is reduced to 30 mg BID in Protocol Version 2.0.  Pediatric subjects (Stratum B) will be treated on a BID 
dosing schedule of 32 mg/m2, which has been established as the pediatric RP2D by study NCT02285439; 
maximum dose will be 45mg/dose (which corresponds to the adult MTD). Given the difference in the 
clinical behavior of plexiform neurofibromas in the adult and pediatric setting, Stratum A and B will be 
analyzed independently. Each course is 4 weeks duration. Subjects who have a 20% or greater reduction 
in target tumor volume at the end of 12 courses can continue on therapy for up to an additional year 
(maximum of 24 total courses). However, subjects who do not achieve at least 20% reduction in volume 
of the target tumor after 12 courses will be considered treatment failures and taken off study. Of note, 
subjects may begin course 13 while central MRI tumor response evaluations are pending.  
 
Subjects entered on the trial will be carefully monitored for the development of binimetinib associated 
toxicities. Stopping and modification rules for toxicity are outlined in section 8.  
 
Since plexiform neurofibromas may significantly impact the lives of patients with NF1[24], this study 
will evaluate the effects of the disease and treatment with binimetinib on the quality of life (QOL) and 
pain of subjects. Involvement in this part of the study will be required.  
 
For subjects who respond to binimetinib (≥20% tumor volume reduction of target lesion by 12 courses), an 
MRI scan of the target lesion must be performed at 4 and 12 months after stopping drug (as long as the 
subject is still on protocol) in order to determine whether response is maintained post-therapy. These studies 
will not be requested from subjects who experience disease progression (> 20% tumor growth or increase 
of target lesion) while on study drug. 
 
As of Protocol version 3.0, study participants who completed 24 courses of binimetinib and discontinued 
treatment at that time per protocol, but subsequently have tumor progression (>20% increase in volume) 
within one year of therapy completion, will be allowed to restart binimetinib at the same dose they were 
receiving at the end of the initial 24 courses, on the Re-Treatment Arm of the study. 
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
The NF Operations Center should be contacted to ensure availability of a treatment slot. 
 
3.1 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
subject or the subject’s parent(s) or guardian if the subject is a child, and a signed informed consent and 
assent will be obtained according to institutional and federal guidelines. In addition, study participants 
should sign the institution’s HIPAA Consent if not already included in the study consent document. 

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3.2 
Screening Procedures 
 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be 
done after obtaining written informed consent. Documentation of the informed consent for screening will 
be maintained in the subject’s research chart. Studies or procedures that were performed for clinical 
indications (not exclusively to determine eligibility) may be used for baseline values even if the studies 
were done before informed consent was obtained. 
 
Before the subject can be enrolled, the responsible institutional investigator must sign and date the 
completed eligibility checklist. The completed eligibility checklist and de-identified supporting clinical 
documentation should be scanned and emailed for review and signed off by the Study PI and/or Study 
Co-PI and the NF Operations Center to confirm eligibility prior to subject enrollment. 
3.3 
Study Enrollment 
 
Subjects may be enrolled on the study once all eligibility requirements for the study have been met and a 
treatment number for subject treatment has been confirmed by the NF Consortium Operations Center as 
well as either the study chair or study co-chair. Subjects who give informed consent for the protocol to 
undergo screening for eligibility are not considered enrolled and should not be registered until the 
screening is completed and they are determined to meet all eligibility criteria. Treatment must start within 
14 days of enrollment. Subjects must not receive any protocol therapy prior to enrollment.  
 
4.0 
PATIENT ELIGIBILITY 
All studies to determine eligibility must be performed within 2 weeks prior to enrollment unless otherwise 
noted. All clinical and laboratory data required for determining eligibility of a subject enrolled on this trial 
must be available in the subject's medical or research record which will serve as the source document for 
verification at the time of audit/monitoring.  
 
4.1 
Inclusion Criteria for subjects at time of initial enrollment: 
 
4.1.1 
All subjects must have EITHER the clinical diagnosis of NF1 using the NIH Consensus Conference 
criteria (see Appendix III) OR have a constitutional NF1 mutation documented in a CLIA/CAP 
certified lab.  
 
4.1.2 
Subjects must have plexiform neurofibroma(s) that are progressive (see section 4.1.2.1) OR are 
causing significant morbidity, such as (but not limited to) head and neck lesions that are 
compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve 
compression and loss of function, lesions causing major deformity (e.g., orbital lesions) or are 
significantly disfiguring (see section 4.1.2.2), lesions of the extremity that cause limb hypertrophy 
or loss of function, and painful lesions. Subjects with paraspinal plexiform neurofibromas will be 
eligible for this trial. Histologic confirmation of tumor is not necessary in the presence of consistent 
clinical and radiographic findings but should be considered if malignant degeneration of a 
plexiform neurofibroma is clinically suspected.  
 
4.1.2.1 For subjects enrolled for tumor progression, progression is defined as:  
• Presence of new plexiform neurofibroma on MRI or CT (documented by comparison 
with prior MRI or CT), OR 

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• A measurable increase in plexiform neurofibroma size (≥ 20% increase in the volume, or 
a ≥ 13% increase in the product of the two longest perpendicular diameters, or a ≥ 6% 
increase in the longest diameter) documented by comparison of two scans (MRI or CT) in 
the time period of approximately 18 months or less prior to evaluation for this study. 
 
4.1.2.2 For subjects enrolled for a “major deformity” or “significantly disfiguring” tumor, eligible 
tumors will be limited to tumors of the head & neck or those on other areas of the body that are 
unable to be concealed by standard garments. In order to enroll a plexiform neurofibroma for 
these indications, the Study Chair and/or Co-Chair must be contacted to review subject eligibility 
prior to enrollment. 
 
4.1.3 
Measurable disease: Subjects must have measurable plexiform neurofibroma(s) amenable to 
volumetric MRI analysis. For the purpose of this study, the target lesion must be seen on at least 3 
consecutive MRI slices and the field of view must contain the entire tumor of interest. Tumors 
must be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria). If the 
tumor is <3 cm in longest diameter, the subject may still be eligible. Central review of the MRI 
of the target plexiform is required prior to enrollment to ensure that the tumor is 
measurable and amenable to volumetric analysis. After consenting, please send the images on 
a CD along with the form in Appendix IVa to Eva Dombi (see Appendix IVa for 
address). Central review will take 3-7 days (please plan accordingly). 
 
4.1.4. Age:   
4.1.4.1. Stratum A: Subjects must be ≥ 18 years of age at the time of enrollment. 
4.1.4.2. Stratum B: Subjects must be ≥ 1 year and < 18 years of age at the time of study 
enrollment. 
 
4.1.5. Performance Level: 
Karnofsky or Lansky  50% (Appendix II). Note: Subjects who are unable to walk because of 
paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of 
assessing the performance score. 
 
4.1.6. Prior Therapy:  
Subjects are only eligible if complete resection of a plexiform neurofibroma with acceptable 
morbidity is not feasible, or if a subject with surgical option refuses surgery. 
 
Subjects who underwent surgery for a progressive plexiform neurofibroma will be eligible to 
enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected 
and is evaluable by volumetric analysis (see section 4.1.3). 
 
Subjects may have been previously treated for a plexiform neurofibroma or other 
tumor/malignancy but must have fully recovered from the acute toxic effects of all prior 
chemotherapy or radiotherapy prior to entering this study. 
 
a. Myelosuppressive chemotherapy: Must not have received within 3 weeks of entry onto this 
study.  
b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth 
factor that supports platelet, red or white cell number or function.   
c. Biologic (anti-neoplastic agent): At least 4 weeks since the completion of therapy with a 
biologic agent. For agents that have known adverse events occurring beyond 14 days after 
administration, this period must be extended beyond the time during which adverse events are 

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known to occur. These subjects must be discussed with the Study Chair on a case-by-case 
basis. 
d. Investigational Drugs: Subjects must not have received an investigational drug within 4 
weeks. 
e. Steroids: Subjects with endocrine deficiencies are allowed to receive physiologic or stress 
doses of steroids if necessary.   
f. Radiation:  6 months from involved field radiation to index plexiform neurofibroma(s);  6 
weeks must have elapsed if subject has received radiation to areas outside index plexiform 
neurofibroma(s). Subjects who have received radiation to the orbit at any time are excluded. 
g. Surgery: At least 3 weeks since undergoing any major surgery and must be recovered from 
effects of surgery. 
 
4.1.7. Organ Function Requirements 
 
4.1.7.1. 
Adequate bone marrow function defined as: 
- 
Peripheral absolute neutrophil count (ANC)  1500/L and 
- 
Platelet count  100,000/L (transfusion independent, defined as not receiving 
platelet transfusions for at least 7 days prior to enrollment) and 
- 
Hemoglobin  10.0 gm/dL without transfusions. 
 
4.1.7.2. 
Adequate renal function defined as: maximum serum creatinine based on age/gender as 
per institutional standards OR a creatinine clearance or radioisotope GFR  
70ml/min/1.73 m2 
 
4.1.7.3. 
Adequate liver function defined as: 
- Bilirubin (sum of conjugated + unconjugated)  1.5  x upper limit of normal (ULN) 
for age, and 
- SGPT (ALT)  2.5 x upper limit of normal (ULN) for age, and 
- Serum albumin  2 g/dL. 
4.1.7.4. 
The effects of binimetinib on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study participation, and 3 months after completion of binimetinib 
administration. Should a woman become pregnant or suspect she is pregnant while she 
or her partner is participating in this study, she should inform her treating physician 
immediately.  
4.1.7.5. 
Adequate cardiac function defined as: left ventricular fractions (LVEF) ≥50% as 
determined by a multigated acquisition (MUGA) scan or echocardiogram, and QTc 
interval ≤480 ms. 
4.1.7.6. 
Ability to comply with follow up procedures. 
4.1.7.7. 
Negative urine or serum β-HCG test (females of childbearing potential only). 
4.1.7.8. 
Patients must have a weight of  >10 kg at enrollment 
 
 
 

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4.2 
Exclusion Criteria for all subjects (including the Re-Treatment Arm) 
 
4.2.1 
Exclusion Criteria 
• 
Chronic treatment with systemic steroids or another immunosuppressive agent. Subjects with 
endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if 
necessary. 
• 
Evidence of an active optic glioma or other low-grade glioma, requiring treatment with 
chemotherapy or radiation therapy. Subjects not requiring treatment are eligible for this 
protocol. 
• 
Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other malignancy 
requiring treatment in the last 12 months. 
• 
Subjects who have received radiation to the orbit at any time previously. 
• 
Ophthalmologic conditions: 
• 
Current or past history of central serous retinopathy  
• 
Current or past history of retinal vein occlusion 
• 
Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or uncontrolled 
glaucoma (irrespective of IOP). Patients with known glaucoma and increased IOP who do 
not have meaningful vision (light perception only or no light perception) and are not 
experiencing pain related to the glaucoma, may be eligible after discussion with the study 
chair. Patients with orbital plexiform neurofibromas should have IOP measured prior to 
enrollment.   
• 
Subjects with any other significant abnormality on ophthalmic examination should be 
discussed with the Study Chair for potential eligibility. 
• 
Ophthalmological findings secondary to long-standing optic pathway glioma (such as 
visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such 
as visual loss, strabismus) will NOT be considered a significant abnormality for the 
purposes of the study. 
• 
Uncontrolled arterial hypertension despite medical treatment defined as CTCAE grade 3 or 
higher. Use age and gender appropriate normal values >95th percentile ULN for pediatric 
patients. See Appendix XVII. 
• 
Impaired cardiovascular function or clinically significant cardiovascular diseases, including: 
• 
History of acute coronary syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) <6 months prior to 
screening 
• 
Symptomatic chronic heart failure, history or current evidence of clinically significant 
cardiac arrhythmia and/or conduction abnormality <6 months prior to screening except 
atrial fibrillation and paroxysmal supraventricular tachycardia 
• 
Other concurrent severe and/or uncontrolled medical disease, which could compromise 
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe 
infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration, 
congestive heart failure, etc.) 
• 
Subjects who have an uncontrolled infection. 
• 
Known positive serology for HIV (human immunodeficiency virus), active hepatitis B, and/or 
active hepatitis C infection. 
• 
Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).  

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• 
History of Gilbert’s syndrome or patients who are known to be homozygous for UGT1A1 
(7/7). 
• 
Patients who have neuromuscular disorders that are associated with elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular 
atrophy) 
• 
Subjects who are planning to embark on a new strenuous exercise regimen after first dose of 
study treatment. NB: muscular activities, such as strenuous exercise, that can result in 
significant increases in plasma CK levels should be avoided while on binimetinib treatment.  
• 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to binimetinib. 
• 
Women who are pregnant or breast feeding.  
• 
Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow, social/ 
psychological issues, etc. 
• 
History of noncompliance to medical regimens. 
• 
Subjects unwilling to or unable to comply with the protocol, or who in the opinion of the 
investigator may not be able to comply with the safety monitoring requirements of the study. 
• 
Prior treatment with a MEK inhibitor of any kind (not applicable for the Re-Treatment Arm). 
 
4.3 
Re-Treatment Arm 
 
All studies to determine eligibility for Re-Treatment must be performed within 2 weeks prior to 
“enrollment” on the Re-Treatment arm except for MRI, ophthalmology, Echo, and EKG (which is 
required within 4 weeks prior to “enrollment” on the Re-Treatment Arm), unless otherwise indicated. Re-
Treatment eligibility studies may be counted as the Re-Treatment baseline studies as long as there has 
been no concerning change in clinical status prior to starting study drug, except for pregnancy testing in 
females of childbearing age which must be negative within 7 days prior to re-starting binimetinib. Study 
drug must start within 14 days of “enrollment” on the Re-Treatment Arm. 
 
4.3.1 Inclusion Criteria for Re-Treatment 
• 
Participants who had a partial response to binimetinib, completed 24 courses of initial treatment 
and discontinued treatment at that time as per study protocol.  
• 
Progression of the originally identified target PN (defined as >20% increase in tumor volume 
compared with post course 24 volume) within one year of stopping initial treatment as per central 
review. 
• 
Must have recovered to grade 1 or less from any prior binimetinib-related toxicities.  
• 
Performance Level: Karnofsky or Lansky > 50% (Appendix II). Note: Subjects who are unable to 
walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the 
purpose of assessing the performance score. 
• 
Organ Function Requirements: Must meet all organ function requirements as per section 4.1.7. 
 
4.3.2 Exclusion Criteria for Re-Treatment 
• 
Participants who stopped binimetinib treatment for any other reason other than discontinuation 
after completion of 24 courses of initial treatment as per protocol.  
• 
Treatment with tumor-directed therapy for the target PN or any other tumor since discontinuing 
binimetinib. 

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• 
Surgery on the target PN since discontinuing binimetinib. 
• 
>13 months have elapsed since discontinuing binimetinib. 
• 
All exclusion criteria in section 4.2.1 must be met except for prior treatment with a MEK 
inhibitor of any kind. 
 
 
5.0 
REQUIRED DATA 
 
IRB Approvals 
 
The University of Alabama at Birmingham’s Office of Institutional Review Board for Human Use has 
offered to serve as the Lead IRB for all institutions via SMART IRB. Participating sites of this protocol 
are encouraged to utilize this infrastructure to expedite the review process. Participating sites will need 
to have an existing Master Common Reciprocal Institutional Review Board Authorization Agreement 
with “SMART IRB” to utilize the UAB IRB as their IRB of record. Sites that use the single IRB will 
rely on the UAB IRB approval so that all study sites have the same IRB determination, consent 
template(s), and expiration date.   
 
Sites that choose not to use the UAB IRB as IRB of record must provide the NF Consortium Operations 
Center with a copy of the initial IRB protocol approval and the yearly IRB continuing reviews. The NF 
Clinical Trial Consortium Regulatory Specialist will submit these to the USAMRMC ORP HRPO on 
behalf of each site and maintain a master regulatory file. Registration will be halted at a participating 
institution if a current continuing approval is not on file at the NF Consortium Operations Center. 
 
Each participating institution is required to maintain a current MPA or FWA in order to participate in 
government-sponsored Group research. The files will be copied or made available for review by 
authorized persons as required for conduct of this trial. 
 
Amendments and Consents 
 
The PI from each participating institution will provide the NF Consortium Operations Center with a copy 
of IRB approval of all amendments to the protocol or consent. The Regulatory Specialist representing 
the NF Consortium Operations Center will provide these institutional reviews to the USAMRMC ORP 
HRPO on behalf of each site and maintain a master regulatory file.   
 
As this trial receives funding by the US Army, substantive amendments to the research protocol and any 
amendments that could potentially increase risk to subjects must be submitted to the HRPO for approval 
prior to implementation and site distribution. The USAMRMC ORP HRPO defines a substantive 
amendment as a change in Principal Investigator, change or addition of an institution, elimination or 
alteration of the consent process, change in the IRB of Record, change to the study population that has 
regulatory implications (e.g. adding children, adding active duty population, etc.), significant change in 
study design (i.e. would prompt additional scientific review), or a change that could potentially increase 
risks to subjects.  
 
Data Collection and Toxicity Reporting 
 
The trial is being conducted by the NF Consortium in collaboration with PNOC. Case report forms 
developed by the NF Consortium Operations Center and Protocol Chair will be used for submitting 
clinical data to the Operations Center. Data must be submitted to the Operations Center within two 

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weeks of completing each required evaluation while the subject is on study. Delinquent data delays will 
be reported to the NF Consortium’s Site Evaluation Committee and the NF Operations Center.  
 
The NCI POB will receive MRI studies electronically or on CD and completed worksheets for 
volumetric analysis. When sending the CD, the site must provide tracking # (FedEx or UPS) by email to 
Eva Dombi: dombie@mail.nih.gov.  
 
Completed QOL and pain evaluations will be submitted in real-time by email to the NF Operations 
Center.  
 
Cincinnati Children’s Hospital Medical Center will receive cytokine samples along with completed 
worksheets as outlined in Appendix VII. Upon analysis of these studies, results will be transmitted to the 
NF Consortium Operations Center for entry into the study databases. 
 
Biological specimens for banking will be handled and stored in the biorepository located in the Colket 
Translational Research Building at the Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA.  
The specimens will be under the management of the Center for Data Driven Discovery in Biomedicine 
(D3b) and the Biorepository Core (BioRC), according to their standard operating procedures (SOPs).  
Samples will be stored at -80°C. Biological specimens will be coded with a randomly generated study 
number prior to shipping to the biorepository in order to prevent identification of subjects and protect 
confidentiality. The study number will not be derived from or related to information about the subject 
and will not contain any elements of PHI. The specimen number will be entered into the NF Consortium 
Operations Center eDES, thus providing a link between the specimen and the study data.  Specimens 
may be shared with outside investigators/laboratories, who may analyze (and store, if applicable) the 
samples. Shared specimens will be labeled only with a study number. Requests for samples will be 
reviewed by the NF108 Study Chairs and the NFCTC Biology Committee. If a subject withdraws 
consent to store samples after collection, existing samples in the biorepository will be destroyed; 
however, any samples already shared to an outside laboratory or other entity will not be destroyed and 
any data generated already from the samples will not be destroyed. 
 
Representatives from the FDA, NF Consortium Quality Assurance Committee, University of Alabama at 
Birmingham’s Institutional Review Board and the U.S. Army Medical Research and Material Command 
will have access to the data and research records as required. Independent research monitor and DSMB 
will also have access to data and research records as required. 
 
Julia Bender will serve as the research monitor and will serve as a patient advocate and is independent of 
the clinical study team. She will oversee the progress of the protocol, especially issues of individual 
subject/patient management and safety. The research monitor is required to review all unanticipated 
problems involving risks to subjects or others, including all serious and unexpected adverse events 
associated with the protocol as defined in Section 10.0. She will be automatically notified by the data 
entry system as soon as any SAE is entered into the study system. The monitor provides an unbiased 
written report of the event and may request additional information if needed for her determination.  
 
Handling of Research Samples 
 
This study is conducted at NF and PNOC Consortium Sites and will be coordinated by the NF 
Consortium Operations Center. Sample labeling, collection and initial processing will be conducted as 
outlined in the study Section 9, as well as in Appendix VII. Blood samples for cytokine studies will be 
sent to Cincinnati Children’s Hospital Medical Center for analysis. Samples will be stored in designated 
monitored freezers and will be identified by the protocol specific subject ID number. Once analyzed for 
the studies outlined in this protocol, any remaining samples will be stored by the Cincinnati lab until the 

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study is complete and the manuscript describing the study has been accepted for publication. Any use of 
samples not outlined in Section 9 or Appendix VII will require Study Leadership approval and 
prospective IRB review and approval. The study will remain open and status reported to the IRB until all 
samples have been analyzed, reported or destroyed. Unintentional loss or destruction of any samples will 
be reported to the IRB as part of annual continuing reviews. MRI studies of PN will be obtained as 
described in Appendix IV and will be sent on CD to the NCI POB. MRI studies will be loaded on one of 
three Sun Workstations, which are password protected and allow access only to Drs. Dombi, Widemann, 
or associate investigators on the trial. CDs will be stored in locked filing cabinets. Data results will be 
electronically submitted to the Operations Center for curation in the study database. 
 
Data and Center Audits 
 
The trial will be monitored by the data center during the course of the study and monitored on-site by the 
NF Consortium Operations Center as needed for compliance and safety. Monitors may visit participating 
sites and review case report forms and source documentation. Missing or spurious information and 
protocol deviations will be communicated in a report to the NF Consortium Operations Center. Protocol 
deviations, which may compromise the ability to safely administer study drug or to accurately determine 
study endpoints, will be included in the annual protocol review to the USAMRMC ORP HRPO, the 
FDA, medical monitor, NF Consortium IRB and the DSMB for this study.   
 
All unexpected and serious adverse events will be forwarded to the Medical Monitor, the Study PI, FDA, 
the DSMB and the USAMRMC ORP HRPO by the NF Consortium Operations Center as defined in 
Section 10.0.  
 
Volumetric MRI analysis performed by the NCI-POB will be used to determine disease progression, and 
subjects will not be removed from study based on 1-D or 2-D MRI measurements or based on clinical 
measurement of superficial lesions.  
 
5.1 
Tests and Observations   
 
See section 9.0 and Appendix I. Unless otherwise noted, all tests to determine eligibility must be 
completed within 14 days of study enrollment. 
 
5.2 
Records to be Kept 
 
Subject Registration and Case Report Forms 
 
Subjects will be registered with the NF Consortium Operations Center via the electronic data entry system 
(eDES). Electronic and paper Case Report Forms will be developed by the Consortium Operations Center 
and Protocol PI. All data must be entered into the eDES. Sites have the option of maintaining a printed 
copy of completed forms in the subject’s study binder that have been initialed and dated by the study team 
member entering the data into the paper case report form.   
 
Subjects must not be identified by name on any study documents that are sent off site to any agency. The 
Subject Identification Number received upon data entry registration and placed on all case report forms 
and regulatory documents will identify subjects. 
 
All data entered on a paper CRF must be legibly recorded in indelible ink or typed. A correction should 
be made by striking through the incorrect entry with a single line and entering the correct information 
adjacent to it. The correction must be initialed and dated by the investigator or designated qualified 

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individual. Any requested information that is not obtained as specified in the protocol should have an 
explanation noted on the CRF as to why the required information was not obtained. The electronic CRF 
provides audit trail showing when data is revised. 
 
5.3 
Role of Data Management 
 
5.3.1 
Instructions concerning the recording of study data on CRFs will be provided by the NF 
Operations Center. 
5.3.2 
It is the responsibility of the NF Operations Center to assure the quality of data for this study in 
partnership with the study investigators. This role extends from protocol development to 
generation of the final study database. 
 
6.0 
TREATMENT PROGRAM 
 
6.1 
Agent Information/ binimetinib 
 
6.1.1 
Source and Pharmacology:  
 
Absorption and distribution: Study [CMEK162A2102] investigated the absorption, 
distribution, metabolism, and elimination (ADME) of a single oral dose of 45 mg of [14C]- 
binimetinib in healthy male subjects. The overall recovery of radioactivity in the excreta for all 
six subjects was 93.6 ± 3.27%, indicating that good mass balance was achieved. A lower limit on 
the extent of oral absorption for binimetinib in this study can be set at ~ 50% based on the 
percentage of radioactive dose recovered in the excreta. However, the actual value could be 
greater if a portion of the unchanged binimetinib observed in the feces was absorbed and then 
either excreted in bile, intestinally secreted, or metabolized to a glucuronide that was then 
hydrolyzed back to binimetinib in the gut. The mean blood to plasma concentration ratio for total 
radioactivity was comparable to the mean in vitro value for [14C] binimetinib (0.63 versus 0.72). 
On average, ~60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. 
 
Food effects: Food-effect clinical studies have shown influence of food on PK of binimetinib is 
mild and not clinically relevant; therefore, binimetinib can be taken with food.  
 
Pharmacokinetics and Metabolism:  
In animals, exposure (AUC) and Cmax generally increased in a dose proportional manner. The 
plasma clearance is low (range: ~2 to 8 mL/min/kg) and the mean plasma half-life values ranges 
from 2 to 9 hours. Binimetinib has moderate membrane permeability. 
Binimetinib exhibited high plasma protein binding in vitro (> 96%, except dog 84%) and is 
predicted to have good stability with respect to hepatic metabolism. Nonclinical in vitro and in 
vivo data indicated that binimetinib is metabolized by multiple routes but primarily by 
glucuronidation pathways (mainly via UGT1A1, 1A3 and 1A9) and to a lesser extent by 
oxidation pathways (mainly via CYP1A2 and 2C19). UGT1A1 is considered the primary enzyme 
to mediate glucuronidation of binimetinib. The formation of active metabolite AR00426032 is 
mediated primarily by CYP1A2 with minor contribution by 2C19 and 2B6. 
Excretion of [14C] binimetinib in rats was split between the fecal and urinary routes. The 
predominant route of excretion in monkey was urinary. Binimetinib was mainly eliminated 
through glucuronidation and parent drug excretion. The major circulating component in rat and 
monkey plasma was binimetinib. The direct glucuronide was also observed in monkey plasma. 

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Binimetinib is a potent reversible inhibitor of CYP2B6. In vitro evidence also suggests that 
binimetinib could induce CYP3A. 
Pre-clinical studies in mice support that >50% inhibition in pERK in HT-29 tumors for 24 hours 
is optimal for significant tumor growth inhibition. This degree of sustained pERK inhibition was 
best achieved with BID dosing at lower doses (< 10 mg/kg/dose) or QD dosing at higher doses (> 
30 mg/kg/dose). Given that little to no drug was apparent in plasma at 24 hours post-dose (at low 
doses) in the pre-clinical xenograft studies, a BID dosing regimen was considered to be the most 
reliable murine schedule to maintain plasma concentrations for optimal efficacy. Therefore, a 
BID dosing regimen (i.e., 45 mg) should provide sufficient exposure with acceptable safety and 
adequate continuous pharmacological inhibition of the primary target. 
In healthy subjects and patients with rheumatoid arthritis, the analysis of PK data was done using 
model independent (NCA) methods only. These analyses suggested that absorption was rapid, 
that there was extensive distribution and that the apparent terminal half-life was short. Contrary to 
expectation, given the short half-life, accumulation greater than that predicted by linear PK was 
observed. Overall, when given BID, accumulation was around 1.5 to 1.7-fold. This apparent non-
linearity in the PK of binimetinib may have been related to a combination of a relatively high 
LLOQ of the assay used (5 ng/mL) and the schedule of blood collection for PK used. In order to 
overcome these limitations and to fully characterize the PK of binimetinib in cancer patients a 
model-based analysis was conducted using a population PK method. For this analysis, 
information from 130 subjects from two clinical studies, [CMEK162X2201] and [ARRAY-162-
111], were used. Dose levels range from 30 mg BID to 80 mg BID. 
Binimetinib PK was best described by a two-compartment disposition model with first-order 
elimination and first-order absorption with a lag time. The estimated between subject variability 
on apparent clearance (CL/F) was moderate (44%) and very high (~150%) for the apparent 
central volume of distribution (Vc/F) and apparent peripheral volume of distribution (Vp/F). The 
covariate effect of dose on relative bioavailability was identified as significant (at an α = 0.001 
significance level). Relative to the 45 mg dose, the bioavailability of the 30 mg dose level was 
120%; while the relative bioavailability of 60 mg and 80 mg doses were 88% and 77%. This dose 
dependence was not seen using model independent methods but most likely represents either 
solubility limited absorption of binimetinib or the impact of P-gp or a combination of the two. 
Based on the PK parameters estimated in this analysis when administered BID, binimetinib 
steady state is reached around Day 15 and the accumulation is around 1.7-fold which is consistent 
with observation. For further information refer to the current binimetinib Investigator’s Brochure. 
For further details on non-clinical pharmacokinetics and metabolism, please refer to the current 
binimetinib Investigator’s Brochure. 
 
Excretion: The human ADME [CMEK162A2102] study showed that after a single oral dose of 
45 mg of [14C] binimetinib, a mean of 62.3% of the radioactivity dose was eliminated in the feces 
while 31.4% was eliminated in the urine. In urine, 6.5% of the radioactivity dose was excreted as 
binimetinib. The estimated mean CLr value of 1.78 L/h was 6.3% of the total mean CL/F value of 
28.2 L/h. 
 
6.1.2 
Formulation and Stability 
 
Tablet information: Binimetinib drug product is supplied as film-coated tablets in dosage 
strength of 15 mg. The film-coated tablets consist of binimetinib, lactose monohydrate, 
microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate 
and a commercial film coating. The tablets are yellow to dark yellow and capsule shaped. 

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Storage Conditions:  Binimetinib film-coated tablets should not be stored above 25°C and 
should be protected from light. Tablets are packaged in plastic bottles acceptable for 
pharmaceutical use. 
Relative molecular mass: 441.23  
 
Chemical Structure: 
 
 
CAS Name: 606143-89-9 
Systematic (IUPAC) Name: 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-
hydroxyethoxy)-1-methyl-1Hbenzimidazole-6-carboxamide. 
Molecular Formula: C17H15BrF2N4O3 
Physical Description: White to light tan powder or white to slightly beige powder 
6.1.3 Supplier 
 
Array BioPharma, a wholly owned subsidiary of Pfizer Inc. will supply the drug in 15mg film-
coated tablets. Pharmacy preparation instructions for liquid suspension can be found in Appendix 
XVIII. 
 
6.1.4 
Toxicities 
 
Acute, subchronic, chronic and reproductive toxicity, genotoxicity and phototoxicity studies were 
completed to support the chronic administration of binimetinib to adult cancer patients. The toxic 
effects of MEK inhibitors in humans are similar to the toxic effects observed in monkeys. The 
toxic effects include gastro-intestinal intolerance and diarrhea, rash, central serous retinopathy 
(only seen in humans) and retinal vein occlusion (rarely seen in humans). In vitro and in vivo 
phototoxicity studies conducted in mice indicate that binimetinib has a very low risk of weak 
phototoxic potential at therapeutic doses. Furthermore, there has been no evidence of 
phototoxicity or photosensitivity in humans being treated with binimetinib for cancer or for 
rheumatoid arthritis. This includes 2555 patients and healthy volunteers who have received at 
least one dose of binimetinib and is based on data as of January 20, 2016. Given the embryo-
lethal effects seen in rats and rabbits and the teratogenic effects seen in rabbits, binimetinib 
should not be used in pregnant women. Women of child-bearing potential must be advised to use 
highly effective contraception methods.  
 

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Data collected in the nonclinical and clinical programs, as well as class effects with MEK 
inhibitors overall, indicates that binimetinib exposure may be associated with rash-like events, 
gastrointestinal events (including diarrhea, nausea and vomiting, stomatitis/mucositis), reversible 
elevations of CK, edema, cardiac events, retinal events, and interstitial lung disease or non-
infectious pneumonitis. 
 
6.2 
Treatment Overview 
Binimetinib will be administered to adult subjects orally on a daily BID schedule, continuously without 
breaks, as a flat-fixed dose of 30 mg BID, and not by body weight or body surface area for patients ≥ 18 
years of age. Subjects who have been enrolled prior to protocol version 2.0 and tolerate binimetinib at 45 
mg PO BID can continue on that dosing regimen if the treating physician believes that this is in the best 
interest of the patient.  
Binimetinib will be administered to children between 1 and 17 years orally as a BID schedule, 
continuously without breaks, at a dose of 32 mg/m2 (maximum: 45mg dose) dose will be calculated based 
on body surface area and should be calculated approximately monthly; see Appendix XIX for liquid 
dosing and Appendix XX for tablet dosing.     
The interval between dosing is 12 hours +/- 2 hours. If the patient is not able to take the medication within 
this time frame, that particular dose should be skipped and marked as missed on the drug diary. Patients 
will be supplied with a sufficient number of tablets, or liquid suspension, for the number of doses to be 
taken prior to the next scheduled visit. Tablets must be swallowed whole. In the pediatric stratum, a liquid 
suspension can be created, for ease of dosing and administration – please see Appendix XVIII. Patients in 
the pediatric stratum can take whole tablets if preferred and the dosage is within 10% of the 
recommended dose. Patients in the adult stratum may also use a liquid suspension if they are unable to 
swallow whole pills, following the dose reduction as in Section 8.2. Patients who require doses not within 
10% of a whole tablet dose, may use a combination of tablets and liquid to achieve a dose, as the 
bioavailability of both formulations is excellent. For example, if the dose were 22 mg, and the volume of 
liquid was too challenging for the patient to take, they may take a 15 mg tablet + 7 mg liquid to achieve 
the dose. In addition, patients will be provided a dosing diary and should document in this diary each 
prescribed dose, and whether it was taken or not. Both a tablet and liquid diary should be used if 
formulations are being combine. 
Each course is 4 weeks duration. Subjects who have a 20% or greater reduction in target tumor volume at 
the end of 12 courses can continue on therapy for up to an additional year (maximum of 24 total courses). 
Subjects who have not had at least 20% tumor shrinkage by volumetric analysis by the end of the 12th 
course will be removed from protocol therapy. Of note, subjects may begin course 13 while central 
review of tumor response is ongoing. 
As of Protocol version 3.0, study participants who completed 24 courses of binimetinib and discontinued 
treatment at that time per protocol, but subsequently have progression of their target PN (>20% increase 
in volume) within one year of that time, will be allowed to restart binimetinib at the same dose they were 
receiving at the end of the initial 24 courses, on the Re-Treatment Arm of the study. Once they re-start 
treatment, participants may receive up to 24 courses of binimetinib, as long as the tumor does not 
progress (>20% increase in tumor volume compared with pre-Re-Treatment baseline). After 24 courses of 
re-treatment, for participants who are deriving benefit and for whom both the participant and treating 
physician agree that continued treatment with a MEK inhibitor is appropriate, such participants may 
continue to receive binimetinib via the study for up to 12 courses, while arrangements are being made to 
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be made to transition the participant and perform end of study assessments as soon as possible after 24 
courses of re-treatment. 
Binimetinib can be taken with food.  
Re-administration of dose: If a patient vomits at any time after dosing, the dose of study drug should not 
be re-administered. Doses of binimetinib that are omitted for AEs or any other reason should not be made 
up later in the day, or at the end of the dosing period. 
 
6.3 
Criteria for Starting Subsequent Courses 
 
Unless the subject has developed toxicity requiring interruption or withdrawal from protocol therapy (see 
section 8.0), a course may be repeated every 28 days if the subject has at least stable disease and has again 
met laboratory parameters (when study evaluations are required) as defined in the eligibility section. Of 
note, subjects may begin a course while central review of tumor response is ongoing.  
 
If weight falls below 10 kg during treatment, binimetinib should be held until weight recovers to ≥ 10 kg. 
If binimetinib is not resumed within 28 days, the patient should be removed from protocol therapy. 
 
 
7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
Subjects must be instructed not to take any additional medications (including over-the-counter products) 
during the trial without prior consultation with the investigator. All medications taken within 30 days of 
screening should be recorded. If concomitant therapy must be added or changed, the reason and name of 
the drug/therapy should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the subject 
are allowed, including drugs given prophylactically (e.g. anti-emetics), with the following exceptions: 
• No other investigational therapy should be given to subjects 
• No chronic treatment with systemic steroids or another immunosuppressive agent (see section 
7.4) except for subjects with endocrine deficiencies who are allowed to receive physiologic or 
stress doses of steroids, if necessary.  
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or biologic 
therapy may NOT be administered.  
 
7.1 
Supportive Care 
 
Appropriate antibiotics, blood products, fluids, electrolytes, and general supportive care are to be used as 
necessary. Anti-emetics, other than systemic steroids, are allowed. Corticosteroids are permissible as 
premedication for blood product transfusions, or as treatment for an acute allergic reaction. 
 
7.2 
Growth Factors 
 
Growth factors that support platelet or white cell number or function can only be administered for culture 
proven bacteremia, clinical sepsis, or invasive fungal infection with neutropenia. The Study Chair should 
be notified when growth factors are initiated. 

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7.3 
Surgery 
 
Subjects undergoing surgical procedures should have the study drug held for 2 weeks prior to the 
procedure, if feasible, and for 2 weeks after. Surgery to a non-target plexiform neurofibroma does not 
require removal from protocol therapy (i.e. subject can continue on therapy once he/she recovers from 
surgery, as described above). 
7.4 
Management of Hypertension, Skin Toxicity, and Nausea and Vomiting 
 
Management of Hypertension  
Patients that will receive binimetinib must have their blood pressure monitored as per the observation 
table in Appendix 1. If elevated blood pressure is observed, additional monitoring should occur per 
institutional guidelines. 
The investigator is to educate the patient on the signs and symptoms of hypertension and use of the home 
blood pressure monitor. More frequent assessments during the study drug treatment period may also be 
performed at the discretion of the investigator and if medically indicated.  
For patients monitoring their blood pressure at home, it is suggested to develop a patient diary to record 
their self-assessed blood pressure measurements and present the collected data to the investigator for 
evaluation and appropriate management per institutional guidelines. This diary must be maintained in the 
patient’s source documentation. 
 
 
Management of Skin Toxicity 
 
Skin toxicity has been reported for binimetinib and has been encountered in this trial, often soon after 
starting medication. Therefore, it is recommended that patients are educated on the possibility of 
occurrence of these side effects prior to starting study treatment. Patient education as well as proper 
management of skin toxicity at the first sign is important. The following recommendations have been 
established to help minimize and manage skin toxicity and should be followed if deemed appropriate by 
the treating physician.  
 
The following medications may be useful in managing these rashes: 
 
Acneiform rash 
• Doxycycline 100 mg BID (for patients >8 years of age weighing >45 kg) 
• Doxycycline 2.2 mg/kg/dose BID (for patients >8 years of age weighing <45 kg) 
• Clindamycin phosphate 1% lotion BID 
 
Dry/flaky scalp  
• 
Ketoconazole 2% shampoo 
 
Eczematous rash 
• 
Low potency topical steroid cream/ointment (not lotion) for face, axilla, groin 
• 
Mid potency topical steroid cream/ointment (not lotion) for other locations 
 

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It is recommended that at the time of initial study drug dispense, that patients be sent home with 
prescriptions for doxycycline and clindamycin lotion, and that these be filled and started at the first sign 
of acneiform rash. 
 
Management of Nausea and Vomiting 
 
Because nausea and vomiting have been reported for binimetinib, it is recommended that patients are 
educated on the possibility of occurrence of these side effects prior to starting study treatment. Patient 
education as well as proper management of nausea and/or vomiting at the first sign is important. Clinical 
judgment and experience of the treating physician should guide the management plan of each patient. 
Patients experiencing nausea and/or vomiting CTCAE ≥ grade 1 will receive antiemetics at the discretion 
of the treating physician (as per local guideline). It is recommended that patients be provided a 
prescription for antiemetics and are instructed on the use of antiemetics on the first day of study drug 
treatment.  
Dose interruption/reduction decisions for nausea and/or vomiting should be based on the CTCAE 4.03 
grade of the toxicity and guidelines as listed in section 8.0.  
 
7.5 
Concomitant Medications  
Permitted concomitant therapy requiring caution and/or action 
Binimetinib potently inhibits CYP2B6 in vitro (Ki of 1.67 µM). Based on these findings, binimetinib may 
inhibit the metabolic clearance of co-medications metabolized by CYP2B6, if sufficiently high 
concentrations are achieved in vivo. At 45 mg BID, the maximum concentrations achieved in plasma are 
normally <1.5 µM so the risk of drug interaction is limited.   
In vitro data showed that binimetinib is a substrate of P-gp. Binimetinib is also a substrate of BCRP. 
Thus, the use of drugs that are known to inhibit or induce P-gp and BCRP should be used with caution.  
Binimetinib has been identified to be primarily metabolized by UGT1A1 in vitro. It is advised that 
inhibitors and inducers of UGT1A1 should be taken with caution when co-administered with MEK162. 
Patients should be closely monitored for the occurrence of adverse events. Please refer to Appendix VI 
for a list of these known drugs but this list may not be exhaustive. 
Drugs with a conditional, possible, or known risk to induce Torsade de Pointes (TdP) should be used with 
caution. Patients receiving such medications must be carefully monitored for potentiating of toxicity due 
to any individual concomitant medication and may require dose titration of the drug substance. 
Investigators should use caution when prescribing co-medications, as clinical experience with these 
compounds in patients with cancer is often limited. Please refer to Appendix VI for a list of permitted 
medications to be used with caution. 
      
 
8.0 
MODIFICATIONS FOR ADVERSE EVENTS 
 
Guidelines for Treatment Delay, Dose Reduction, or Study Drug Discontinuation for Toxicity 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the last dose 
of study treatment and for any serious adverse event (SAE) assessed as related to study treatment or study 
procedures, even if the SAE occurs more than 30 days after the last dose of study treatment. 

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Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or reduction(s) in 
their dose in order to continue with study treatment.  
Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) (v4.03). 
Any subject experiencing a dose reduction toxicity (as described in table 8.6) that is possibly, probably, or 
definitely related to binimetinib should have the drug held until the toxicity improves to and remains 
stable at grade 1 or less (see section 8.2).  In addition, the site should notify the study chair 
sabine.mueller@ucsf.edu and co-chairs Fisherm@email.chop.edu and Alyssa.reddy@ucsf.edu 
along with the NF Operations Center nfcop@uab,edu immediately of any drug toxicity and/or dose 
reduction toxicity or study drug interruptions. Notifications should be by email.   
8.1 
Grading of common adverse events for MEK inhibitors 
 
Table 8-1 
CTCAE grading for eye disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL 
3 
Severe or medically significant but not immediately sight threatening; 
Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care 
ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the 
affected eye 
ADL= activities of daily living 
 
Retinal Detachment should be graded according to the CTCAE version 4.03 as described below in Table 
8-2. 
Table 8-2 
CTCAE grading for retinal detachment 
Grade 
Description 
1 
Asymptomatic 
2 
Exudative and visual acuity 20/40 or better 
3 
Rhegmatogenous or exudative detachment; operative intervention indicated; decline in vision 
(worse than 20/40*but better than 20/200*) 
4 
Blindness (20/200* or worse) in the affected eye 
 
 
Uveitis should be graded according to the CTCAE version 4.03 as described below in Table 8-3.  
Table 8-3 
CTCAE grading for uveitis 
Grade 
Description 
1 
Asymptomatic; clinical or diagnostic observations only 
2 
Anterior uveitis; medical intervention indicated 
3 
Posterior or pan-uveitis 
4 
Blindness (20/200* or worse) in the affected eye 
* 
Please refer to Snellen Equivalence (Visual Acuity Conversion Chart). 
 

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Hand Foot Skin Reaction should be graded according to CTCAE version 4.03 as described below in Table 
8-4. 
Table 8-4 
CTCAE grading of Hand foot skin reaction (HFSR)a 
Grade 
Description 
1 
Minimal skin changes or dermatitis (e.g., erythema, edema, numbness, dysesthesia, paresthesia, 
tingling or hyperkeratosis) without pain 
2 
Skin changes (e.g.,peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
3 
Severe skin changes (e.g., peeling, ulceration, blisters, bleeding, edema, or hyperkeratosis) with 
pain; limiting self-care ADL 
ADL=activities of daily living 
aHFSR or palmar-plantar erythrodysesthesia syndrome, a disorder characterized by redness, marked discomfort, 
swelling, and tingling in the palms of the hands or the soles of the feet; 
bMore specifics examples to grade 1 and grade 3 are added to facilitate proper grading [from the sorafenib package 
insert (West Haven, CT: Bayer Pharmaceuticals Corporation; 2007); Porta et al 2007]. 
 
Diarrhea should be graded according to CTCAE version 4.03 as described below in Table 8-5. 
Table 8-5 
CTCAE grading of diarrhea 
Grade 
Description 
1 
Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline 
2 
Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared to 
baseline 
1-2 Complicated  
Definition as above with the following complicating signs/symptoms: 
- 
Moderate to severe cramping 
- 
Grade ≥ 2 nausea/vomiting 
- 
Decreased performance status 
- 
Fever 
- 
Sepsis 
- 
Neutropenia 
- 
Frank bleeding 
- 
Dehydration 
- 
Unresolved diarrhea after 48 hours of treatment with loperamide (including high dose 
administration) and initiation of second-line treatment 
3 
Increase of ≥ 7 stools per day over baseline; hospitalization indicated; severe increase in ostomy 
output compared to baseline; limiting selfcare ADL 
4 
Life threatening consequences; urgent intervention indicated 
ADL=activities of daily living 
 
Weight Gain 
 As weight gain can be considered a desired effect in children who are growing, weight gain will be assessed 
as follows:  
• 
For any weight gain ≥ 20% above the baseline growth curve, evaluation of underlying organ 
function should be completed (including, but not limited to, echocardiogram, thyroid function 
studies and renal function panel).  
• 
If underlying organ dysfunction is found and/or if weight gain is associated with generalized edema, 
patient discomfort or concern that the weight gain may have negative health consequences, the 
weight gain should be graded as an AE as per the CTCAE guidelines.  

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• 
If the patient is asymptomatic and no underlying organ dysfunction is found as detailed above, the 
primary study team may consider the weight gain to be a desirable effect. In this case, weight gain 
would not be considered an adverse event and therefore would not be graded as such. 
8.2 
Binimetinib dose modification guidelines 
Pediatric Subjects 
For pediatric patients who do not tolerate the 32 mg/m2 BID dosing schedule (per tables 8.6 and 8.7), dose 
adjustment to 24 mg/m2 is permitted in order to allow the patient to continue on study drug, but dose level 
-1 may not exceed 30 mg/dose for any subject. Further dose adjustment to 16 mg/m2 and 12 mg/m2 will be 
permitted following the same rules as outlined in the dose modification tables 8.6 and 8.7, and as per 
Appendix XIX and XX. Changes must be recorded on the specific section of the CRF.  
A dose reduction below 12 mg/m2 is not allowed. Patients with AEs that require a dose modification at the 
12 mg/m2 BID dose must be discontinued from study treatment. Dose interruptions of more than 28 days 
are not allowed. 
 
Pediatric Stratum Dose Level 
Binimetinib Dose 
0 
32 mg/m2 BID 
-1 
24 mg/m2 BID 
-2 
16 mg/m2 BID 
-3 
12mg/m2 BID 
Adult Subjects 
Initially, adult subjects (Stratum A) received binimetinib by mouth on a BID dosing schedule of 45mg/dose 
(the established adult RP2D). Because 4 of the first 11 enrolled subjects chose to remove themselves from 
study for “intolerable” skin AE’s at the 45 mg BID dosing, the starting dose for the adult stratum is reduced 
from 45 mg BID to 30 mg BID in Protocol Version 2.0. Subjects who enrolled prior to protocol version 2.0 
and tolerate binimetinib at 45 mg PO BID can continue on that dosing regimen if the treating physician 
believes that this is in the best interest of the patient.  For adult patients who do not tolerate the 45 mg BID 
dosing schedule (per tables 8.6 and 8.7), dose adjustment to 30 mg BID is permitted in order to allow the 
patient to continue on study drug. For patients taking 30 mg bid further dose adjustment to 15 mg BID will 
be permitted following the same rules as outlined in the dose modification tables 8.6 and 8.7. Subjects who 
enrolled with protocol version 2.0 or later start binimetinib at 30 mg PO BID. For adult patients who do not 
tolerate the 30 mg BID dosing schedule (per tables 8.6 and 8.7), dose adjustment to 15 mg BID is permitted. 
A dose reduction below 15 mg BID is not allowed. Dose interruptions of more than 28 days are not allowed. 
Changes must be recorded on the specific section of the CRF.   
 
 
Adult Stratum Dose Level 
Binimetinib Dose 
-1 
30 mg BID 
-2 
15 mg BID 
 
For all subjects 
When the toxicity that resulted in a dose reduction improves to and remains stable at Grade 1 or less for a 
minimum of 28 days, the dose can be re-escalated at the investigators discretion provided there are no other 
concomitant toxicities. However, if the same toxicity occurs, the dose must be de-escalated again and re-
escalation for a 2nd time is not permitted. Of note, NO subjects were dose reduced to 30 mg PO BID or 
less, may not re-escalate their dose higher than 30 mg BID.   
 

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No dose re-escalation is allowed after dose reduction due to left ventricular dysfunction or prolonged 
QTcF > 500 msec. 
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade of the toxicity 
and the guidelines provided below. In general, doses should not be reduced or interrupted for Grade 1 
toxicities, but treatment to control symptoms should be provided as appropriate. All AEs should be followed 
weekly or as clinically appropriate until stabilization or resolution. 
 
Please refer to section 8.3 for dose adjustment recommendations for binimetinib induced toxicities.  
 
Table 8-6 Criteria for holding study drug 
 
For details on management of specific adverse events, please see table 8.7. Please email study chairs 
sabine.mueller@ucsf.edu, FisherM@email.chop.edu and Alyssa.reddy@ucsf.edu if there is an AE 
that prompts a study drug hold.  
 
 
TOXICITY 
STUDY DRUG HOLD CRITERIA 
Hematology 
CTCAE grade 4 neutropenia lasting more than 7 consecutive  days  
CTCAE grade 4 thrombocytopenia  
CTCAE Grade 3 or 4 neutropenia with fever (temperature ≥ 38.5°C)  
Skin and subcutaneous 
tissue disorders 
 
Rash, HFSR or photosensitivity CTCAE Grade 3 for> 7 consecutive days 
despite maximum skin toxicity treatment (as per local practice) 
Rash, HFSR or photosensitivity CTCAE Grade 4 
Eye disorders 
CSR (Retinopathy) CTCAE Grade 2 for > 14 consecutive days confirmed 
by ophthalmologic examination 
CSR (Retinopathy) or other Visual event CTCAE Grade ≥ 3, confirmed by 
ophthalmologic examination 
Gastro-intestinal 
≥ CTCAE grade 3 nausea or vomiting ≥ 48 hrs despite optimal anti-emetic 
therapy 
≥ CTCAE grade 3 diarrhea ≥ 48 hrs despite optimal anti-diarrhea treatment 
Hepato-biliary 
≥ CTCAE grade 3 total bilirubin  
≥ CTCAE grade 3 ALT (isolated increases in AST without concomitant 
increases in ALT will not be considered dose-limiting, because of the non-
specific nature of AST) 
Serum alkaline phosphatase CTCAE Grade 4 for > 7 consecutive days 
ECG QT Interval 
QTc interval ≥ 501 ms confirmed on a least 2 ECGs  
Renal 
Serum creatinine > 2x ULN 
Non-hematologic 
events 
≥ CTCAE grade 3, except for the exclusions noted below 
The following do not 
require holding drug 
≥ CTCAE Grade 3 alopecia 
 

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8.3 
Criteria for dose-modification in case of suspected binimetinib toxicity and re-initiation of treatment  
Table 8-7  
Binimetinib – Recommended dose modifications associated with treatment-related adverse 
events  
Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specifieda) 
Dose adjustment for binimetinib 
Eye disorder - CSR like events  
Grade 1 
Maintain dose level of binimetinib and increase frequency of ophthalmic monitoring to at least every 
14 days 
Grade 2 or 3  
Interrupt binimetinib and refer the patient to ophthalmologist within one week: 
- If resolved to Grade ≤ 1 in ≤ 28 days, reduce 1 dose levelb of binimetinib 
- If not resolved to Grade ≤ 1 in ≤ 28 days, discontinue patient from study drug treatment 
Grade 4 
Permanently discontinue binimetinib and immediately follow up with ophthalmic monitoringc 
Eye disorder - RVO  
RVO of any grade 
Permanently discontinue binimetinib 
Other eye disorders (i.e. retinal detachment)  
Grade 1 
Maintain dose level of binimetinib and increase frequency of ophthalmic monitoring to at least every 
14 days 
Grade 2 - 3 
Interrupt binimetinib and refer patient to ophthalmologist within one week: 
- If resolved to Grade ≤ 1 in ≤ 28 days, reduce 1 dose levelb of binimetinib 
- If not resolved to Grade ≤ 1 in ≤ 28 days, permanently discontinue binimetinib 
Grade 4 
Permanently discontinue binimetinib 
Liver related adverse events  
AST or ALT 
Grade 1 (> ULN - 3 x ULN) 
Maintain dose level of binimetinib  
Grade 2 
AST or ALT (> 3 - 5.0 x ULN or 3 
x baseline value) AND blood 
bilirubin* ≤ 2.0 x ULN 
 
 
AST or ALT (> 3.0 - 5.0 x ULN) 
AND blood bilirubin* > 2.0 x ULN 
Interrupt dose of binimetinib until resolved to Grade ≤1, then: 
- If resolved in ≤ 14 days, maintain dose level of binimetinib  
- If resolved in > 14 days, reduce dose level of binimetinib  
 
Interrupt dose of binimetinib until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, reduce dose level of binimetinib. 
- If resolved in > 7 days, discontinue patient from study drug treatment. 
Grade 3 
AST or ALT (> 5.0 - 8.0 x ULN)  
AND blood bilirubin* ≤ 2.0 x ULN 
 
 
AST or ALT (>8 x ULN) AND 
blood bilirubin* ≤ 2.0 x ULN 
 
AST or ALT (> 5.0 x ULN) AND 
blood bilirubin* > 2.0 x ULN 
Interrupt dose of binimetinib until resolved to Grade ≤ 1), then: 
 
- If not resolved to Grade ≤ 1 in ≤ 28 days, permanently discontinue binimetinib  
- If resolved to Grade ≤ 1 in ≤ 28 days, reduce 1 dose level of binimetinib  
 
Permanently discontinue binimetinib 
 
 
Permanently discontinue binimetinib  

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Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specifieda) 
Dose adjustment for binimetinib 
AST or ALT Grade 4 (> 20.0 x 
ULN) 
First occurrence Grade 4: 
Withhold binimetinib for up to 4 weeks. 
- If improved to Grade 0 or 1, or Grade ≤2 if liver metastasis, then resume at reduced 
dose. 
- If not improved to Grade 0 or 1 within 4 weeks, permanently discontinue. 
 
Recurrent Grade 4: 
Permanently discontinue binimetinib 
Cardiac disorders (dose adjustment for binimetinib only) 
Left ventricular 
systolic dysfunctiona 
Asymptomatic 
decrease of >10% in 
LVEF compared to 
baseline and the 
LVEF is below the 
institution’s lower 
limit of normal 
Interrupt dose of binimetinib and repeat evaluation of LVEF within 2 weeks 
If the LVEF recovers (defined as ≥ LLN and decrease ≤ 10% compared to baseline) ≤ 4 weeks, 
reduce 1 dose levelb. Monitor LVEF 2 weeks after restarting on binimetinib, every 4 weeks for 12 
weeks and subsequently as per protocol. 
If the LVEF does not recover within 4 weeks, permanently discontinue patient from study treatment. 
Closely monitor LVEF until resolution (or 16 weeks). 
Grade 3 – 4 
Permanently discontinue patient from binimetinib. Closely monitor LVEF until resolution (or 16 
weeks) 
Note: Copies of ECHO and/or MUGA scans could be requested for patients with decrease of >10% in 
LVEF compared to baseline and LVEF < LLN 
CK elevation (dose adjustment for binimetinib only) 
Grade 1-2 
Continue treatment on same dose level 
(If total CK ≥ 3 X ULN, measure isoenzymes and myoglobin in blood and urine 
Grade 3 
(> 5.0 - 10.0 x ULN) 
If asymptomatic, maintain dose of binimetinib. Monitor closely and measure isoenzymes and 
myoglobin in blood and urine  
If symptomatic (muscle pain/spasms), interrupt dose of binimetinib until resolved to CTCAE Grade ≤ 
1 and monitor closely then: 
- If resolved in ≤ 28 days, reduce 1 dose levelb of binimetinib 
- If resolved in > 28 days, permanently discontinue binimetinib 
Grade 4 
If asymptomatic, interrupt dose of binimetinib and monitor closely 
- If resolved in ≤ 28 days, reduce 1 dose levelb of binimetinib 
- If resolved in > 28 days, permanently discontinue binimetinib 
If symptomatic, permanently discontinue binimetinib 
QTc Prolongation 
QTcF > 500 msec 
(Grade 3) 
(confirmed by at least 2 
ECGs 5 minutes apart) 
1st occurrence: a repeat ECG confirming the prolonged QTc should be obtained. While waiting to 
have the 2nd ECG completed, treatment with binimetinib should be temporarily suspended.  
Electrolyte abnormalities, if any, should be corrected and any concomitant medication that may 
potentially prolong QT should be discontinued prior to repeating the ECG. Patient monitoring 
until resolution of the adverse event should be implemented in the hospital including a 
consultation with a cardiologist. Once the QTc prolongation has resolved (CTC Grade < 1), 
binimetinib may be restarted at a reduced dose. 
2nd occurrence: If a second episode occurs that is attributed to binimetinib, study drug must be 
permanently discontinued. 
Rash 
Grade 1 
Treatment with binimetinib should be maintained at the current dose 
Initiate prophylactic regimen if it was not already started and monitor closely 

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Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specifieda) 
Dose adjustment for binimetinib 
Grade 2  
1st occurrence: Treatment with binimetinib should be maintained at the current dose and rash should 
be closely monitored. Initiate prophylactic regimen if it was not already started. 
Reassess within a maximum of two weeks. If rash worsens or does not improve, current dosing may 
be continued, as long as it is not intolerable to patient. and does not increase in grade. If rash worsens 
or does not improve, and is intolerable to patient, interrupt dosing until improvement to Grade ≤ 1. 
Resume treatment at reduced dose level. If there is no re-occurrence of grade 2 rash, the treating 
physician has the option to re-escalate after 28 days if thought to be in the best interest of the patient.  
2nd occurrence: Treatment with binimetinib should be dose reduced and rash should be closely 
monitored.    
Reassess within a maximum of two weeks. If rash worsens or does not improve, interrupt dosing until 
improvement to Grade ≤ 1. Resume treatment at reduced dose level. If there is no re-occurrence of 
grade 2 rash, the treating physician has the option to re-escalate after 28 days if thought to be in the 
best interest of the patient.  
Grade 3 
1st occurrence:  Treatment with binimetinib should be interrupted. Reassess the patient weekly.  
Consider referral to dermatologist and manage rash per dermatologist’s recommendation. 
-Interrupt treatment until improvement to Grade ≤ 1. Resume treatment with binimetinib at reduced 
dose level. If there is no re-occurrence of grade 3 rash, the treating physician has the option to re-
escalate after 4 weeks if though to be in the best interest of the patient.  
 
2nd occurrence: Interrupt treatment until improvement to Grade ≤ 1. Resume treatment with 
binimetinib at a reduced dose level. 
Consider referral to dermatologist and manage rash per dermatologist’s recommendation 
Grade 4 
Permanently discontinue binimetinib 
Diarrhea 
Grade 1-2 
Consider temporary interruption of binimetinib until resolved to Grade ≤ 1. Treatment with 
binimetinib may then be resumed at the same dose level 
Grade 3 
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. If diarrhea resolves within 3 
days to grade 1 or less, patient can be restarted on the same dose level. If > 3 days, restart binimetinib 
at a reduced dose level 
Grade 4 
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. Restart binimetinib at a 
reduced dose level 
Nausea/Vomiting 
Grade 1-2 
Treatment with binimetinib should be maintained at the current dose. Promptly institute antiemetic 
measure.  
Grade 3 
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. Resume treatment with 
binimetinib at the same dose if, in the judgment of the investigator, the toxicity is considered to be 
unrelated to binimetinib, or at one reduced dose level. 
Note: Interupt dose for ≥ grade 3 vomiting or grade 3 nausea only if the vomiting or nausea cannot be 
controlled with optimal antiemetics (as per local practice) 
Grade 4 
Permanently discontinue binimetinib treatment 
All other adverse events (suspected to be related) 
Grade 2 (intolerable) 
adverse reactions 
- Withhold binimetinib for up to 4weeks or until resolved to Grade 0 or 1 and restart at a reduced dose. 
If there is no re-occurrence of the grade 2 intolerable adverse event, the treating physician has the 
option to re-escalate after 4 weeks if thought to be in the best interest of the patient. 
Grade 3 or 4 
Withhold binimetinib for up to 3 weeks. 
- If improved to Grade 0 or 1 or pretreatment/baseline level, resume at reduced dose. 
- If not improved, permanently discontinue. 
 
 
a Not according to CTCAE 

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Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specifieda) 
Dose adjustment for binimetinib 
b Dose reduction below 15 mg (for adults) or 12 mg/m2 (for children) BID for binimetinib is not allowed 
c Ophthalmic monitoring recommended: further evaluation with specialized retinal imaging (e.g. ocular coherence 
tomography, angiography) 
*Refers to total bilirubin 
 
 
Weight Gain 
For patients who experience ≥ grade 3 weight gain, binimetinib can be restarted when weight has resolved 
to ≤ grade 2 at investigator discretion. 
8.4 
Toxicities Requiring Removal from Protocol Therapy 
 
For the adult stratum: Any toxicity defined in section 8.2 or 8.3 that is at least possibly related to study 
medication that recurs on the lowest dose of binimetinib (dose level -2). No subject may be dose-reduced 
past dose level -2. 
 
For the pediatric stratum: Any toxicity defined in section 8.2 or 8.3 that is at least possibly related to 
study medication that recurs on the lowest dose of binimetinib (dose level -3). No subject may be dose-
reduced past dose level -3. 
 
Any ≥ Grade 3 toxicity that is at least possibly due to study drug that does not resolve to ≤ Grade 1 within 
the guidelines in section 8.3 requires dose reduction by one dose level. If the subject cannot be further 
dose reduced, then this requires removal from protocol therapy.     
 
Development of retinal vein occlusion of any grade will also require removal from protocol therapy. 
 
Development of glaucoma, intraocular pressure >21 mmHg, or any other significant abnormality on 
ophthalmic examination (performed by an ophthalmologist) while on study treatment will require removal 
from protocol therapy. Ophthalmological findings secondary to long-standing Optic Pathway Glioma 
such as optic nerve pallor or strabismus will NOT be considered significant for the purposes of the study. 
 
The study chair, the study co-chair and the NF Operations Center should be contacted for any questions 
regarding toxicity. 
 
9.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Study evaluations are summarized in the observation table in Appendix I. 
9.1 
Required Clinical, Laboratory and Disease Evaluation 
 
All entry/eligibility studies must be performed within 2 weeks prior to enrollment into the trial (unless 
otherwise specified). The baseline MRI study documenting disease status is required within 4 weeks prior 
to enrollment. Entry/eligibility studies (laboratory and MRI) may be counted as the baseline (pre-study) 
studies as long as there has been no concerning change in clinical status prior to starting study drug. Study 
drug must start within 14 days of enrollment. 
 

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All studies to determine eligibility for Re-Treatment must be performed within 2 weeks prior to 
“enrollment” on the Re-Treatment arm except for MRI, ophthalmology, Echo, and EKG (which is 
required within 4 weeks prior to “enrollment” on the Re-Treatment Arm), unless otherwise indicated. Re-
Treatment eligibility studies may be counted as the Re-Treatment baseline studies as long as there has 
been no concerning change in clinical status prior to starting study drug, except for pregnancy testing in 
females of childbearing age which must be negative within 7 days prior to re-starting binimetinib. Study 
drug must start within 14 days of “enrollment” on the Re-Treatment Arm. 
 
9.2 
History and physical examination and vital signs  
 
Initial Treatment 
Physical examination will be performed prior to entry, at the end of courses 1 (+1week); 2 (+1week), 3 
(+1 week), 4 (+1 week), 6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 
(+2 weeks), 21(+2 weeks), and 24 (+2 weeks).  In addition, at the end of treatment +2 weeks if this is not 
encompassed in the times above. The exam must comprise a total body examination (general appearance, 
skin, neck, including eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and 
basic nervous system). This should also include a neurological exam. Concomitant medications should be 
reviewed at each visit. Significant findings made after the start of study drug which meet the definition of 
an Adverse Event must be recorded.  
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, temperature, and 
weight.  
Complete medical history should be recorded at the baseline visit. 
 
Re-Treatment 
Physical examination will be performed prior to entry, at the end of courses 2 (+1week), 4 (+1 week), 6 
(+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 weeks), 21(+2 weeks), 
and 24 (+2 weeks).  In addition, at the end of treatment +2 weeks if this is not encompassed in the times 
above.  For participants staying on study while arrangements are being made to transition the participant 
to a MEK inhibitor off study (see section 6.2), physical examination should be performed after every 3 
cycles (27, 30, 33, 36) +2 weeks. 
 
The exam must comprise a total body examination (general appearance, skin, neck, including eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and basic nervous system). This 
should also include a neurological exam. Concomitant medications should be reviewed at each visit. 
Significant findings made after the start of study drug which meet the definition of an Adverse Event 
must be recorded.  
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, temperature, and 
weight.  
Complete medical history should be recorded at the baseline visit. 
9.3 
Ophthalmological Toxicity Exam 
 
Initial Treatment 
Subjects will have a standard ophthalmological exam with emphasis on corneal, lens and retinal changes. 
In subjects with orbital plexiform neurofibromas the intraocular pressure should be measured at baseline 
and subsequently if feasible. Exams should occur prior to entry, and post courses 4 (+2 weeks), 8 (+2 
weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks). In addition, at the end of treatment +2 weeks if 
this is not encompassed in the times above. 

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Re-Treatment 
All subjects will have a standard ophthalmological exam with emphasis on corneal, lens and retinal 
changes. In subjects with orbital plexiform neurofibromas the intraocular pressure should also be 
measured at baseline and subsequently if feasible. Exams should occur prior to entry, and post courses 6 
(+2 weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks). In addition, at the end of treatment +2 
weeks if this is not encompassed in the times above.  For participants staying on study while 
arrangements are being made to transition the participant to a MEK inhibitor off study (see section 6.2), 
ophthalmological exam should be performed after every 6 cycles (30, 36) +2 weeks. 
 
Subject with evidence of disease (retinal vein occlusion) should have a full evaluation (such as 
fluorescein angiography and/or optical coherence tomography) as per institutional guidelines.   
 
For details how to record visual functioning please refer to Appendix XII. 
9.4 
Hematology 
 
Initial Treatment 
CBC must include hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential.  
CBC must be performed within two weeks prior to entry on trial, at the end of courses 1 (+1 week), 2 (+1 
week), 3 (+1 week), 4 (+1 week), 6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 
weeks), 18 (+2 weeks), 21(+2 weeks), and 24 (+2 weeks). In addition, at the end of treatment +2 weeks if 
this is not encompassed in the times above. 
 
Re-Treatment 
CBC must include hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential.  
CBC must be performed within two weeks prior to entry, at the end of courses 2 (+1 week), 4 (+1 week), 
6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 weeks), 21(+2 weeks), 
and 24 (+2 weeks).  In addition, at the end of treatment +2 weeks if this is not encompassed in the times 
above. For participants staying on study while arrangements are being made to transition the participant to 
a MEK inhibitor off study (see section 6.2), hematology labs should be performed after every 3 cycles 
(27, 30, 33, 36) +2 weeks. 
 
9.5 
Blood chemistry 
 
Initial Treatment 
Blood chemistry must include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, glucose, 
creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, 
alkaline phosphatase, and CPK. Blood chemistries should be drawn within two weeks prior to study 
entry, at the end of courses 1 (+1 week), 2 (+1week), 3 (+1 week), 4 (+1 week), 6 (+2 weeks), 8 (+2 
weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 weeks), 21(+2 weeks), and 24 (+2 weeks).  
In addition, at the end of treatment +2 weeks if this is not encompassed in the times above.  
 
Re-Treatment 
Blood chemistry must include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, glucose, 
creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, 
alkaline phosphatase, and CPK. Blood chemistries should be drawn within two weeks prior to entry, at 
the end of courses 2 (+1 week), 4 (+1 week), 6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 
15 (+2 weeks), 18 (+2 weeks), 21(+2 weeks), and 24 (+2 weeks). In addition, at the end of treatment +2 
weeks if this is not encompassed in the times above. For participants staying on study while arrangements 

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are being made to transition the participant to a MEK inhibitor off study (see section 6.2), chemistry labs 
should be performed after every 3 cycles (27, 30, 33, 36) +2 weeks. 
9.6 
Serum or Urine Pregnancy Test 
 
Initial Treatment 
Standard pregnancy tests will be given to all females of childbearing age within 7 days prior to starting 
treatment medication. In addition, tests will be administered post courses 1 (+1 week),  2 (+1week), 3 (+1 
week), 4 (+1 week), 6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 
weeks), 21(+2 weeks), and 24 (+2 weeks) to ensure that females are not pregnant while on the study 
medication. In addition, at the end of treatment +2 weeks if this is not encompassed in the times above. 
 
Re-Treatment 
Standard pregnancy tests will be given to all females of childbearing age within 7 days prior to starting 
treatment medication. In addition, tests will be administered at the end of courses 2 (+1 week), 4 (+1 
week), 6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 weeks), 21(+2 
weeks), and 24 (+2 weeks).  In addition, at the end of treatment +2 weeks if this is not encompassed in the 
times above. For participants staying on study while arrangements are being made to transition the 
participant to a MEK inhibitor off study (see section 6.2), standard pregnancy testing should be performed 
after every 3 cycles (27, 30, 33, 36) +2 weeks. 
9.7 
ECHO (or MUGA) and ECG 
 
Initial Treatment 
Standard ECHO (or MUGA) and ECG should be obtained within 4 weeks prior to study entry and after 
courses 4 (+2 weeks), 8 (+2 weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks) while on study and 
at end of study (+2 weeks). In addition, at the end of treatment (+2 weeks) if this is not encompassed in 
the times above. 
 
Re-Treatment 
Standard ECHO (or MUGA) and ECG should be obtained within 4 weeks prior to study entry and after 
courses 6 (+2 weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks) while on study and at end of 
study (+2 weeks). In addition, at the end of treatment (+2 weeks) if this is not encompassed in the times 
above. For participants staying on study while arrangements are being made to transition the participant to 
a MEK inhibitor off study (see section 6.2), standard ECHO (or MUGA) and ECG should be performed 
after every 6 cycles (30, 36) +2 weeks. 
 
9.8 
MRI for volumetric analysis of plexiform neurofibroma (Appendix IV) 
 
Initial Treatment 
Evaluate the plexiform neurofibromas(s) by MRI within 4 weeks prior to enrollment and after courses 4 
(+2 weeks), 8 (+2 weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks) while on study and at end of 
study (+2 weeks). In addition, at the end of treatment (+2 weeks) if this is not encompassed in the times 
above. To evaluate the durability of response, subjects who responded while on treatment (>20% target 
lesion shrinkage by course 12), should have a follow-up MRI scan at approximately 4 months and 12 
months following completion of therapy. Of note, this scan does not have to be performed at the study 
site but needs to be submitted for evaluation by the enrolling site. If a subject starts another tumor-
directed therapy during the one year follow-up time, then they are off-study and no further MRIs 
requested. 
 

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Re-Treatment 
Evaluate the plexiform neurofibromas(s) by MRI within 4 weeks prior to entry and after courses 4 (+2 
weeks), 8 (+2 weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks) while on study and at end of 
study (+2 weeks). In addition, at the end of treatment (+2 weeks) if this is not encompassed in the times 
above. For participants staying on study while arrangements are being made to transition the participant to 
a MEK inhibitor off study (see section 6.2), MRI should be performed after every 6 cycles (30, 36) +2 
weeks. 
The imaging protocol outlined in Appendix IV will be used each time MRI examinations are performed to 
assess progression or response. In subjects with clinical suspicion of disease progression, MRI analysis 
should be performed earlier using the protocol outlined in Appendix IV. If because of unforeseen reasons, 
an MRI time window is passed, but not yet at the time of the opening of the subsequent window, the MRI 
should be performed and the protocol violation noted. 
9.9 
Photographs and Functional Evaluations (Appendix XVI) (Initial Treatment only) 
 
Subjects will take photographic documentation of visible target PN (Appendix XVI) and functional 
evaluations based on tumor location (Appendices XII-XIV) at the following time points: within 4 weeks 
prior to course 1 and after courses 4 (+2 weeks), 8 (+2 weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 
weeks) while on study and at end of study (+2 weeks). In addition, at the end of treatment (+2 weeks) if 
this is not encompassed in the times above. Functional assessments are ideally carried out by the same 
person for any given subject. 
9.10 
Plexiform Neurofibroma Clinician Morbidity Assessment (Appendix XI)  
 
Initial Treatment 
This form should be completed by the treating physician at baseline and after courses 4 (+2 weeks), 8 (+2 
weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks) while on study and at end of study (+2 weeks).  
In addition, at the end of treatment (+2 weeks) if this is not encompassed in the times above. This 
assessment is ideally carried out by the same person for any given subject. 
 
Re-Treatment 
This form should be completed by the treating physician at baseline and after courses 4 (+2 weeks), 8 (+2 
weeks), 12 (+2 weeks), 18 (+2 weeks), and 24 (+2 weeks) while on study and at end of study (+2 weeks).  
In addition, at the end of treatment (+2 weeks) if this is not encompassed in the times above. This 
assessment is ideally carried out by the same person for any given subject. This is not required for 
participants staying on study while arrangements are being made to transition the participant to a MEK 
inhibitor off study (see section 6.2). 
9.11 
Binimetinib diary (Appendix V) 
 
Initial Treatment 
A diary will be kept by the subject and/or proxy (see Appendix V). A document developed by the local 
institution can be used as a substitute for Appendix V. The diary will be reviewed with the treating 
physician at the history/physical visit at the end of courses 1 (+1week); 2 (+1week), 3 (+1 week), 4 (+1 
week), 6 (+2 weeks), 8 (+2 weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 weeks), 21(+2 
weeks), and 24 (+2 weeks). In addition, at the end of treatment +2 weeks if this is not encompassed in the 
times above. 
 
Re-Treatment 

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A diary will be kept by the subject and/or proxy (see Appendix V). A document developed by the local 
institution can be used as a substitute for Appendix V. The diary will be reviewed with the treating 
physician at the history/physical visit at the end of courses 2 (+1 week), 4 (+1 week), 6 (+2 weeks), 8 (+2 
weeks), 10 (+2 weeks), 12 (+2 weeks), 15 (+2 weeks), 18 (+2 weeks), 21(+2 weeks), and 24 (+2 weeks).   
In addition, at the end of treatment +2 weeks if this is not encompassed in the times above. For 
participants staying on study while arrangements are being made to transition the participant to a MEK 
inhibitor off study (see section 6.2), diary should be reviewed with the treating physician after every 3 
cycles (27, 30, 33, 36) +2 weeks. 
9.12 
Plasma Cytokines and Growth Factors (Optional) (Appendix VII) (Initial Treatment only) 
 
Procedure: 10 ml blood will be drawn into EDTA tubes before treatment initiation, post course 1 and post 
course 4. The sample will be collected at least 30 min but no more than 2 hours after taking the morning 
dose. Any remaining specimens will be stored for future research with subject consent. See Appendix VII 
for more details. 
 
Maximum blood volumes for cytokine studies: 
Institutional guidelines will be followed for maximum blood volumes for research samples. The table 
below provides details regarding blood volumes obtained for research studies during the study. 
 
 
Type of test 
Volume per sample (ml) 
Number of samples 
(volume for all samples, ml) 
Plasma Cytokines and Growth 
Factors 
10 
3 (30) 
 
Total volume for research samples 
3 (30) 
 
 
9.13 
Biological Specimens for banking (Appendix XXI)  
 
Initial Treatment (only) 
Blood Samples will be drawn at baseline (pre-treatment), after course 4 (+2 weeks), after course 12 (+2 
weeks), and at the end of treatment (+2 weeks) if this is not encompassed in the times above. In addition, 
blood samples should be drawn around the time of tumor biopsy if tumor tissue is being submitted. 
 
The following will be collected at each time point: 
• 
Streck tube (for plasma):  ~ 2 mL.  
• 
EDTA tube (for DNA):  ~ 5 mL.   
• 
PAXGene tube (for RNA) ~ 2.5 mL. 
 
Tubes should be inverted at least 10 times after being drawn. 
 
The samples will only be obtained if the total blood volume does not exceed 5 mL/kg. If not enough 
blood can be drawn for all tubes, the priority order for obtaining the specimens is:   
1) Streck tube, 2) EDTA tube, 3) PAXGene tube. 
 
Label the specimens with the specimen labels provided with the specimen kit. 
 

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Blood specimens must be shipped (unprocessed) same day at ambient temperature to the biorepository by 
overnight delivery using shipping container provided by the biorepository (see Appendix XXI). 
 
Any time on study (Initial Treatment or Re-Treatment) 
Tumor Tissue (optional) will be collected from subjects undergoing a clinically indicated procedure and 
who consent: 
• 
Fresh frozen tissue: 1-2 pea sized aliquots (~ 0.3 cm3, equivalent to 0.8 cm in diameter) of excess 
(left over) tumor tissue. Place each aliquot in a separate cryovial and label the specimen with 
subject’s study number. Snap freeze the aliquots in liquid nitrogen (preferred) or dry ice and then 
store in a freezer at -80°C or below until they can be sent to the biorepository. 
• 
1 H&E-stained slide cut from each submitted piece to confirm tumor is present.  
• 
If fresh frozen tissue is unavailable, please submit processed DNA (at least 3 micrograms) and 
RNA (at least 400 nanograms with optimal RIN > 7) if available.  
 
Fresh frozen tissue or DNA/RNA must be shipped on dry ice via overnight delivery using shipping 
materials provided by the biorepository (see Appendix XXI). H&E slide should be shipped at ambient 
temperature.   
9.14 
Baseline PN location and morbidity form (Appendix X) (Initial Treatment only) 
 
This form should be completed by the Site PI at the time of enrollment. 
9.15 
Symptom checklist completed by subject or their guardian (Appendix IX) 
 
Initial Treatment 
This form should be completed pre-treatment, after course 4 (+2 weeks), 8 (+2 weeks), 12 (+2 weeks), 18 
(+2 weeks), and 24 (+2 weeks). In addition, at the end of treatment (+2 weeks) if this is not encompassed 
in the times above. 
 
Re-Treatment 
This form should be completed pre-treatment, after course 4 (+2 weeks), 8 (+2 weeks), 12 (+2 weeks), 18 
(+2 weeks), and 24 (+2 weeks). In addition, at the end of treatment (+2 weeks) if this is not encompassed 
in the times above. This is not required for participants staying on study while arrangements are being 
made to transition the participant to a MEK inhibitor off study (see section 6.2). 
9.16 
Patient-reported Outcomes (PROs): Quality of Life (QOL) and Pain Evaluations (Required) 
 
This study will evaluate quality of life, pain intensity, and pain interference in subjects during treatment 
with binimetinib. Age-appropriate patient-reported outcome (PRO) measures will be administered based 
on a Pediatric Module and an Adult Module.   
 
The Pediatric Module (ages 1- 17 at study entry) will consist of the self-report and parent proxy Pediatric 
Quality of Life Inventory (PedsQL) Generic Module (Toddler, Child, Teen, and Young Adult forms) to 
assess QOL. Pain intensity will be assessed by self-report with the Numeric Rating Scale-11 (NRS-11) 
and pain interference will be measured by the Pain Interference Index (PII).  
 
The Adult Module (ages > 18 years at study entry) will consist of the Adult PedsQL™ NF1 Module 
(Adult self-report form) and the PlexiQoL to assess disease-specific QOL. Pain intensity will be assessed 
by self-report with the Numeric Rating Scale-11 (NRS-11) and pain interference will be measured by the 
Brief Pain Inventory (BPI) Pain Interference Scale.  
 

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The following table specifies the PRO module (pediatric or adult) to be administered by age of the 
subjects at study entry. The specific PRO measures to be administered within each module are 
specified in Appendix VIII. 
 
PRO Module Administered by Age of Subject at Study Entry* 
 
 
 
 
 
 
 
 
 
*See Appendix VIII for specific PRO questionnaires to administer per module, a 
detailed description of each measure, and important administration instructions.   
 
PRO Assessment Schedule 
 
Initial Treatment  
Baseline and follow-up PRO assessments 
The PRO forms should be completed pre-treatment, and again after course 4 +2 weeks, 8 +2 weeks, 12 +2 
weeks, 18 +2 weeks, and 24 +2 weeks. In addition, they should be administered at the end of treatment +2 
weeks if this is not encompassed in the times above.   
 
Re-Treatment  
Baseline and follow-up PRO assessments 
The PRO forms should be completed pre-treatment, and again after course 4 +2 weeks, 8 +2 weeks, 12 +2 
weeks, 18 +2 weeks, and 24 +2 weeks. In addition, they should be administered at the end of treatment +2 
weeks if this is not encompassed in the times above. This is not required for participants staying on study 
while arrangements are being made to transition the participant to a MEK inhibitor off study (see section 
6.2). 
 
Transmission of Completed Forms 
Completed and checked PRO forms should be sent (email copies) to the NF Consortium Operations 
Center within 2 weeks of completion along with the NF QOL Cover sheet to record the forms being sent 
and explain any issues with administration. Please make notes about any unclear responses or problems 
encountered. For any questions regarding the QOL/pain assessment please contact: Karin Walsh at 
KWalsh@childrensnational.org.  
 
PRO Central Review 
The QOL documents will be reviewed centrally by Dr. Karin Walsh. If any responses are noted that 
suggest serious emotional distress, the PI at the subject’s site will be notified but please note that central 
review will be conducted in real time. The site PI will be responsible for acknowledging to Dr. Walsh 
receipt of these concerns, and for initiating appropriate action as deemed clinically necessary. 
9.17 
Phone Call (Re-Treatment arm only) 
End of course 1 (+1week). To assess drug compliance and toxicity. 
 
Module of PRO questionnaires 
Age of Subject (years) at 
Study Entry 
 
1-17 
>18 
Pediatric PRO Module* 
X 
 
 
Adult PRO Module* 
 
 
X 

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10.0 
ADVERSE REPORTING REQUIREMENTS 
10.1 
Definitions 
 
• Adverse Events: An adverse event is any new, undesirable medical occurrence or change (worsening) 
of an existing condition in a subject that occurs during treatment, whether or not considered to be 
product related. Therefore, adverse events are treatment emergent signs or symptoms. Elective 
hospitalizations for pretreatment conditions (e.g., elective cosmetic procedures) are not adverse events. 
Non-clinically significant abnormal laboratory values should not be reported as adverse events; 
however, any clinical consequences of the abnormality should be reported as adverse events. All 
adverse events must be noted on the case report forms and submitted to the operations center within 2 
weeks of completion of every treatment course. 
 
For all adverse events, the site investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for classification 
as a serious adverse event requiring immediate notification (within 24 hours) to the Protocol PI and NF 
Consortium Operations Center clinical research nurse manager. Follow-up of the adverse event, even 
after the date of therapy discontinuation, is required if the adverse event or its sequelae persist. Follow-
up is required until the event or its sequelae resolve or stabilize at a level acceptable to the investigator 
and sponsor. 
• Serious Adverse Events: A serious adverse event is defined by regulatory agencies as one that suggests 
a significant hazard or side effect, regardless of the investigator’s or sponsor’s opinion on the 
relationship to investigational product. 
 
This includes, but may not be limited to, any event that (at any dose): 
• 
is FATAL 
• 
is LIFE THREATENING (places the subject at immediate risk of death); 
• 
requires HOSPITALIZATION or prolongation of existing hospitalization; 
• 
is a persistent or significant DISABILITY/INCAPACITY; or 
• 
is a CONGENITAL ANOMALY/BIRTH DEFECT 
 
Important medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or require intervention to prevent one of the outcomes 
listed above, or result in urgent investigation, may be considered serious. Examples include allergic 
bronchospasm, convulsions, and blood dyscrasias. A planned medical or surgical procedure is not, in 
itself, an SAE. 
 
10.2 
Common Terminology Criteria for Adverse Events (CTCAE) V.4.03 
 
This study will utilize the CTCAE of the National Cancer Institute for reporting and grading of adverse 
events. A copy of the current version of the CTCAE version 4.03 can be downloaded from the CTEP 
home page: http://ctep.cancer.gov/reporting/ctc.html. 
 
10.3 
Attribution: Definitions of relationship to study medication are as follows: 
 
• UNRELATED: bears no relation to timing of medication, similar to symptoms or signs expected in the 
disease process, does not recur on re-challenge. 

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• UNLIKELY: does not have temporal relationship to intervention, could readily have been produced by 
the subject’s clinical state, environmental, or other interventions, does not reappear or worsen with 
reintroduction of intervention. 
• POSSIBLY: bears relation to timing of medication, similar to symptoms or signs expected in the disease 
process, does not recur on re-challenge. 
• PROBABLY: bears clear relation to timing of medication, distinct from symptoms or signs expected in 
the disease process, does not recur on re-challenge. 
• DEFINITELY: bears clear relation to timing of medication, distinct from symptoms or signs expected in 
the disease process, occurs on re-challenge. 
 
The expected adverse events related to administration of binimetinib are listed in Section 6.1.4. All 
other adverse events not attributed to study drug will be considered unexpected. Adverse events 
attributable to study drug will be reported if the adverse events are at an intensity that is more severe 
than previously documented or considered significant by the investigator. 
 
10.4 
Reporting Procedures for All Adverse Events 
 
All observed or volunteered adverse events, regardless of suspected causal relationship to study drug, will 
be recorded as Adverse Events in the case report forms and submitted to the Operations Center within 2 
weeks of completion of each treatment course. Events involving adverse drug reactions, illnesses with onset 
during the study, or exacerbation of pre-existing illnesses should be recorded. Objective test findings (e.g., 
abnormal laboratory test results) should also be recorded.  
 
It will be left to the investigator’s clinical judgment whether or not an adverse event is of sufficient 
severity to require that the subject should be removed from treatment. A subject may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable adverse event. If either of these 
occurs, the subject will be given appropriate care under medical supervision until symptoms cease or until 
the condition becomes stable. 
 
Adverse events will be assessed by the treating investigator for relationship to the study drug (unrelated, 
unlikely, possible, probable, or definitely related).  
 
10.5 
Expedited Reporting Guidelines 
 
The following adverse events require expedited reporting: 
 
• 
All adverse events that are both serious and unexpected per section 6.1.4 
• 
Adverse events that, in the opinion of the treating physician, might influence the benefit-risk assessment 
of administration of  binimetinib as outlined in the protocol 
• 
All grade 5 adverse events 
• 
A serious adverse event that occurs within 30 days of the last dose of the investigational agent 
• 
In addition, if a male who has been exposed to binimetinib within 28 days prior to the time of 
conception, impregnates a female partner, then the female partner and fetus are considered “exposed 
during pregnancy”, and this event is reportable as an SAE irrespective of the presence of an associate 
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• 
In the case of an exposed female and fetus, follow-up will be conducted to obtain general information 
on the pregnancy (both the female and the fetus) and its outcome until the infant is 1 month postnatal. 
Neonatal deaths that occur within one month of birth should be reported, irrespective of causality, as 
SAEs. In addition, infant deaths after one month should always be reported when the investigator 
assesses the infant death as related to exposure to the investigational product. 
• 
Expedited AE reporting timelines defined: 
“24 hours; 24 hours” – The investigator must initially report the AE within 24 hours (or immediately 
if the event is fatal or life-threatening) of learning of the event to the Study Chairs 
(sabine.mueller@ucsf.edu), FisherM@email.chop.edu, and Alyssa.reddy@ucsf.edu, and NF 
Operations Center (nfcop@uab.edu) followed by a complete written report within 24 hours of the 
initial 24-hour report.  
 
Adverse events requiring expedited reporting will be reported and documented on Form FDA 3500A 
MedWatch Form http://www.fda.gov/medwatch/getforms.htm) and forwarded to: 
 
NF Consortium Operations Center 
Clinical Research Manager:  Lynn Merritt, RN                 
205-934-5376 
Program Director: Karen Cole – Plourde, BS                                205-934-5140 
Research Compliance Manager: Juliette Southworth, BS                205-975-4075 
Direct Email:  nfcop@uab.edu  
 
The clinical research nurse manager from the NF Consortium Operations Center will forward all related 
adverse events that are both serious and unexpected to Dr. Mueller and the PNOC operation’s office on 
Form FDA 3500A MedWatch Form http://www.fda.gov/medwatch/getforms.htm for submission to the 
FDA.   
  
MedWatch 
Fax: 1-800-FDA-0178 
 
Research Monitor, DSMB, NF Consortium IRB and other designated regulatory agencies will also 
receive MedWatch Form documents for adverse events requiring expedited reporting. 
 
10.5.1 Array BioPharma, a wholly owned subsidiary of Pfizer Inc. Expedited Reporting Guidelines 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has 
provided main informed consent and until at least 30 days after the patient has stopped study treatment 
must be reported to Array within 24 hours of learning of its occurrence. 
 
Any SAEs experienced after this 30 day period should only be reported to Array if the investigator 
suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression 
of the initial SAE must be reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough report. The 
investigator must assess and record the relationship of each SAE to each specific study treatment (if 
there is more than one study treatment), complete the SAE Report Form in English, and send the 

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completed, signed form by fax within 24 hours to the oncology Array Drug Safety department. 
 
PPD Pharmacovigilance (PVG) Fax: 1-888-488-9697 
 
The original copy of the SAE Report Form and the fax confirmation sheet, provided by NF Consortium 
Operations Center, must be kept with the case report form documentation at the site. 
 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, 
using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving 
the date of the original report. Each re-occurrence, complication, or progression of the original event 
should be reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated, and whether the 
patient continued or withdrew from study participation.   
 
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be related to 
the Array study treatment, an oncology Array Drug Safety associate may urgently require further 
information from the investigator for Health Authority reporting. Array may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
10.6 
Reporting of Protocol Violations/Deviations and Unanticipated Problems 
 
Site reporting to NF Operations Center 
Sites will report unanticipated problems and/or protocol deviations that impact subject safety or the 
scientific integrity of the study to the Operations Center promptly at nfcop@uab.edu. Other protocol 
violations and deviations should be reported to the NF Operations Center annually.   
 
NF Operations Center reporting requirements 
The Operations Center will report unanticipated problems that impact subject safety or the scientific 
integrity of the study to the USAMRMC ORP HRPO promptly. Unanticipated problems will also be 
reported to the protocol team, Research Monitor, FDA, NF Consortium IRB, Array BioPharma, a wholly 
owned subsidiary of Pfizer Inc., and DSMB. 
 
All unanticipated problems involving risk to subjects or others must be promptly reported by the NF 
Operations Center via phone (301-619-2165), email (usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil), or facsimile (301-619-7803) to the HRPO. A complete written report 
will follow the initial notification. In addition to the methods above, the complete report can be sent to the 
US Army Medical Research and Materiel Command, ATTN: MCMR-RP, 810 Schreider Street, Fort 
Detrick, Maryland 21702-5000.   
 
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the IRB, the 
institution, the Sponsor, or regulatory agencies will be promptly reported to the USAMRMC ORP HRPO. 
 
Other protocol violations and deviations that do not impact subject safety or affect scientific integrity of 
the study will be provided annually to the Sponsor. 
 
 

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11.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA  
 
11.1 
Criteria for Removal from Protocol Therapy  
 
a. Progressive disease (See Section 13) compared with pre-Treatment baseline for initial therapy. 
b. Completion of course 24 of initial therapy 
c. <20% reduction in target tumor volume (from baseline) after course 12 of initial therapy (Of note, 
subjects may begin course 13 while central review of tumor response is ongoing).  Of note, this does 
not apply to subjects on the Re-Treatment arm. 
d. Progressive disease (See Section 13) compared with pre-Re-Treatment baseline for Re-Treatment. 
e. Completion of course 24 of Re-Treatment (unless “f” below applies).   
f. For participants deriving benefit and for whom the treating team is working on transitioning the 
participant to a MEK inhibitor off study (see section 6.2), completion of course 36 of Re-Treatment 
or when off study MEK inhibitor is started, whichever is sooner.  
g. Treatment delays ≥ 28 days 
h. Refusal of further protocol therapy by subject/parent/guardian 
i. 
Non-compliance that in the opinion of the investigator does not allow for ongoing participation. 
j. 
Physician determines it is not in the subject’s best interest. 
k. Subject becomes pregnant 
l. 
Subject is prescribed a non-allowed concomitant medicine during study. 
m. Withdrawal of protocol consent 
n. Any surgical procedure on a target PN. 
o. Binimetinib-related toxicity requiring removal (see Section 8). 
 
Subjects who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below).  
  
11.2 
Off Study Criteria 
 
For subjects who did not have a response (<20% shrinkage of target tumor by course 12) or have tumor 
progression (≥ 20%) at any time: 
a) 
Thirty days after the last dose of binimetinib (but note that subjects with ongoing toxicity should be 
followed until the toxicity resolves or 30 days, whichever is longer) 
 
For subjects who had a response (≥20% target tumor shrinkage by course 12) and never experience tumor 
progression on initial treatment: 
b) 
Completion of their one year follow-up MRI scan unless they meet the criteria for “enrollment” on the 
Re-Treatment Arm 
 
For subjects who “enroll” on the Re-Treatment Arm and complete 24 courses: 
c) 
Thirty days after the last dose of binimetinib (but note that subjects with ongoing toxicity should be 
followed until the toxicity resolves or 30 days, whichever is longer). Note: for participants deriving 
benefit and for whom the treating team is working on transitioning the participant to a MEK 
inhibitor off study (see section 6.2), when off study MEK inhibitor is started. 
 
For all subjects (supercedes “a” or “b”): 
d) 
Death 
e) 
Lost to follow-up 
f) 
Withdrawal of consent for any further data submission. 

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g) 
Initiation of subsequent other medical treatment directed towards the plexiform neurofibroma 
h) 
Initiation of medical treatment (e.g. chemotherapy, biologic therapy, radiation therapy) directed 
towards other NF1-related tumor such as an optic pathway glioma 
 
12.0 
STATISTICAL AND ETHICAL CONSIDERATIONS   
 
12.1 
Subject Accrual 
 
Subjects of both genders, from all racial and ethnic groups are eligible for this trial if they meet the 
criteria outlined in Section 4.0. To date, there is no information that suggests differences in drug 
metabolism or disease response among racial or ethnic groups or between the genders, indicating that 
results of the trial will be applicable to all groups. Efforts will be made to extend the accrual to a 
representative population, but in a phase II study with limited accrual, a balance must be struck between 
subject safety considerations and limitations on the number of individuals exposed to potentially toxic or 
ineffective treatments on the one hand, and the need to explore gender, racial, and ethnic aspects of 
clinical research on the other. If differences in outcome that correlate to gender, age, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
12.2 
Statistics and Feasibility 
 
The primary objective of this study is to determine if there is an adequate level of disease responsiveness 
to binimetinib in children and adults with NF1 and inoperable plexiform neurofibromas. 
 
Sample Size 
 
Enroll 25 evaluable subjects per stratum (pediatric and adult). Target: minimum of 17 evaluable subjects 
per cohort. To allow for up to 25% unevaluable subjects, a maximum of up to 25 subjects per cohort will 
be enrolled. We anticipate enrollment to be completed within 12 months with the primary outcome 
measure defined in 24 months. 
 
The sample size for this trial is based on the primary factors: Safety and feasibility data needed:  
thus, safety based on risk versus benefit. For feasibility, we expect at least efficacy of a 25% response 
rate. We are only interested if binimetinib is positive and thus, assume a 1-sided test using a Type I error 
of 5%. We also want to achieve reasonable power within each of the two strata to enable its evaluation 
separately. We assume a null hypothesis success rate of 5% in each stratum versus a treatment with a 25% 
response rate. If all 20 patients are evaluable there is 80% power to detect differences between 25% and 
5% in each stratum with 80% power. The power in the strata is 64% when the minimal sample size is 
realized. If both strata perform the same, the power to reject the null hypothesis that the efficacy rate is 
5% versus 25% is 95% when the minimal sample size is available (2n=34). 
 
12.3 
Statistical Analysis Plan 
 
The basic statistical analysis plan for this proof-of-concept study will describe the subject population by 
baseline characteristics: clinical, PD, functional assessments, Quality of Life and pain scores at baseline. 
Following complete accrual, study logistics will be summarized as per a Consort Diagram with reasons 
for withdrawal or unable to complete the study tabulated. Appropriate data analysis sets will be defined. 
The full-analysis set will include data from all subjects who receive ≥1 dose of therapy on this study; a 

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safety analysis set will comprise data from subjects in the full-analysis set with any treatment doses. 
Other data sets (responding, evaluable, and pharmacodynamic data sets) will be defined and will include 
data from subjects who have the necessary baseline and on-study measurements to provide interpretable 
results for specific parameters of interest. 
 
Descriptive summaries will be prepared to show sample size, mean, standard deviation, 95% confidence 
intervals (CIs) on the mean, median, minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables. This will be done for each cohort 
separately. For endpoints relating to tumor control, subject well-being, and biomarkers, analyses will be 
done based on the full-analysis, responding, evaluable, or pharmacodynamic data sets, as appropriate.   
Comparison against the hypothesized control rate will be done using exact tests for a binomial with the 
full cohort and then by strata. Time-to-event analyses will be performed with reference to the date of first 
treatment on this study. Analyses will focus on evaluation of outcomes and will be largely descriptive in 
nature as per the sample size justification section within cohort. Changes in tumor volumes, etc. will be 
summarized by medians, ranges, and the corresponding 95% CI. Continuous and categorical variables 
will also be summarized as appropriate.  
 
Based on the safety analysis set, information regarding study treatment administration, drug dosing and 
course compliance, safety variables, will be described and summarized. Safety will be assessed via 
tabulations of AEs and SAEs as well as Diary recordings following treatment dose/course of therapy. 
 
All analyses for outcome results will be based on evaluable subjects, as defined in section 12.4. 
 
An early stopping rule will be invoked for both Strata separately to potentially prevent accrual of subjects 
onto the study in the event that binimetinib is associated with a higher than acceptable rate of dose-
limiting toxicity (DLT) requiring removal from study (set at 10% or higher) during the first 2 
courses. Toxicity will be continuously monitored.  As per the 2nd table below, if at any time >2 of the first 
10 subjects or 4 or more of the first 15 total subjects are removed for toxicity as per Section 8.3, then 
accrual will be stopped until the DSMB reviews safety and efficacy data for the study and recommends 
termination or despite the DLT (because of the benefit:risk assessment or other reasoning) recommends 
reopening recruitment.  Boundaries for DSMB for consideration of terminating each cohort (both stratum 
A and B) would be the same. 
 
Table 1:  Stopping Boundaries requiring DSMB to consider terminating trial  
Number of subjects 
Trial will be stopped if the number of subjects with severe 
toxicity is greater than or equal to the number below 
10 
3 
(equivalent to a p-value of 0.07 that the rate of severe toxicity is 
10% or less) 
15 
4 
(equivalent to a p-value of 0.055 that the rate of severe toxicity 
is 10% or less) 
 
 
Using these rules and the binomial distribution, the chance of putting the trial on hold and potentially 
stopping early within the first 10 subjects: 
 
Table 2   
True probability of toxicity 
Chance of stopping early 

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.10 
7% 
.20 
32% 
.25 
47% 
.30 
62% 
.35 
74% 
.40 
83% 
 
In addition, if at any time during the trial a third subject experiences a grade 2 or higher ophthalmologic 
toxicity, the DSMB will be asked to review the toxicity data to date with estimates of the upper limit of 
adverse event rate, evaluate the benefits versus risks, and recommend whether any changes to the protocol 
are required. This review will not automatically halt enrollment, unless the toxicities noted are dose-
limiting and trigger the early stopping rule noted above. 
 
For the comparison of volumetric measures, 60 consecutive patients enrolled on Neurofibromatosis 
Clinical Trials Consortium PN studies will be included (including NF108). Two groups of independent 
volume measurements (NCI-MEDx and MGH-3DQI) will be performed of the target lesions on up to 5 
MRIs per subject (pre-study, baseline, pre-cycle 5, pre-cycle 9, pre-cycle 13). Interval change will be 
calculated to classify disease status as follows: progressive disease (PD) if volume increase is > 20%, 
partial response (PR) if volume decrease is > 20%, and stable disease (SD) if change is < 20% between 
time points. Of note, the results of the MEDx analysis at the NCI will be utilized in analyzing and making 
decisions on the clinical trial, as has been done on all previous Neurofibromatosis Clinical Trials 
Consortium PN trials. The results of the 3DQI analysis of each scan performed at the MGH will not be 
released to sites or the study team while the study is ongoing. Wilcoxon signed rank test will be used to 
statistically compare the numerical difference between PN volumes at each time-point, and the numerical 
difference between the percent changes in PN volumes over time. The Jonckheere-Terpstra trend test will 
be used to establish the degree of significance of the association in disease status classifications. After 
establishing the overall degree of agreement, the McNemar test for paired categorical data (for two 
categories) or an exact marginal homogeneity test (for 3 ordered categories) will be used to demonstrate 
the degree of balance in the discordant results. For the fraction of concordant disease status classifications 
and the overall response rate 95% confidence intervals will be calculated. 
 
For the Re-Treatment arm, statistical analyses will largely mirror that of the initial Treatment arm. The 
basic statistical analysis plan for the Re-Treatment arm of this proof-of-concept study will describe the 
subject population by Re-Treatment baseline characteristics: clinical, Quality of Life and pain scores at 
Re-Treatment baseline. Descriptive summaries will be prepared to show Re-Treatment sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, minimum, and maximum for 
continuous variables and counts, percentages, and 95% CIs on the percentage for categorical variables. 
Time-to-event analyses will be performed with reference to the date of first Re-Treatment on this study. 
Analyses will focus on response rate and disease stability rate of Re-Treatment and will be largely 
descriptive for the expected smaller sample size in the Re-Treatment arm within each cohort. Changes in 
tumor volumes, etc. will be summarized by medians, ranges, and the corresponding 95% CI. This will be 
done for each cohort separately. For endpoints relating to tumor control and subject well-being, analyses 
will be done based on the full-analysis, responding, or evaluable data sets, as appropriate. Comparison 

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against the hypothesized control rate will be done using exact tests for a binomial with the full cohort and 
then by strata. Based on the safety analysis set, information regarding study treatment administration, 
drug dosing and course compliance, safety variables, will be described and summarized. Safety will be 
assessed via tabulations of AEs and SAEs as well as Diary recordings following treatment dose/course of 
therapy. 
 
12.4 
Definitions of Evaluable 
 
12.4.1  Evaluable for Toxicity 
12.4.1.1 
Any subject who received ≥ one dose of binimetinib and had a ≥ Grade 3 
binimetinib-associated toxicity is evaluable for toxicity. 
12.4.1.2 
In the absence of a ≥ Grade 3 toxicity, any subject who completed one full course of 
therapy is evaluable for toxicity. 
12.4.2  Evaluable for Response – Subjects who have completed at least two courses of therapy and have 
had their first follow-up MRI evaluation. Subjects who did not respond and are later found to 
have a target tumor other than a plexiform neurofibroma (e.g. malignant peripheral nerve sheath 
tumor) are not evaluable for response. 
 
12.4.3 
Evaluable for Plasma Cytokines/Growth Factors – Any subject who has at least one sample 
drawn for plasma cytokines/growth factors prior to starting therapy plus at least one other 
sample drawn is evaluable for plasma cytokines/growth factors. 
 
13.0 
RESPONSE CRITERIA  
For initial treatment, response is assessed by the NCI-POB at the time that follow-up 3D-MRI scans are 
performed (after course 4, 8, 12, and then after completion of every 6 courses thereafter), until disease 
progression or end of treatment, whichever occurs first. For the purpose of determining the level of 
response (complete, partial, etc.) measurements from the follow-up scans are compared to the target 
lesion size in the pretreatment MRI scan using 3D data analysis.  
 
For the Re-Treatment Arm, response is assessed after course 4, 8, 12, and then after completion of every 6 
courses thereafter, until disease progression or end of treatment, whichever occurs first. For the purpose 
of determining the level of response (complete, partial, etc.) measurements from the follow-up scans are 
compared to the target lesion size in the MRI scan at the time of pre-Re-treatment using 3D data analysis. 
 
Complete Response (CR): A complete resolution of the target plexiform neurofibroma for ≥ 4 weeks 
Partial Response (PR): A ≥20% reduction in the volume of the target plexiform neurofibroma lesion for 
≥4 weeks.  
Stable Disease (SD): A <20% increase, and < 20% decrease in the volume of the target plexiform 
neurofibroma lesion for ≥4 weeks.  
Progressive Disease (PD): A  20% increase in the volume (by 3D-MRI) of the target plexiform 
neurofibroma compared to the pretreatment volume. 
 
The appearance of new discrete subcutaneous neurofibromas does not qualify for disease progression.  
 

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Worsening of existing symptoms or the appearance of new symptoms that persist for more than 7 days and 
that are felt to be definitely related to the plexiform neurofibroma should be evaluated by repeating the 
MRI. Subjects should not be classified as having progressive disease solely on the basis of new or increased 
symptoms without discussing the case with the protocol Principal Investigator. 
 
Subjects with other evidence of disease progression than outlined above should also be discussed with the 
Principal Investigator. 
 
14.0 
HUMAN SUBJECTS PROTECTION & DATA SAFETY MONITORING PLAN 
 
Rationale for Subject Selection 
Neurofibromatosis type 1 is a genetic disorder and the incidence of the disease in the various racial and 
ethnic groups may vary. This may impact on our ability to recruit sufficient numbers of subjects within 
each group to this trial. Subject accrual regarding gender, and racial and ethnic groups is described in 
Section 4.0. None of these groups are excluded from participation in the trial. Females who are pregnant 
or breast feeding will not be eligible for entry onto the trial because of the potential risks that binimetinib 
could pose to the fetus or newborn. This trial is designed to determine the activity of binimetinib in 
children and adults with NF1 and inoperable PN and therefore, subjects <18 years old will be entered 
onto this research trial. Individuals will be enrolled at one of the sites that participate in the NF 
consortium as well as PNOC sites. Subjects may also be referred from outside centers but treatment will 
be directed at an NF or PNOC consortium site. 
  
Participation of Subjects < 18 years of age 
The primary endpoint of this trial is to determine whether binimetinib can result in tumor shrinkage in 
children and adults with PN. Therefore children ≥1 year of age who meet eligibility criteria for this trial 
will be entered in the study.  
 
Evaluation of benefits and risks/discomforts  
The potential benefit from participation in this trial is the stabilization or reduction in the size of the PN, 
relief of symptoms caused by the PN, and prolongation of life. The primary risk to the subjects from 
participation in this trial is from binimetinib toxicity (Section 6.1.4). Toxicities from binimetinib are 
outlined in Section 6.1.4 and are typically reversible when they occur. Subjects enrolled on this trial will 
be carefully monitored for the development of toxicities, and guidelines for discontinuation of drug and a 
toxicity stopping rule are in place. Blood samples will be obtained on this trial for optional 
pharmacodynamics studies. Samples will be identified by a code number that can be traced to the subject 
only by contacting the trial coordinating center. However, as the blood samples are linked to the subject’s 
name, a small risk persists that unauthorized persons could gain access to information. Some testing may 
eventually reveal information that could result in discrimination with health or life insurance or 
employment. We believe that these risks are minimal since it is already known that subjects enrolled on 
the study have neurofibromatosis. All research results will be kept confidential. Results from the 
pharmacodynamic studies will be considered preliminary and will require further analysis for verification. 
Therefore, results will not be communicated with the research subjects. Subjects also have the right to 
withdraw the blood obtained for research purposes at any time.  
 
Risks to subjects from banking biological specimens include the risks of the blood draws for research 
purposes. Tumor specimens will be taken only from leftover specimens that were obtained for clinical 
purposes. The amount of blood to be obtained is minimal (approximately 10 ml) and no more than 5 
mL/kg will be taken from any subject in a single day. Risks associated with blood draw are pain, bleeding 
or bruising at the spot where the needle is inserted, and rarely fainting or infection. Every attempt to draw 
the research blood samples in conjunction with other clinical blood draws will be made so that the risk of 
infection is not increased. Blood draws will be performed by trained personnel who are experienced in 

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working with children and familiar with the challenges of drawing blood from this population. The risk of 
biological specimen banking is minimized by coding the specimens prior to shipping to the biorepository 
in order to prevent identification of subjects and protect confidentiality. In addition, the study subject ID 
number linked to the specimen will be maintained separately at the NF Consortium Operations Center at 
UAB.   
 
Depending on the age of the subject MRI studies may require sedation or anesthesia, which is associated 
with additional risks. Consent will be obtained from subjects for sedation or anesthesia for MRI scans as 
per institutional guidelines. 
 
Risk/benefit analysis 
The primary objective of this phase II trial is to define the objective response rate of PN treated with 
binimetinib, and thus subjects entered on the trial will be treated with therapeutic intent and response to 
the therapy will be closely monitored. Therefore, this protocol involves greater than minimal risk, but 
presents the potential for direct benefit to individual subjects. The potential benefit of this treatment with 
binimetinib is that it may stop or slow down the growth of PN or shrink PN. In addition, binimetinib may 
lessen the symptoms, such as pain, that are caused by the tumor. The MRI data in this study will be 
analyzed by a special approach called “volumetric MRI,” in addition to being read in a standard manner 
by a radiologist. The volumetric MRI approach will provide more precise measurement of the size of PN, 
and therefore will give more complete and objective information on which to base any possible future 
treatment decisions. Volumetric MRI is currently not available on a routine clinical basis. 
 
Consent and assent process and documentation 
The investigational nature and objectives of this trial, the procedures and treatments involved and their 
attendant risks and discomforts and benefits, and potential alternative therapies will be carefully explained 
to the subject and the subject’s parents or guardian if he/she is a child, and a signed informed consent 
document will be obtained. Consent will be obtained by the site PI or an associate investigator on the trial 
according to state and institutional guidelines. Age-appropriate assent forms for children have been 
developed for this trial. This is a multi-institutional trial, and the NF Operations Center will require 
evidence of local IRB approval and of USAMRMC ORP HRPO approval of the protocol prior to 
allowing for accrual of subjects at that institution. This trial will be conducted in compliance with the 
protocol, Good Clinical Practice (GCP) and the applicable regulatory requirements.  
 
Research Monitor and Data Safety Monitoring Plan 
The Study Chairs and Operations Center clinical research nurse manager will review study progress and 
safety issues regularly with the NF Operations Center Research Trial Manager. Subject eligibility, 
deviations and adverse events will be reviewed to ensure that the study is implemented as outlined in the 
protocol. Monthly reports will be generated by the NF Consortium Operations Center to assess 
completeness of data. There will be monthly phone conferences between the NF Consortium Operations 
Center and the Protocol Team to address QA issues. A Data Safety Monitoring Board and a Research 
Monitor for this study will be established for the purpose of ensuring data compliance and regular 
monitoring.  
 
We will assign a research monitor for this study. He/she will be a qualified physician and is not associated 
with this particular protocol. He/she will work closely with the Principal Investigator to monitor the 
participants’ treatment while on this study.   
 
The research monitor’s duties should be based on specific risks or concerns about the research. The 
research monitor may perform oversight functions and report their observations and findings to the IRB 
or a designated official. The research monitor may be identified from within or outside the PI’s 
institution.  

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Research Monitor functions may include:  
• 
observing recruitment and enrollment procedures and the consent process for individuals, 
groups or units,  
• 
overseeing study interventions and interactions,  
• 
reviewing monitoring plans and UPIRTSO reports;  
• 
overseeing data matching, data collection, and analysis  
 
There may be more than one research monitor (e.g., if different skills or experiences are necessary). The 
monitor may be an ombudsman or a member of the data safety monitoring board.  
At a minimum, the research monitor:  
• 
may discuss the research protocol with the investigators, interview human subjects, and 
consult with others outside of the study about the research;  
• 
shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report;  
• 
shall have the responsibility to promptly report their observations and findings to the IRB 
or other designated official and the HRPO.  
 
In addition, on this study, the research monitor is specifically required to review all unanticipated 
problems involving risk to subjects or others, serious adverse events and all subject deaths associated with 
the protocol and provide an unbiased written report of the event. At a minimum, the research monitor 
should comment on the outcomes of the event or problem, and in the case of a serious adverse event or 
death, comment on the relationship to participation in the study. The research monitor should also 
indicate whether he/she concurs with the details of the report provided by the study investigator.   
 
 

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15.0 
REFERENCES 
 
1. 
Wu, J., et al., Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 
loss in desert hedgehog-expressing cells. Cancer Cell, 2008. 13(2): p. 105-16. 
2. 
Citak, E.C., et al., Management of plexiform neurofibroma with interferon alpha. 
Pediatr Hematol Oncol, 2008. 25(7): p. 673-8. 
3. 
Kebudi, R., F.B. Cakir, and O. Gorgun, Interferon-alpha for unresectable progressive 
and symptomatic plexiform neurofibromas. J Pediatr Hematol Oncol, 2013. 35(3): p. 
e115-7. 
4. 
Jakacki, R.I., et al., Phase I trial of pegylated interferon-alpha-2b in young patients 
with plexiform neurofibromas. Neurology, 2011. 76(3): p. 265-72. 
5. 
Widemann, B.C., et al., Phase 1 trial and pharmacokinetic study of the farnesyl 
transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: 
a report from the Children's Oncology Group. Pediatr Blood Cancer, 2011. 56(2): p. 
226-33. 
6. 
Widemann, B.C., et al., Phase I trial and pharmacokinetic study of the 
farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or 
neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol, 2006. 24(3): p. 
507-16. 
7. 
Babovic-Vuksanovic, D., et al., Phase II trial of pirfenidone in adults with 
neurofibromatosis type 1. Neurology, 2006. 67(10): p. 1860-2. 
8. 
Babovic-Vuksanovic, D., et al., Phase I trial of pirfenidone in children with 
neurofibromatosis 1 and plexiform neurofibromas. Pediatr Neurol, 2007. 36(5): p. 
293-300. 
9. 
Kim, A., et al., Phase I trial and pharmacokinetic study of sorafenib in children with 
neurofibromatosis type I and plexiform neurofibromas. Pediatr Blood Cancer, 2013. 
60(3): p. 396-401. 
10. 
Lasater, E.A., et al., Nf1+/- mice have increased neointima formation via 
hyperactivation of a Gleevec sensitive molecular pathway. Hum Mol Genet, 2008. 
17(15): p. 2336-44. 
11. 
McCormick, F., Ras signaling and NF1. Curr Opin Genet Dev, 1995. 5(1): p. 51-5. 
12. 
Sherman, L.S., et al., Single cell Ras-GTP analysis reveals altered Ras activity in a 
subpopulation of neurofibroma Schwann cells but not fibroblasts. J Biol Chem, 2000. 
275(39): p. 30740-5. 
13. 
Downward, J., Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer, 
2003. 3(1): p. 11-22. 
14. 
Weiss, B., G. Bollag, and K. Shannon, Hyperactive Ras as a therapeutic target in 
neurofibromatosis type 1. Am J Med Genet, 1999. 89(1): p. 14-22. 
15. 
Wu, J., et al., Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre 
mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr 
Blood Cancer, 2012. 58(2): p. 173-80. 
16. 
Kissil, J.L., et al., What's new in neurofibromatosis? Proceedings from the 2009 NF 
Conference: new frontiers. Am J Med Genet A, 2010. 152A(2): p. 269-83. 
17. 
Yang, F.C., et al., Nf1-dependent tumors require a microenvironment containing Nf1+/-
- and c-kit-dependent bone marrow. Cell, 2008. 135(3): p. 437-48. 

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18. 
Jessen, W.J., et al., MEK inhibition exhibits efficacy in human and mouse 
neurofibromatosis tumors. J Clin Invest, 2013. 123(1): p. 340-7. 
19. 
Chang, T., et al., Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 
mutant mice. J Clin Invest, 2013. 123(1): p. 335-9. 
20. 
Dombi, E., et al., Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform 
Neurofibromas. N Engl J Med, 2016. 375(26): p. 2550-2560. 
21. 
Rosser, T. and R.J. Packer, Neurofibromas in children with neurofibromatosis 1. J Child 
Neurol, 2002. 17(8): p. 585-91; discussion 602-4, 646-51. 
22. 
Le, L.Q. and L.F. Parada, Tumor microenvironment and neurofibromatosis type I: 
connecting the GAPs. Oncogene, 2007. 26(32): p. 4609-16. 
23. 
Prada, C.E., et al., Neurofibroma-associated macrophages play roles in tumor growth 
and response to pharmacological inhibition. Acta Neuropathol, 2013. 125(1): p. 159-
68. 
24. 
Wolkenstein, P., et al., Quality-of-life impairment in neurofibromatosis type 1: a cross-
sectional study of 128 cases. Arch Dermatol, 2001. 137(11): p. 1421-5. 
 
 
 
 
 
 
 

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APPENDIX IA: SCHEDULE OF EVALUATIONS FOR INITIAL TREATMENT  
 
 
 
(Please refer to section 9.0 for details) 
† See section 9 for definitions of end of course. 
1. All studies to determine eligibility must be performed within 2 weeks prior to enrollment unless otherwise indicated below (See section 9.0). Consent must be obtained prior to enrollment but does not expire 
at 2 weeks. 
2. Height only required at baseline 
3. Ophthalmology toxicity evaluation: Eye exam with emphasis on corneal, lens and retinal changes. In subjects with orbital plexiform neurofibromas the intraocular pressure should be measured at baseline and 
subsequently if feasible. 
4. For females of childbearing age 
5. Subjects who had a response (>20% target lesion shrinkage by 12 courses) must  have an MRI performed at 4 months and 12 months after stopping drug if they are still on study. Of note these MRIs can be 
done at a local institution but needs to be submitted by the enrolling site,  
6. Blood samples should be drawn at the indicated time points as well as around the time of tumor biopsy if tumor tissue is being submitted (if the patient undergoes a clinically indicated tissue collection 
procedure). The following will be collected at each time point: Streck tube (for plasma):  ~ 2 mL; EDTA tube (for DNA):  ~ 5 mL; PAXGene tube (for RNA) ~ 2.5 mL. 
STUDIES TO BE OBTAINED 
Pre-Study1 
Course 1 
Subsequent courses 
Completion of Rx 
Informed Consent or Assent 
X 
 
 
 
Eligibility Checklist 
X 
 
 
 
PN Location and Morbidity checklist (see Appendix X) 
X 
 
 
 
History 
X 
End† 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Physical Exam with vital signs (including T, P, RR, BP) 
X 
End† 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Neurological exam  
X 
End† 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Performance Status (see Appendix II) 
X 
End† 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Ophthalmological toxicity exam 3 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
Binimetinib Diary Review 
 
End† 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
CBC, differential, platelets 
X 
End† 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Electrolytes and blood chemistries including Na, K, Cl, 
bicarb, BUN, Cr, glucose, Ca, phosphorous, albumin, 
total protein, alk phos, SGOT, SGPT, bilirubin, CPK 
X 
 
 
End† 
 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
 
Urine/Serum Pregnancy4 
 
X  
(within 7 days prior) 
End† 
 
Post course 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
ECHO (or MUGA) and ECG 
X 
(within 4 weeks prior) 
 
Post course 4, 8, 12, 18, 24 †  
X 
MRI including volumetric analysis 
X 
(within 4 weeks prior) 
 
Post course 4, 8, 12, 18, 24 †  
X5 
Functional Evaluation (see Appendix XII-XV) 
X 
(within 4 weeks prior) 
 
Post course 4, 8, 12, 18, 24 †  
X 
Photography of Visible PN (see Appendix XVI) 
X 
(within 4 weeks prior) 
 
Post course 4, 8, 12, 18, 24 †  
X 
PN Clinician Morbidity Assessment (see Appendix XI) 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
PN Symptom checklist (see Appendix IX) 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
Health-related quality of life and pain assessments 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
Cytokine studies (see Appendix VII) 
X 
end 
Post course 4  
 
Blood and Tissue collection6 (see Appendix XXI) 
X 
 
Post course 4 and 12  
X 

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APPENDIX IB: SCHEDULE OF EVALUATIONS FOR RE-TREATMENT  
 
 
(Please refer to section 9.0 for details) 
† See section 9 for definitions of end of course. 
1. All studies to determine eligibility must be performed within 2 weeks prior to enrollment except for MRI, ophthalmology, Echo, and EKG (which is required within 4 weeks prior to “enrollment” on the Re-
Treatment Arm), unless otherwise indicated. Consent must be obtained prior to enrollment but does not expire at 2 weeks. Re-Treatment eligibility studies may be counted as the Re-Treatment baseline studies as 
long as there has been no concerning change in clinical status prior to starting study drug, except for pregnancy testing in females of childbearing age which must be negative within 7 days prior to re-starting 
binimetinib. 
2. Height required only at baseline 
3. Ophthalmology toxicity evaluation: Eye exam with emphasis on corneal, lens and retinal changes. In subjects with orbital plexiform neurofibromas the intraocular pressure should be measured at baseline and 
subsequently if feasible. 
4. For females of childbearing age 
5. For participants staying on study while arrangements are being made to transition the participant to a MEK inhibitor off study (see section 6.2), evaluations should occur as per protocol section 9. 
STUDIES TO BE OBTAINED 
Pre-Study1 
Course 1 
Subsequent courses5 
Completion of Rx 
Informed Consent or Assent 
X 
 
 
 
Eligibility Checklist 
X 
 
 
 
PN Location and Morbidity checklist (see Appendix X) 
X 
 
 
 
Phone Call (to assess drug compliance and toxicity) 
 
End† 
 
 
History 
X 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Physical Exam with height, weight, and vital signs 
(including T, P, RR, BP)2 
X 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Neurological exam  
X 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Performance Status (see Appendix II) 
X 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Ophthalmological toxicity exam3 
X 
(within 4 weeks prior) 
 
Post course 6, 12, 18, 24 † 
X 
Binimetinib Diary Review 
 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
CBC, differential, platelets 
X 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
Electrolytes and blood chemistries including Na, K, Cl, 
bicarb, BUN, Cr, glucose, Ca, phosphorous, albumin, 
total protein, alk phos, SGOT, SGPT, bilirubin, CPK 
X 
 
 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
 
Urine/Serum Pregnancy4 
 
X  
(within 7 days prior) 
 
Post course 2, 4, 6, 8, 10, 12, 15, 18, 21, and 24 † 
X 
ECHO (or MUGA) and ECG 
X 
(within 4 weeks prior) 
 
Post course 6, 12, 18, 24 †  
X 
MRI including volumetric analysis 
X 
(within 4 weeks prior) 
 
Post course 4, 8, 12, 18, 24 †  
X 
PN Clinician Morbidity Assessment (see Appendix XI) 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
PN Symptom checklist (see Appendix IX) 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 
Health-related quality of life and pain assessments 
X 
 
Post course 4, 8, 12, 18, 24 † 
X 

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APPENDIX II: PERFORMANCE STATUS SCALES/SCORES 
 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence 
of disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the 
day; no active play, able to participate in 
all quiet play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
 
 

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APPENDIX III:  NIH CONSENSUS CLINICAL DEFINTION OF NEUROFIBROMATOSIS 
 
 
• 
Six or more café-au-lait spots (≥0.5 cm in prepubertal subjects or ≥1.5 cm in postpubertal 
subjects) 
• 
Two or more neurofibromas of any type or one plexiform neurofibroma  
• 
Freckling in the axilla or groin 
• 
Optic glioma 
• 
Two or more Lisch nodules 
• 
A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long 
bone cortex) 
• 
A first-degree relative with NF1 
 
 
 

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APPENDIX IV:  PROTOCOL FOR REQUIRED PRE-STUDY AND ON-STUDY MRI STUDIES 
Prior to starting treatment, a measurable target plexiform neurofibroma must be identified. In addition, up 
to two non-target plexiform neurofibromas may be identified as well.  
The goal will therefore be to use 3-D MRI only to follow the target and non-target plexiform 
neurofibroma(s) (a maximum of three lesions), which will be defined as index lesion(s).  
Pre-study imaging evaluation: 
1. Identify and select the index plexiform neurofibroma(s) (a maximum of three lesions) for 3-D 
MRI evaluation based on prior imaging studies. Should there be more than 3 progressing 
plexiform neurofibromas; the three most clinically relevant plexiform neurofibromas should be 
followed by 3-D MRI analysis. 
2. Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI acquisition 
protocols below.  
 
On study imaging evaluation: 
 
Unless clinically indicated otherwise obtain MRI of the index lesion(s) (target and non-target) only as 
outlined in the MRI acquisition protocol below after course 4, 8, 12, 18, and 24 while on study. 
 
MRI protocols: 
 
Images intended for volumetric analysis need to be performed without gaps between slices. Every attempt 
should be made to image the entire PN. The target tumor should be positioned close to the center of the 
imaging field and the outer edge of the tumor should be within the field of view. Peripheral nerve sheath 
tumors can be well visualized without the use of contrast agents on short TI inversion recovery (STIR) 
sequences because they have high signal intensity relative to normal tissues. The imaging protocol in the 
table below should be used for the imaging of the target and non-target PN.  
 
If necessary, participating institutions may modify the MRI sequences to optimize differentiation of tumor 
and surrounding tissue. Modifications should be noted, such that the same imaging protocol, and, if 
possible, the same MRI scanner, can be used for all subsequent MRI studies.   
 
All MRI studies requested per protocol will be submitted to the NCI POB within 1 week of acquisition 
for volume analysis.  
 
 
Volumetric sequence for PN** 
Axial STIR 
Recommended 
Range 
Head-Neck or 
Small## Trunk-
Extremity PN 
Large## Trunk-
Extremity PN 
Echo Train Length 
5 - 15 
7 
15 
TR 
3000 - 6000 
6000 
4000 

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TE 
30 - 50 
34 
30 
TI 
150-180 
150 
150 
Slice Thickness 
3 - 10 mm 
3 mm 
10 mm 
Skip 
0 
0 
0 
Matrix 
256x256 -  
512x512 
256x256 
320 x256 - 
512x512 
FOV 
18 - 50 cm 
22 cm 
45 cm 
Phase FOV 
0.8 
0.8 
0.8 
NEX 
2 - 4 
3 
2 
Frequency Direction 
A→P 
A→P 
A→P 
**Spinal/paraspinal PN should be imaged with the appropriate protocol based on tumor size. Tumors that 
include the neck and trunk, for which the majority of the tumor is in the trunk, should be imaged with the 
Large Trunk-Extremity PN protocol. 
##Tumors < 5 cm in longest diameter would be considered small. Tumors > 10 cm longest diameter 
would be considered large. Tumors between 5-10 cm in longest diameter should be imaged with the 
appropriate protocol based on best FOV coverage.   
Please contact Dr. Dombi if there are questions regarding the appropriate coverage or imaging protocol. 
 
 Data Analysis:  
• 
All MRI data will be analyzed at the Pediatric Oncology Branch of the NCI. The MRI data from each 
scan will be processed to assess the volume of the index plexiform neurofibroma. The tumor will be 
traced on subsequent contiguous MR slices, the numbers summed and then multiplied by the slice 
thickness to obtain a numerical volume measurement. The tumor will be identified by high signal on 
the STIR images not corresponding to known normal anatomic structures and corresponding with the 
course of known nerves. Each subject’s volumetric measurement obtained from the initial MRI will 
serve as the baseline against which to assess incremental changes in volume that occur during the 
subsequent intervals. Volumetric measurements and 1-D, and 2-D data analysis will be done by 3 
physicians trained in 1-D, 2-D, and 3-D MRI data analysis at the Pediatric Oncology Branch, NCI at 
an Image Review Workstation using MEDx software (Sensor Systems Inc.). Volumetric 
measurements will be used to determine disease progression as outlined in Section 13. Drs. Dombi 
and Widemann will inform Participating Investigators, the Principal Investigator, and the NF 
Consortium Operations Center about the results of the MRI study by written report.  
 
Image and Data Acquisition: 
• 
In order to perform quantitative analysis, the Pediatric Oncology Branch must receive the imaging data 
from the investigator sites. All MRI studies requested per protocol will be submitted to the NCI POB 
within 1 week of acquisition for volume analysis. The Pediatric Oncology Branch will check all 
materials received for completeness and will notify the site if data, images, or information are missing 

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or incomplete. Dr. Dombi will confirm for each patient in screening that the MRI imaging is adequate 
and that the target PN is measurable and amenable to volumetric MRI analysis. 
• 
Address for shipment of imaging studies: 
Dr. Eva Dombi, MD 
NCI, POB 
10 Center Drive, Building 10, room 1-5750 
Bethesda, MD 20892-1101 
Phone 301-451-7023,  
e-mail:  dombie@mail.nih.gov 
fax: 301-402-1734  
 

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APPENDIX IVa:  MRI ELIGIBILITY FORM 
 
This form must accompany all MRI studies sent to the NCI POB for review of target plexiform 
neurofibroma eligibility (i.e. whether it is measurable and amenable to volumetric analysis).  Please mail 
the MRI on a CD along with this form to: 
 
 
Eva Dombi, MD 
 
NCI, POB 
 
10 Center Drive, Building 10 CRC, Room 1-5750 
 
Bethesda, MD 20892 
 
Phone: 301-451-7023 
 
E-mail: dombie@mail.nih.gov 
 
 
PID#1:________ 
Date of MRI:  ___________ 
 
 
Location of target plexiform: 
_______________________________________________ 
 
 
 
 
From: 
Name of Investigator:  _______________________________________________ 
 
Study Center:   
_______________________________________________ 
 
Phone #: 
 
_______________________________________________ 
 
Email Address:   
_______________________________________________ 
 
 
 
 
 
_____________________________________________________________________________ 
From Eva Dombi, MD:  
 
The target PN is measurable and amenable to volumetric analysis:  
 
 
Yes:_____________ 
No: ____________ 
 
Comments: _______________________________________________ 
 
_________________________________________________________ 
 
_________________________________________________________ 
 
 

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APPENDIX V: SUBJECT DIARY ON BINIMETINIB PROTOCOL 
 
* For patients taking binimetinib in tablet form * 
 
 
 
 
 
Instructions: 
1) 
Record the date and time (circle AM or PM) for each daily dose and number of tablets of  binimetinib taken 
2) 
Binimetinib should be taken at approximately the same time each day, with or without food 
3) 
If you miss a dose (e.g., due to vomiting), do not take another dose. Resume dosing with the next scheduled dose. 
4) 
Please enter the information for this diary as it occurs daily. 
 
 
                                        Date 
Dose taken 
# of tablets 
taken 
Dose 
taken 
# of tablets 
taken 
 
Comments 
Day 1 
 
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M 
 
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Day 2 
 
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Patient Name: ___________________________________________ 
Drug:  
 
Start Date :   ____/____/ ____                   End Date : ____/ ____/ ____ 
 
Dose:           mg 

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Day 17 
 
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* For patients taking liquid suspension of binimetinib * 
 
 
 
 
 
Instructions: 
5) 
Record the date and time (circle AM or PM) for each daily dose and number of mLs of  binimetinib taken 
6) 
Binimetinib should be taken at approximately the same time each day, with or without food 
7) 
If you miss a dose (e.g., due to vomiting), do not take another dose. Resume dosing with the next scheduled dose. 
8) 
Please enter the information for this diary as it occurs daily. 
 
 
                           
Date 
Dose taken 
# of mLs 
Dose 
taken 
# of mLs  
Comments 
Day 1 
 
: 
A
M 
 
: 
PM 
 
 
Day 2 
 
: 
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M 
 
: 
PM 
 
 
Day 3 
 
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Day 17 
 
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Patient Name: ___________________________________________ 
Drug:  
 
Start Date :   ____/____/ ____                   End Date : ____/ ____/ ____ 
 
Dose:           mg 

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Day 18 
 
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APPENDIX VI: INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
 
List of inhibitors and inducers of UGT1A1 to be used with caution  
 
Inhibitors of UGT1A1 
Inducers of UGT1A1 
Atazanavir, erlotinib, flunitrazepam, gemfibrozil, indinavir, 
ketoconazole, nilotinib, pazopanib, propofol, regorafenib, 
sorafenib 
Carbamazepine, nicotine, rifampicin, testosterone propionate 
 
Table VI - 1  List of drugs with a conditional risk of Torsades de Pointes 
Generic Name 
Brand Name 
Class/Clinical Use 
Amisulpride 
Solian® and others 
Antipsychotic, atypical / schizophrenia 
Amitriptyline 
Elavil® 
Tricyclic Antidepressant / depression 
Ciprofloxacin 
Cipro® 
Antibiotic / bacterial infection 
Clomipramine 
Anafranil® 
Tricyclic Antidepressant / depression 
Desipramine 
Pertofrane® 
Tricyclic Antidepressant / depression 
Diphenhydramine 
Benadryl®, Nytol® 
Antihistamine / Allergic rhinitis, insomnia 
Doxepin 
Sinequan® 
Tricyclic Antidepressant / depression 
Fluconazole 
Diflucan® 
Anti-fungal / fungal infection 
Fluoxetine 
Sarafem®, Prozac® 
Anti-depressant / depression 
Galantamine 
Reminyl® 
Cholinesterase inhibitor / Dementia, Alzheimer's 
Imipramine 
Norfranil® 
Tricyclic Antidepressant / depression 
Itraconazole 
Sporanox® 
Anti-fungal / fungal infection 
Ketoconazole 
Nizoral® 
Anti-fungal / fungal infection 
Nortriptyline 
Pamelor® 
Tricyclic Antidepressant / depression 
Paroxetine 
Paxil® 
Anti-depressant / depression 
Protriptyline 
Vivactil® 
Tricyclic Antidepressant / depression 
Ritonavir 
Norvir® 
Protease inhibitor / HIV 
Sertraline 
Zoloft® 
Anti-depressant / depression 
Solifenacin 
VESIcare® 
muscarinic receptor anatagonist / treatment of overactive 
bladder 
Trazodone 
Desyrel® 
Anti-depressant / Depression, insomnia 
Trimethoprim-Sulfa 
Septra® or Bactrim® 
Antibiotic / bacterial infection 
Trimipramine 
Surmontil® 
Tricyclic Antidepressant / depression 
Substantial evidence supports the conclusion that these drugs prolong the QT interval and have a risk of TdP but only under 
certain known conditions (e.g. excessive dose, drug interaction, etc.). 
 
Table VI - 2  List of drugs with a possible risk of Torsades de Pointes 
Generic Name 
Brand Name 
Class/Clinical Use 
Alfuzosin 
Uroxatral® 
Alpha1-blocker / Benign prostatic hyperplasia 
Amantadine 
Symmetrel® 
Dopaminergic/Anti-viral / Anti-infective/ Parkinson's Disease 
Artenimol+piperaquine 
Eurartesim® 
Anti-malarial / malaria infection 
Atazanavir 
Reyataz® 
Protease inhibitor / HIV 
Chloral hydrate 
Noctec® 
Sedative / sedation/ insomnia 
Clozapine 
Clozaril® 
Anti-psychotic / schizophrenia 
Dolasetron 
Anzemet® 
Anti-nausea / nausea, vomiting 
Dronedarone 
Multaq® 
Anti-arrhythmic / Atrial Fibrillation 

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Generic Name 
Brand Name 
Class/Clinical Use 
Eribulin 
Halaven® 
Anti-cancer / metastatic breast neoplasias 
Escitalopram 
Cipralex®, 
Lexapro® 
Anti-depressant / Major depression/ Anxiety disorders 
Famotidine 
Pepcid® 
H2-receptor antagonist / Peptic ulcer/ GERD 
Felbamate 
Felbatrol® 
Anti-convulsant / seizure 
Fingolimod 
Gilenya® 
Immunosuppressant / Multiple Sclerosis 
Foscarnet 
Foscavir® 
Anti-viral / HIV infection 
Fosphenytoin 
Cerebyx® 
Anti-convulsant / seizure 
Gatifloxacin 
Tequin® 
Antibiotic / bacterial infection 
Gemifloxacin 
Factive® 
Antibiotic / bacterial infection 
Granisetron 
Kytril® 
Anti-nausea / nausea and vomiting 
Iloperidone 
Fanapt® 
Antipsychotic, atypical / Schizophrenia 
Indapamide 
Lozol® 
Diuretic / stimulate urine & salt loss 
Isradipine 
Dynacirc® 
Anti-hypertensive / high blood pressure 
Lapatinib 
Tykerb®, Tyverb® 
Anti-cancer / breast cancer, metastatic 
Levofloxacin 
Levaquin® 
Antibiotic / bacterial infection 
Lithium 
Lithobid®, 
Eskalith® 
Anti-mania / bipolar disorder 
Moexipril/HCTZ 
Uniretic® 
Anti-hypertensive / high blood pressure 
Nicardipine 
Cardene® 
Anti-hypertensive / high blood pressure 
Nilotinib 
Tasigna® 
Anti-cancer / Leukemia 
Octreotide 
Sandostatin® 
Endocrine / acromegaly, carcinoid diarrhea 
Ofloxacin 
Floxin® 
Antibiotic / bacterial infection 
Ondansetron 
Zofran® 
Anti-emetic / nausea and vomiting 
Oxytocin 
Pitocin® 
Oxytocic / Labor stimulation 
Paliperidone 
Invega® 
Antipsychotic, atypical / Schizophrenia 
Perflutren lipid microspheres 
Definity® 
Imaging contrast agent / Echocardiography 
Quetiapine 
Seroquel® 
Anti-psychotic / schizophrenia 
Ranolazine 
Ranexa® 
Anti-anginal / chronic angina 
Risperidone 
Risperdal® 
Anti-psychotic / schizophrenia 
Roxithromycin* 
Rulide® 
Antibiotic / bacterial infection 
Sertindole 
Serdolect®, Serlect® 
Antipsychotic, atypical / Anxiety, Schizophrenia 
Sunitinib 
Sutent® 
Anti-cancer / RCC, GIST 
Tacrolimus 
Prograf® 
Immunosuppressant / Immune suppression 
Tamoxifen 
Nolvadex® 
Anti-cancer / breast cancer 
Telithromycin 
Ketek® 
Antibiotic / bacterial infection 
Tizanidine 
Zanaflex® 
Muscle relaxant / spasticity 
Vardenafil 
Levitra® 
phosphodiesterase inhibitor / vasodilator 
Venlafaxine 
Effexor® 
Anti-depressant / depression 
Voriconazole 
VFend® 
Anti-fungal / anti-fungal 
Ziprasidone 
Geodon® 
Anti-psychotic / schizophrenia 
Substantial evidence supports the conclusion that these drugs cause QT prolongation but there is insufficient evidence that 
they, when used as directed in labeling, have a risk of causing TdP. 
 
 
 

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Table VI - 3  List of drugs with a known risk of Torsades de Pointes 
Generic Name 
Brand Name 
Class/Clinical Use 
Amiodarone 
Cordarone®, Pacerone® 
Anti-arrhythmic / abnormal heart rhythm 
Arsenic trioxide 
Trisenox® 
Anti-cancer / Leukemia 
Astemizole 
Hismanal® 
Antihistamine / Allergic rhinitis 
Azithromycin 
Zithromax® 
Antibiotic / bacterial infection 
Bepridil 
Vascor® 
Anti-anginal / heart pain 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
Chlorpromazine 
Thorazine® 
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Citalopram 
Celexa® 
Anti-depressant / depression 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial infection 
Disopyramide 
Norpace® 
Anti-arrhythmic / abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Anti-arrhythmic / abnormal heart rhythm 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Droperidol 
Inapsine® 
Sedative; Anti-nausea / anesthesia adjunct, nausea 
Erythromycin 
E.E.S. ®, Erythrocin® 
Antibiotic;GI stimulant / bacterial infection; increase GI motility 
Flecainide 
Tambocor® 
Anti-arrhythmic / abnormal heart rhythm 
Halofantrine 
Halfan® 
Anti-malarial / malaria infection 
Haloperidol 
Haldol® 
Anti-psychotic / schizophrenia, agitation 
 
 
 

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APPENDIX VII: PHARMACODYNAMIC STUDIES 
 
Plasma Cytokines and Growth Factors 
CYTOKINE STUDIES Worksheet  
_____________ BSA (m2)     
Binimetinib dose (mg) ___, if 
given 
 
 
Plasma Cytokines and Growth Factors Procedure:  
10 ml blood will be drawn into EDTA tubes before treatment initiation, end of course 1 and end of course 
4. The sample will be collected at least 30 min but no more than 2 hours after taking the morning dose. To 
summarize: 
• 
Pre-study measurement needed 
• 
Post Course 1: collection 30 minutes to 2 hours after taking the morning dose 
• 
Post Course 4: collection 30 minutes to 2 hours after taking the morning dose 
 
• After collection, samples should be gently inverted 15 times to completely mix whole blood and 
anticoagulant  
• Blood samples should then be immediately placed into an ice bath so that they are kept at 2-8° Celsius  
• Whole blood samples should be centrifuged at 4 °Celsius for 10 minutes at 1,700 x g to separate the 
plasma from the red blood cells  
• Transfer plasma layer using a clean disposable pipette into the appropriately labeled 3.6mL cryovial  
• Immediately store plasma sample in a -70 °Celsius freezer until shipment. Once frozen, samples should 
not be allowed to thaw, including during shipment.  
• Time from blood collection to freezing of plasma should not exceed 30 minutes  
 
Samples will be shipped on dry ice Monday through Thursday.  
Samples will be shipped to Cincinnati Children’s Hospital Medical Center. Samples should be 
shipped with express next day priority delivery. Samples will be shipped to the following 
address: 
 
Cincinnati Children’s Hospital Medical Center  
S Dock, Ratner Laboratory S7.348 
240 Albert Sabin Way  
Cincinnati, OH 45229  
c/o Nancy Ratner S7.250     Phone: 513-636-3502 
Email: Lindsey.Aschbacher-Smith@cchmc.org 
Other email contacts in the lab: Nancy.Ratner@cchmc.org; Jianqiang.Wu@cchmc.org;  
 
Please include this completed worksheet with the sample shipment: 
Subject ID 
 
Course 
 
Course day 
 
Date of sample 
 
Date and time of last binimetinib dose: 
 
 
 

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APPENDIX VIII:  CONSORTIUM QOL AND PAIN MEASURES 
 
PEDIATRIC PRO MODULE 
 
(Ages 2 – 17 years)* 
 
I. QOL and Pain Measures for Pediatric Patients 
 
In pediatric participants with plexiform neurofibromas in all locations, this study will assess 
general health-related qualify of life (QOL) and pain (pain intensity and pain interference) using 
patient-reported outcomes (PROs) as described below. 
*IMPORTANT ADMINISTRATION GUIDELINES:  If a participant is 17 years at study entry they should 
be administered the PROs in the Pediatric Module, continuing on the same pediatric measures even if they 
turn 18 years old.  However, if they are 18 years at study entry, they should be administered the PROs in 
the Adult Module. 
 
Description of QOL and Pain Measures 
 
General Health-Related Quality of Life 
Pediatric Quality of Life Inventory (PedsQL; Varni, 2001):  The PedsQL 4.0 Generic Core Scales (Acute 
Form assessing the past 7 days) are multidimensional child self-report and parent proxy report scales to 
assess health-related quality of life (QOL) in children, adolescents, and young adults ages 2 – 25 years. It 
is a brief standardized pediatric QOL scale with good reliability and validity, which includes both generic 
and disease specific modules. It consists of a 23-item core measure of global QOL that has four subscales:  
physical functioning, emotional functioning, social functioning, and school functioning. The domain of 
physical functioning will be used as a specific secondary outcome measure for this study, especially the 
parent proxy for younger children as it assesses children under 6 years of age.  
There are different forms for parents of patient’s ages 2 – 17 years (toddler: 2 – 4; young child: 5 – 7; child: 
8 – 12; adolescent:  13 – 17) and parallel self-report forms for patient’s ages 5 – 25 years (young child: 5 – 
7; child: 8 – 12; adolescent: 13 – 17; young adult:  18 – 25). It takes approximately 5 - 10 minutes to 
complete. For this study, children from 8 to 17 years of age will complete self-report measures of the 
PedsQL, and parents or legal guardians of children from 2 to 17 years of age will complete the parent proxy 
report measures of the PedsQL.   
 
Pain Intensity 
The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point numeric scale that assesses 
pain severity (Hawker et al., 2011). It consists of a horizontal line with 0 representing “no pain” at the right 
end of the line and 10 representing “worst pain you can imagine” at the left end.  Patients are asked to circle 
the one number from 0 to 10 that best describes their worst pain over the past week for the following: 1) 
most important tumor pain chosen by the participant, 2) target tumor pain and 2) other pain. It takes less 
than 5 minute to complete. The NRS-11 is recommended as a core outcome self-report measure of pain 
intensity for clinical trials (Dworkin et al., 2005) in children with NF1 (Wolters, et al., 2013).  Children, 
ages 8 to 17 years, will complete self-report measures of the NRS-11 for this study.  
 
Pain Interference 
The Pain Interference Index (PII) is a 6-item measure that assesses the degree to which pain has interfered 
with daily activities in the past week. This measure was developed in Sweden and validated in Swedish 
with a group of children and adolescents with longstanding idiopathic pain (Wicksell, Melin, Lekander, & 
Olsson, 2009). The author (R. Wicksell) translated the measure into English, and members of the 
Neurobehavioral Group (S. Peron and P. Wolters) worked with the Swedish group to modify the wording 

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to make it more readable and to shorten the time frame to one week, and we adapted it to create a parallel 
parent version. Dr. Wicksell and the Swedish research group are supportive of our efforts to validate the 
self-report and parent versions of the PII in NF1. Results of our validation studies in children with NF1 and 
their parents indicate that the internal consistency and construct validity of the PII are good. These data 
support the use of the PII to assess pain interference in youth with NF1 and PNs (Martin et al., submitted).  
For this study, children from 8 to 17 years of age will complete self-report PII, and parents or the legal 
guardian of children from 5 to 17 years of age will complete the parent proxy report PII.   
 
Global Impression of Change 
The patient Global Impression of Change (GIC) Scale evaluates the clinical significance of 
changes in pain intensity. We will administer an adapted version of the self-report GIC Scale at 
the follow-up PRO evaluations only (it should not be given pre-study because it assesses change 
in pain from baseline). A parallel parent proxy report form also was developed. On the adapted 
GIC, patients (and their parents separately) will give their overall impression of change in level 
of the child’s 1) tumor pain, 2) other pain, and 3) other morbidities from before initiation of the 
MEK inhibitor to the current evaluation point for the first year on study. This global measure of 
change will be administered to children >8 years and for parents of children > 5 years of age at 
each PRO assessment through the first year (prior to course 13). The GIC Scale has been used in 
several research studies on chronic pain in adults and more recently children (Arnold et al., 2011; 
Mohammad et al., 2014). It has been recommended by the Initiative on Methods, Measurement, 
and Pain Assessment in Clinical Trials (IMMPACT) for clinical trials involving chronic pain 
(Dworkin et al., 2005; McGrath et al., 2008). The relationship between the numerical scale 
(NRS-11) and the qualitative scale (GIC) will be determined by breaking the participants into 
groups based on their qualitative response and determining the mean point difference associated 
with each qualitative label. This information will help evaluate the effects of the study drug on 
pain as well as provide data on clinically meaningful changes in pain.   
 
Pediatric Background Information 
The Pediatric QOL Background Form should be completed by the parents of all patients ages 
from 2-17 years at each evaluation to document information about demographics, use of pain 
medication, and NF1 disease severity. These data will be used to better interpret the PRO data.   
 
Administration Schedule of the PRO Measures 
• Baseline and follow-up PRO assessments: Child participants and their parents will complete the 
PRO measures at baseline (prior to starting treatment) and then again after course 4 +2 weeks, 8 
+2 weeks, 12 +2 weeks, 18 +2 weeks, and 24 +2 weeks. In addition, they should be administered 
at the end of treatment +2 weeks if this is not encompassed in the times above.   
 
Specific Administration Instructions 
• The instructions for each PRO form should be reviewed with the parent and child prior to 
having them complete it. For children of all ages completing the self-report forms, it is important 
to have an investigator in the room while the child completes them to review the instructions and 
answer any questions. Younger children may need help understanding the directions or reading 
the items. 
 
• Items on the NRS-11 pain intensity scale asking the child to rate their most important tumor 
pain that they pick and their target tumor pain selected by the medical team. The SAME tumor 

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pains rated at the baseline evaluation needs to be rated for each subsequent evaluation so the 
investigator administering the PRO forms needs to write in the tumor pains rated at the baseline 
evaluation each time.   
 
• Prior to seeing the patients for the baseline evaluation, find out the area of the body where the 
target tumor is located (from the designated investigator at your site) so that you can tell patients 
this location and write it in the blank space for question #2 on the NRS-11.   
• When administering these questionnaires, first review the instructions on each form with the 
parents and child participants. Mention that you can read or explain any of the items if they need 
any help reading or if they have any questions.  
• For participants who may have difficulty reading, it is permissible to read the items to them, or 
explain any items they have difficulty understanding, but the patients should answer the items 
themselves. One way to do this is to give the patient their own form on which to mark his/her 
answers while the staff person reads the items from another copy of the questionnaire.   
• Immediately after the participants are finished filling out the questionnaires and before they 
leave the clinic, please check each form to make sure that the items are completed correctly 
(e.g., only one response circled) and that all the applicable items are answered.  
--If more than one answer is circled for an item, please have the individual choose one response. 
--If they forgot to answer an item, ask them to please try to answer it.  
• Prior to seeing patients for all of the follow-up evaluations, refer back to the completed 
baseline NRS-11 pain intensity questionnaire to identify the location of the tumor that the 
participant previously specified as their most important tumor and then write this information on 
the blank line in question #1 on the current form. Also, write in the target tumor rated at baseline 
for item #2. Specifying these locations will help ensure that the patients rate the severity of pain 
for the same tumor across all evaluations.   
 
Self-report 
• Children, 8 to 17 years of age, will complete the self-report measures of the PedsQL, NRS-11, 
and PII at baseline and all follow-up evaluations. The GIC scale will be done only at the follow-
up evaluations after the other measures have been completed.   
 
Parent Report 
• Parents (or the legal guardian) of children, 2 to 17 years of age, will complete the parent proxy 
measures of the PedsQL and a background form.   
 
• Parents (or the legal guardian) of children, 5 to 17 years of age, also will complete the parent 
proxy measures of the PII. At the follow-up evaluations only, they will be administered the GIC 
scale, which is to be completed after the other measures have been done.   
 
 
 
 
 

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Table 1. PROs administered to all pediatric patients (ages 2 - <18 years)* by age and 
respondent 
 
Parent Questionnaires 
Age of Patient (years) 
 
2 - 7 
8 - 17 
Background Information 
 
 
Parent report: Pediatric Background Form 
√ 
√ 
Pain Interference 
 
 
Parent report: Pain Interference Index 
 
√ 
(5 - 7) 
√ 
General QOL 
 
 
Parent report: PedsQL Generic form 
√ 
2 - 4 
(Toddle
r) 
√ 
5 - 7  
(Young 
Child) 
√ 
8 - 12 
(Child) 
√ 
13 - 17 
(Teen) 
Global Impression of Change 
 
 
 
Parent report: Global Impression of 
Change Scale 
 
√ 
(5 - 7; follow-
ups evals only) 
√ 
(follow-up evaluations 
only) 
√  Administer items with a check mark under the correct age range of the patient 
*IMPORTANT ADMINISTRATION GUIDELINES:  If a participant is 17 years at study entry they should be 
administered the PROs in the Pediatric Module, continuing on the pediatric measures even if they turn 18 years 
old.  However, if they are 18 years at study entry, they should be administered the PROs in the Adult Module. 
Patient Questionnaire 
Age of Patient (years)* 
 
2 - 7 
8 - 17 
Pain Intensity 
 
 
Patient self-report: Numeric Rating Scale-
11 
 
√ 
Pain Interference 
 
 
Patient self-report: Pain Interference Index 
 
√ 
General QOL 
 
 
Patient self-report: PedsQL Generic form 
 
 
√ 
8 - 12 
(Child) 
√ 
13 - <18 
(Teen) 
Global Impression of Change 
 
 
Patient self-report: Global Impression of 
Change Scale 
 
√ 
(follow-up evaluations 
only) 

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ADULT PRO MODULE 
 
(Ages >18 years)* 
 
II. QOL and Pain Measures for Adult Patients 
 
In adult participants with plexiform neurofibromas in all locations, this study will assess general 
health-related qualify of life (QOL) and pain (pain intensity and pain interference) using patient-
reported outcomes (PROs) in the Adult Module as described below. 
 
*IMPORTANT ADMINISTRATION GUIDELINES: If a participant is 18 years or older at study 
entry, they should be administered the PROs in the Adult Module. However, if a participant is 17 
years or younger at study entry, they should be administered the PROs in the Pediatric Module, 
continuing on the same pediatric measures even if they turn 18 years old.  
 
 
NF1 Disease Specific QOL Measure 
 
The Adult PedsQL™ NF1 Module is a 74-item self-report instrument to assess NF1 disease-
specific quality of life (QOL) in adults, ages 18 years and older. It is comprised of 16 scales: 1) 
Physical functioning (8 items), 2) Emotional functioning (5 items), 3) Social functioning (3 items), 
4) Cognitive functioning (5 items), 5) Communication (3 items), 6) Worry (7 items), 7) Perceived 
physical appearance (3 items), 8) Pain and Hurt (3 items), 9) Paresthesias (2 items), 10) Skin 
irritation (5 items), 11) Sensation (4 items), 12) Movement and Balance (4 items), 13) Fatigue (3 
items), 14) Daily activities (12 items), 15) Treatment anxiety (4 items) and 16) Sexual functioning 
(3 items) (Nutakki et al., submitted; N. Swigonski, personal communication, September 26, 2012).   
 
The PedsQL™ NF1 Module format, instructions, and Likert response scale are similar to the 
PedsQL™ 4.0 Generic Core Scales and other PedsQL™ Disease-Specific Modules. The 
instructions ask how much of a problem each item has been during the past one month. A 5-point 
response scale is used for all items in the three versions of the instrument (0= never a problem, 1= 
almost never a problem, 2= sometimes a problem, 3= often a problem, 4= almost always a 
problem). Items are reverse scored and linearly transformed to a scale of 0-100 similar to 
PedsQL™ 4.0 Generic Core Scales (0= 100, 1= 75, 2= 50, 3=25, 4=0). Higher scores indicate 
better HRQOL and fewer symptoms or problems. The total scale score is computed as the sum of 
all items on the PedsQL™ NF1 Module divided by the number of items answered (this accounts 
for missing data). Subscale scores are computed as the sum of the items divided by the number of 
items that were answered in that scale. If more than 50% of the items in the scale are missing, the 
scale score is not computed. 
 
Feasibility, measured by the percentage of missing responses, was 4.8 % for all scales on the adult 
version of the PedsQL™ NF1 Module. Internal consistency reliability for the Total Scale score 
(alpha =0.97) and Scale reliabilities ranging from 0.72 to 0.96 were acceptable for group 
comparisons. The PedsQL™ NF1 module distinguished between NF1 adults with excellent to very 
good, good, and fair to poor health status. Thus, preliminary data demonstrates the initial 
feasibility, reliability and validity of the PedsQL™ NF1 module in adult patients (Nutakki et al., 

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personal communication). The preliminary data in a small sample of adolescents also looks 
promising with good feasibility (percentage of missing responses was 8.9%) and a total scale 
reliability of 0.96 (N. Swigonski, personal communication, October 10, 2012).   
 
The PlexiQoL was developed as an outcome measure specific to adults with NF1 associated 
plexiform neurofibromas. Content for the measure was developed directly from qualitative 
interviews conducted with relevant patients. The measurement model is the needs-based model of 
quality of life which focuses on the extent to which the disease prevents the fulfilment of human 
needs. In this respect, the scale is different from, and complementary to, standard measures of 
health-related quality of life, that assess symptoms and functional limitations. The PlexiQoL is a 
holistic measure that provides an index of quality of life. The PlexiQoL consists of 22 
dichotomous statements, with respondents asked to indicate whether they apply to them ‘at the 
present time’. It can be scored simply by adding the number of positive responses. However, as the 
scale fits the Rasch measurement model, a more accurate and responsive score can be obtained by 
producing Rasch transformed scores. The PlexiQoL has been shown to be well accepted by 
respondents and to have high levels of reproducibility and construct validity. 
 
Pain Measures 
 
1. Pain Intensity 
The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point numeric scale that 
assesses pain intensity. It consists of a horizontal line with 0 representing “no pain” at the right end 
of the line and 10 representing “worst pain you can imagine” at the left end. Subjects are asked to 
circle the one number from 0 to 10 that best describes 1) their “most important tumor pain,” 2) their 
“target tumor pain” at its worst during the past week, and 3) their “other pains” (non-tumor) at their 
worst over the past week. It takes just a few minutes to complete. The NRS-11 is recommended as 
a core outcome measure of pain intensity for clinical trials.   
 
2. Pain Interference 
The Brief Pain Inventory (BPI)—Pain Interference Scale is a 7-item self-report questionnaire that 
measures the extent to which tumor pain interferes with daily functioning. Subjects are asked to 
indicate how much tumor pain interfered with various activities (general activity, mood, walking, 
normal work, relations with other people, sleep, and enjoyment of life) in the past week, with scores 
ranging from 0 (does not interfere) to 10 (completely interferes). A total score is obtained by taking 
the mean of the scores for all 7 items; thus, the total pain interference score can range from 0 to 7. 
This scale takes just a few minutes to complete. These items are recommended to assess pain 
interference in clinical trials.  
 
Global Impression of Change From 
The patient Global Impression of Change (GIC) Scale is a scale that evaluates the clinical 
significance of changes in pain intensity or other morbidities. We will administer an adapted 
version of the GIC Scale at the follow-up PRO evaluations only (it should not be given pre-study 
because it assesses change from baseline). On the adapted GIC, patients will give their overall 
impression of change in their 1) tumor pain, 2) other pain, and 3) tumor-related morbidities from 
before initiation of the MEK inhibitor to the current evaluation point. The GIC Scale has been 
used in several research studies on chronic pain in adults. It has been recommended by the 

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Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) for 
clinical trials involving chronic pain (Dworkin et al., 2005). The relationship between the 
numerical scale (NRS-11) and the qualitative scale (GIC) will be determined by breaking the 
participants into groups based on their qualitative response and determining the mean point 
difference associated with each qualitative label. This information will help evaluate the effects 
of the study drug on pain and other morbidities as well as provide data on clinically meaningful 
change in these problems.   
 
Background Information Form 
To allow for more meaningful analysis of the QOL data, the participant (for subjects > 18 years) 
will complete a background information form at study entry and each subsequent QOL evaluation.  
This form will collect general information such as the subject’s level of education, work status, 
psychiatric diagnoses, and pain medications, as well as the perceived visibility of NF1 tumors and 
severity of NF1 symptoms.   
 
Administration Schedule of the PRO Measures 
• Baseline and follow-up PRO assessments: Adult participants will complete the PRO measures 
(except for the PlexiQoL) at baseline (prior to starting treatment) and then again after course 4 +2 
weeks, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks, and 24 +2 weeks. In addition, they should be 
administered at the end of treatment +2 weeks if this is not encompassed in the times above. The 
PlexiQoL will be completed at baseline (prior to starting treatment) and then again after course 12 
+2 weeks or at the end of treatment +2 weeks if this occurs prior to the end of course 12. 
 
Specific Administration Guidelines 
 
• Prior to seeing the patients for the baseline evaluation, find out the area of the body where the 
target tumor is located (from the designated investigator at your site) so that you can tell patients 
this location and write it in the blank space for question #2 on the NRS-11.   
• When administering these questionnaires, first review the instructions on each form with the 
subjects. Mention that you can read or explain any of the items if they need any help reading or if 
they have any questions.  
• For participants who may have difficulty reading, it is permissible to read the items to them, or 
explain any items they have difficulty understanding, but the patients should answer the items 
themselves. One way to do this is to give the patient their own form on which to mark his/her 
answers while the staff person reads the items from another copy of the questionnaire.   
• The PlexiQoL is to be administered after the other PRO forms. 
• Immediately after the participants are finished filling out the questionnaires and before they 
leave the clinic, please check each form to make sure that the items are completed correctly (e.g., 
only one response circled) and that all the applicable items are answered.  
--If more than one answer is circled for an item, please have the individual choose one response. 
--If they forgot to answer an item, ask them to please try to answer it.  
• Prior to seeing patients for all of the follow-up evaluations, refer back to the completed 
baseline NRS-11 pain intensity questionnaire to identify the location of the tumor that the 

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participant previously specified as their most important tumor and then write this information on 
the blank line in question #1 on the current form. Also, write in the target tumor rated at baseline 
for item #2. Specifying these locations will help ensure that the patients rate the severity of pain 
for the same tumor across all evaluations.   
 
Table 2. PROs administered to all adult patients (ages > 18 years)* by age and 
respondent 
 
√  Administer items with a check mark under the correct age range of the patient 
*IMPORTANT ADMINISTRATION GUIDELINES:  If a participant is 18 years or older at study entry, 
they should be administered the PROs in the Adult Module. However, if a participant is 17 years at study 
entry they should be administered the PROs in the Pediatric Module, continuing on the pediatric measures 
even if they turn 18 years old  
 
 
 
Adult Patient Questionnaires 
Age of Patient (years) 
 
> 18 
Background Information 
 
Self-report:  Adult Background Form 
√ 
Pain Intensity 
 
Self-report: Numeric Rating Scale-11 
√ 
Pain Interference 
 
Self-report: Brief Pain Inventory 
√ 
NF1 QOL 
 
Self-report: PedsQL Adult NF1 Disease-specific QOL 
                      PlexiQoL 
√ 
√ 
Global Impression of Change (Follow-up only) 
 
Self-report: Global Impression of Change Scale 
√ 
     (Follow-up evaluations only) 

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APPENDIX IX: PLEXIFORM NEUROFIBROMA SYMPTOM CHECKLIST  
 
To be completed by patient if able, otherwise completed by the parent/guardian. To be completed 
by the same individual at each time point.  
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24. 
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
 
For each item below, please check one box (unless otherwise indicated) to describe how much 
each of these has been a problem for you in the past two weeks: 
 
 
1) Fatigue/feeling tired 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
2) Sleep problems 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
3) Less appetite 
(eating less) 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
4) More appetite 
(eating more) 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
5) Headaches 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
6) Vision changes 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
7) Decreased hearing 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
8) Mouth Sores 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
9) Trouble swallowing 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
10) Choking 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
11) Snoring 
 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
12) Frequent awakenings 
at night 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 

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13) Cough 
 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
14) Wheezing 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
15) Difficulty breathing 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
16) Chest pain 
 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
17) Palpitations/fluttering 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
18) Shortness of breath    
with activity 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
19) Shortness of breath at 
rest 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
20) Swelling in 
hands/feet 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
21) Abdominal pain 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
22) Heartburn 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
23) Nausea 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
24) Vomiting 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
25) Diarrhea 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
26) Constipation 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
27) Stool incontinence 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
28) Pain with urination 
 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
29) Increased urinary 
frequency/urgency 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
30) Difficulty beginning    
urination 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
31) Urinary incontinence 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
32) Weakness 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 

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If yes, where? 
 
 
 
 
 
 
33) Muscle pain 
 
If yes, where? 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
34) Dizziness 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
35) Numbness 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
 
 
 
36) Tingling 
 Not at all 
 A little 
 Some 
 Pretty much 
 A lot 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX X:  PN LOCATION AND ASSOCIATED MORBIDITIES 
INSTRUCTIONS:  
 
To be completed by the Site PI prior to starting treatment 
- 
Assess PN location(s) by clinical exam and imaging studies (target PN and up to 2 non target PN; fill out a separate form for each PN)  
- 
List morbidities present using numbers below (see list) 
- 
If no morbidity present, list potential morbidities based on PN site(s) 
 
PN Location 
 
PN Associated Morbidities 
 
R 
L 
B/L 
Pain 
(Y/N) 
Present PN Morbidities (using numbers listed 
below)/ Comments 
Potential Morbidities 
Orbit 
 
 
 
 
 
 
Face 
 
 
 
 
 
 
Ear canal 
 
 
 
 
 
 
Tongue 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anterior neck/upper airway 
 
 
 
 
 
 
Posterior neck  
(cervical paraspinal) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mediastinum 
 
 
 
 
 
 
Intra-thoracic 
 
 
 
 
 
 
Thoracic/paraspinal/chest wall 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver 
 
 
 
 
 
 
Abdominal  
 
 
 
 
 
 
Mesentery 
 
 
 
 
 
 
Posterior abdomen/pelvis 
(Lumbo-sacral plexus) 
 
 
 
 
 
 

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Perineum/peri-rectal/bladder 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upper arm 
(Brachial plexus) 
 
 
 
 
 
 
Forearm 
 
 
 
 
 
 
Hand 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thigh/upper leg 
 
 
 
 
 
 
Lower leg 
 
 
 
 
 
 
Foot 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (please specify):  
 
 
 
 
 
 
 
 
Morbidities:  
1- Vision loss 
2- Facial motor 
dysfunction 
3- Auditory loss 
4- Difficulty swallowing 
5- Abnormal speech 
6- Airway obstruction 
7- Respiratory 
compromise 
8- Bladder dysfunction 
9- Bowel dysfunction 
10- Motor weakness 
11- Decreased range of 
motion 
12- Sensory deficit  
13- PN related Disfigurement/ 
appearance 
 
14- Other (please describe): 
 
 
***Instruction to site PI:  Please place asterix next to target lesion morbidity.   

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APPENDIX XI: PLEXIFORM NEUROFIBROMA CLINICIAN MORBIDITY ASSESSMENT 
 
Instructions 
• To be completed by the treating physician. 
• At baseline, please identify morbidities.   
• 
Please fill out a separate form for each PN identified in Appendix X) 
• At follow-up, for each morbidity identified at baseline, please document whether the noted 
morbidity is: 
o worse 
o stable 
o improved but still present 
o resolved 
• Please include comments (ex. previously was using 2 pain medications and now using one; 
previously on Bipap setting of 8, now on Bipap setting of 4). If available, please provide 
any objective applicable testing results related to morbidities (in the comments box). 
 
Please document the baseline morbidities. 
Baseline Morbidity 1:  
 
 
 
 
 
 
 
 
 
Baseline Morbidity 2:  
 
 
 
 
 
 
 
 
 
Baseline Morbidity 3:  
 
 
 
 
 
 
 
 
 
Baseline Morbidity 4:  
 
 
 
 
 
 
 
 
 
 
 

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Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
For each baseline morbidity, please document whether the morbidity is:  
1) worse; 2) stable; 3) improved but still present; or 4) resolved 
 
Evaluation 
Date 
Course Baseline 
Morbidity#1 
Baseline 
Morbidity 
#2 
Baseline 
Morbidity 
#3 
Baseline 
Morbidity 
#4 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMPLETED BY: ___________________________________ DATE:______________ 
  
 

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APPENDIX XII: FUNCTIONAL OPHTHALMOLOGY EVALUATION FOR ORBITAL PN 
Please perform, if feasible, eye exam as outlined below. Additional evaluations can be performed 
at discretion of the site PI. 
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
Location of orbital PN? 
 
☐ right  ☐ left  ☐ both 
 
Does patient have an optic pathway glioma?  
☐ Yes  ☐ No  
 
Examination Protocol  
1. Distance Acuity: 
Testing should be performed using HOTV or Teller Acuity Cards as outlined below.  
Each eye should be tested separately with best correction in place. The same testing 
method must be used for each subject throughout their time on study. HOTV should be 
used for children old enough to perform reliably at the baseline pre-treatment visit.  All 
other children should be tested using Teller Acuity Cards. For analysis, acuity will be 
corrected for normal at the age of testing by calculating an age-based acuity.  Changes > 
0.2 logMAR will be considered significant.  
 
HOTV Testing 
HOTV testing should be performed using the HOTV PEDIG ATS protocol at 3 meters.  
Acuity should be reported in logMAR. 
 
Teller Acuity Card Testing 
Teller Grating Acuity should be measures at 55 cm and reported in Courses/cm (choose 
the best card achieved). Grating acuity will be converted to logMAR by the study team. 
 
2. Exophthalmometry 
Measurements should be made with the same equipment for each subject throughout their 
time on study. Measurements will be made three times during each visit and averaged.  
The type of exophthalmometer and the base between the orbital rims should be the same 
during each measurement and each visit unless the child has significant facial growth 
between visits. Measurement of the amount of proptosis will be reported in mm. For 
analysis, changes in proptosis > 2 mm will be considered significant. 
 
 
 

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OD 
OS 
Distance Acuity 
(best corrected): 
 
Teller Acuity 
(cycle/cm) 
 
 
HOTV 
(logMAR) 
 
 
If acuity has 
declined, what 
is it due to: 
☐ Progressive Orbital PN 
☐ Progressive  amblyopia 
(deprivation, anisometropic, 
stabismic, etc) 
☐ Optic pathway glioma 
☐ Other (describe): 
      
☐ Progressive Orbital PN 
☐ Progressive  amblyopia 
(deprivation, anisometropic, 
stabismic, etc) 
☐ Optic pathway glioma 
☐ Other (describe): 
      
Exophthalmometry 
(mm) 
Measurement 
#1 
 
 
 
Measurement 
#2 
 
 
 
Measurement 
#3 
 
 
 
Average 
 
 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 
 
 

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APPENDIX XIII: MOTOR/STRENGTH EVALUATIONS  
Endurance Evaluation 
All patients ≥ 5 years at enrollment and ambulatory, with lower extremity PN, cord compression, 
or airway PN, should undergo endurance testing using the 6-Minute Walk Test. This evaluation 
should be performed by Rehabilitation Medicine, Physiatry, or Physical Therapy, if possible.   
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
Height (cm):__________          Weight (kg):__________ 
 
Gender:__________    
   Age (year and months): __________ 
 
TOTAL DISTANCE (METERS) 
 
HEART RATE 
 
Before Walk  
At Completion of Walk  
After 5 Minute Cool-down  
BLOOD PRESSURE 
 
Before Walk  
After Completion of Walk  
After 5 Minute Cool-down  
VELOCITY 
(Total Distance (m)/6 Minutes) 
 
 
 
Percentage of normal* distance achieved: _______________ 
 
* Normal values adjusted for age, BMI, and sex as per: Geiger et al. Six-Minute walk test in 
children and adolescents. J of Pediatrics, 2007 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 
 
 

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Strength Evaluation  
Baseline evaluation:  
All patients with PN that cause or have the potential to cause motor dysfunction, weakness, or 
cord compression should undergo evaluation of strength of all muscle groups at baseline. This 
evaluation should be performed by Rehabilitation Medicine, Physiatry, or Physical Therapy, if 
possible, and should ideally be completed by the same examiner at each visit, if feasible.  
 
Please grade strength in the relevant muscle groups using Medical Research Council (MRC) 
grading of 0-5/5 (+/- may be used). Please grade grip and pinch strength in pounds of force. 
(Medical Research Council. Aids to the examination of the peripheral nervous system, 
Memorandum no. 45, Her Majesty's Stationery Office, London, 1981) 
 
Follow-up evaluations: 
At follow-up exams, a focused evaluation of strength of the affected and potentially affected 
muscle groups should be performed. The contralateral side should be tested for comparison. If 
the contralateral side is also potentially affected, a third extremity should be tested as an 
assessment of overall strength. The muscle group(s) to be assessed at follow-up evaluations will 
be specified by the study team based on PN location and baseline findings and will be indicated 
below: 
 
 
   Upper Extremity  
   Lower Extremity    
   Other (Please specify):  
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
 

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Manual Muscle/Strength Testing (include affected and at-risk muscle groups) 
 
POSITION 
LEFT 
RIGHT 
MIDLINE 
SUPINE                   Neck Flexors 
 
SIDELYING        Gluteus Medius 
 
PRONE             Gluteus Maximus 
 
Hamstrings 
 
Plantar flexors 
 
Neck extensors 
 
SITTING                       Trapezius 
 
Deltoids 
 
Biceps 
 
Triceps 
 
Wrist flexors 
 
Wrist extensors 
 
Iliopsoas 
 
Quadriceps 
 
Anterior tibial 
 
Gastrocnemius 
 
Extensor Hallucis Longus 
 
 
 
POSITION 
LEFT 
RIGHT 
Grip*  
 
 
 
Key Pinch* 
 
 
 
 
 
*Please grade grip and pinch strength in pounds of force 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 

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Range of Motion Evaluation 
Baseline evaluation:  
All patients with PN that cause or have the potential to cause motor dysfunction, weakness, or 
cord compression should undergo evaluation of range of motion of all joints at baseline. This 
evaluation should be performed by Rehabilitation Medicine, Physiatry, or Physical Therapy, and 
should ideally be completed by the same examiner at each visit, if feasible.   
 
Follow-up evaluations: 
At follow-up exams, a focused evaluation of range of motion of the affected and potentially 
affected joints should be performed. The contralateral side should be tested for comparison. 
Joint(s) to be assessed at follow-up evaluations will be specified by the study team based on PN 
location and baseline findings and indicated below: 
 
 
   Neck  
 
   Upper Extremity    
  Lower  Extremity 
 
 
  Other (Please specify):  
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
 

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LEFT 
(degrees) 
 
RIGHT  
(degrees) 
MIDLINE 
(degrees) 
 
NECK 
 
 
 
Extension (Sidelying) 
 
 
 
Flexion (Sidelying) 
 
 
 
Lateral Flexion (Supine) 
 
 
 Rotation (Supine) 
 
 
 UPPER LIMB  
 
 
 SHOULDER (Supine) 
 
 
 
Abduction  
 
 
 Internal Rotation  
 
 
 External Rotation  
 
 
 ELBOW (Supine) 
 
 
 Flexion  
 
 
 Extension 
 
 
 WRIST (Supine) 
 
 
 Flexion  
 
 
 Extension  
 
 
 LOWER LIMB 
 
 
 HIP 
 
 
 Flexion (Supine) 
 
 
 Extension (Sidelying) 
 
 
 External Rotation 
(Supine) 
 
 
 Internal Rotation 
(Supine) 
 
 
 Abduction (Supine) 
 
 
 KNEE (Supine) 
 
 
 Flexion  
 
 
 Extension  
 
 
 ANKLE (Supine) 
 
 
 Plantarflexion  
 
 
 Dorsiflexion  
 
 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 
 
 

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Leg Length Evaluation 
All patients with PN located in the lumbosacral plexus or below (i.e. lower limb) should undergo 
leg length measurements to evaluate for discrepancy. This evaluation should be performed by 
Rehabilitation Medicine, Physiatry, or Physical Therapy, and should ideally be completed by the 
same examiner at each visit, if feasible. Measurements should be taken from the Anterior 
Superior Iliac Spine to the Medial Malleolus of the ankle. The subject should be lying supine 
with hips and knees extended. 
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
 
 
LEG LENGTH (cm) 
LEFT 
RIGHT 
 
 
 
 
 
Leg length discrepancy (difference between right and left): _________________ 
 
If leg length discrepancy present, is there associated pelvic obliquity:  
 Yes   
 No 
 
 
 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 

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Grooved Pegboard Test  
All patients ≥ 5 years at enrollment and ability to use one or both upper extremities with PN 
located in the upper extremities or patients with known cervical or upper thoracic cord 
compression should undergo Grooved Pegboard Testing.  
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
 
 
Age: ____________ Gender: _____________ 
 
 
GROOVED PEGBOARD SCORE SHEET 
 
 
Dominant Hand (Circle one): 
 
LEFT  
 
RIGHT 
 
 
Time (Sec) 
# of drops 
# of pegs placed 
X ± SD* 
Z* 
Dominant 
Hand 
 
 
 
 
 
Non-Dominant 
Hand 
 
 
 
 
 
*To be completed by the operations center  
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 

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GROOVED PEGBOARD INSTRUCTIONS 
 
This is a pegboard and these are the pegs. (The examiner points out each and then picks up 
one of the pegs and continues). All the pegs are the same, that is, they have a round side and 
a square side and so do the holes in the board. What you must do is match the groove of the 
peg with the groove in the board and put these pegs into the holes like this.  
 
(The examiner demonstrates by filling the top row. Then remove the pegs, putting them back 
into the tray. For the right-hand trial, the examiner demonstrates that the pegs are placed from the 
patient’s left to right, and from right to left for the left-hand trial. The dominant hand trial is 
administered first, followed by the non-dominant hand trial).  
 
For adolescents (ages ≥9 to <15) and adults (age ≥ 15 years): 
When I say go, begin here and put the pegs into the board as fast as you can, using only 
your (dominant) hand. Fill the top row completely from this side to this side (from left to 
right for right-handed patients, from right to left for left-handed). Do not skip any. Fill each 
row the same way you filled the top row. Any questions? Ready, as fast as you can, go. 
(Repeat this task with the non-dominant hand) 
 
For children (ages ≥5 to <9): Use 10 pegs only 
When I say go, begin here and put the pegs into the board as fast as you can, using only 
your (dominant) hand. Fill the top row completely from this side to this side (from left to 
right for right-handed patients, from right to left for left-handed). Do not skip any. Then go on 
to the second row and fill it the same way you filled the top row. Stop when you have 
completed the second row. Any questions? Ready, as fast as you can, go.  
(Repeat this test with the non-dominant hand).  

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APPENDIX XIV: BLADDER AND BOWEL PATIENT QUESTIONNARIE 
 
Patients with bowel/bladder dysfunction or their guardians should complete the questionnaire 
below. Not applicable for subjects that are not toilet trained.  
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
 
To be completed by Patient if able, otherwise completed by the Parent/Guardian: 
 
1. I pee in my underwear during the day: 
□ Never  
□ 1 day a week 
□ 2–3 days a week  
□ 4–5 days a week  
□ Every day 
 
2. When I pee in my underwear, they are: 
□ I don’t pee in my underwear  
□ Almost dry      □ Damp  
□ Wet   
□ Soaked 
 
3. In a normal day I go to the washroom to pee: 
□ 1–2 times  □ 3–4 times  □ 5–6 times 
 □ 7–8 times  □ More than 8 times 
 
4. I feel that I have to rush to the washroom to pee: 
□ Never 
□ Less than half of the time □ Half of the time 
 
□ More than half of the time  
□ Every day 
 
5. I hold my pee by crossing my legs or sitting down: 
□ Never 
□ Less than half of the time □ Half of the time 
 
□ More than half of the time  
□ Every day 
 
6. It hurts when I pee: 
□ Never 
□ Less than half of the time □ Half of the time 
 
□ More than half of the time    
□ Every day 
 
7. I wet my bed at night: 
□ Never   □ 1-2 nights per week   □ 3-4 nights per week   □ 4–5 nights per week    □ Every night 
 
8. I wake up to pee at night: 
□ Never   □ 1-2 nights per week   □ 3-4 nights per week   □ 4–5 nights per week    □ Every night 
 
9. When I pee, it stops and starts: 
□ Never 
□ Less than half of the time □ Half of the time 
 
□ More than half of the time   □ Every day 
 

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10. I have to push or wait for my pee to start: 
□ Never 
□ Less than half of the time □ Half of the time 
 
□ More than half of the time    
□ Every day 
 
11. I have bowel movements (poop): 
□ More than every day 
□ Every day  □ Every other day 
□ Every 3 days 
 
 
 
12. My stool (poop) is hard: 
□ Never 
□ Less than half of the time □ Half of the time 
 
□ More than half of the time   □ Every day 
 
13. I have bowel (poop) accidents in my underwear: 
□ Never     □ 1–2 times per week     □ 3 times per week     □ 4–5 times per week     □ Every day 
 
14. How easy was it to answer these questions? 
□ Very easy 
□ Easy  
□ Neither easy nor difficult 
□ Difficult 
□ Very difficult 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX XV: FUNCTIONAL HEARING EVALUATION FOR PN THAT COMPRESS THE EAR 
CANAL, CAUSE HEARING LOSS, OR POTENTIALLY CAN CAUSE HEARING LOSS 
 
Please perform, if feasible, audiogram OR auditory brainstem response (ABR/BAER), and a word 
recognition score as clinically indicated and per institutional practice. Additional evaluations can be 
performed at the discretion of the site PI. 
 
Testing should be performed pre-treatment, and then post to courses 4, 8, 12, 18, 24.  
 
Select one:  
Pre-treatment  ☐  
Post  course 4  ☐  
Post course 8  ☐  
Post course 12  ☐ 
 
 
Post course 18  ☐       
Post course 24  ☐  
 
Other (Please specify): _________________________ 
 
Location of PN affecting or potentially affecting? 
☐ right  ☐ left  ☐ both 
 
 
Hearing Test Results (measured in dB HL) 
Please provide results for all frequencies (Hz) tested 
NT = not tested 
 
Air Conduction Thresholds 
 
250 Hz 
500 
1000 
2000 
3000 
4000 
6000 
8000 
Right 
 
 
 
 
 
 
 
 
 
Left 
 
 
 
 
 
 
 
 
 
 
Bone Conduction Thresholds 
 
250 Hz 
500 
1000 
2000 
3000 
4000 
6000 
8000 
Right 
 
 
 
 
 
 
 
 
 
Left 
 
 
 
 
 
 
 
 
 
Unmasked 
 
 
 
 
 
 
 
 
 
 
 
ABR/BAER Results (measured in dB eHL) 
Please provide results for all frequencies (Hz) tested 
NR = No response 
NT = not tested 
 
Air Conduction Thresholds 
 
500 Hz 
1000 
2000 
4000 
8000 
Right 
 
 
 
 
 
 
Left 
 
 
 
 
 
 

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Bone Conduction Thresholds 
 
500 Hz 
1000 
2000 
4000 
8000 
Right 
 
 
 
 
 
 
Left 
 
 
 
 
 
 
 
 
Word Recognition Score 
Please report % words correctly recognized at the optimal dB level based on the speech awareness 
threshold / speech recognition threshold clinically used 
 
 
% 
Right 
 
 
Left 
 
 
 
 
 
 

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APPENDIX XVI: PHOTOGRAPHY OF VISIBLE PN 
 
Photography of visible PN (include visible target and any non-target PN that was identified in 
Appendix X) will be performed in consenting patients. Please store the photos on a password 
protected computer. Please follow the study memos from the operations team for future 
instructions regarding photograph submission. 
 
Testing should be performed pre-treatment, and then post courses 4, 8, 12, 18, 24.  
 
 
 
All photographs at each time point should be taken from the same distance, using similar lighting 
and camera settings, if possible. Baseline photographs should be present at the time of follow up 
photography to allow for the best possible comparison.  
 
 
Please fill out this form at baseline to indicate which body regions are being photographed 
at the specified time points.   
 
Please Circle and Describe the location of each PN being photographed: 
 
Description of Photo body location: 
 
 
 
 
 
 
 
 
#1:        
 
 
#2:        
 
 
#3:        
 
 
#4:        
 
 
#5:        
 
 
 
 
 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE: 
 
 
 

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APPENDIX XVII: BLOOD PRESSURE NORMS FOR SUBJECTS < 18 YEARS OF AGE 
 
In order to use the tables below, please note that the height percentile is determined by the standard growth 
charts. The child's measured systolic and diastolic BP is compared with the numbers provided in the table 
(boys or girls) for age and height percentile. The child is normotensive if BP is below the 90th percentile. If 
the child's BP (systolic or diastolic) is at or above the 95th percentile, the child may be hypertensive and 
repeated measurements are indicated. BP measurements between the 90th and 95th percentiles are high-
normal and warrant further observation and consideration of other risk factors.  
90th and 95th Percentile BP Girls  
 
 

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90th and 95th Percentile Boys 
 
 

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APPENDIX XVIII: INSTRUCTIONS FOR PREPARATION OF MEK162 (BINIMETINIB) ORAL 
SUSPENSION 
 
Objective 
 
This document describes in detail the preparation procedure of MEK162 (binimetinib) oral 
suspensions from MEK162 15 mg film-coated tablet (FCT) and Ora Sweet'/ water 3:1 (v/v) 
vehicle. This document also provides the instruction for administration of the reconstituted oral 
suspensions to the subjects. 
Safety instructions 
 
Utmost care must be exercised while handling (preparation and dosing) MEK162 oral 
suspensions. Follow the hazardous waste disposal procedures applicable to the clinic's site for 
the disposal of contaminated material (e.g. gloves, paper towels, syringes etc.). Avoid direct 
contact with clothes and skin. 
 
In the event of spillage of a MEK162 suspension on hard washable surface. e.g.. work bench. 
table or floor: 
• 
Cleaning should be done while wearing protective equipment (minimum requirement: 
disposable gloves). 
• 
Wipe the area with clean paper towel until the area is dry. 
• 
Use fresh, clean paper towel for each wiping action. 
• 
Wipe the area twice with Ethanol 70% (wear chemically resistant gloves). 
• 
Wipe the area with clean water and dry with a clean paper towel. 
• 
Dispose the wet towels in the appropriate waste bags. 
 
Breakage of a glass bottle containing the MEK162 suspension: 
• 
Do not attempt to pick up broken glass as it can pierce through gloves and might cut the skin. 
• 
Use a brush to pick up the broken glass pieces. 
• 
Wipe the area with a wet paper towel to remove any trace of broken glass. 
• 
Wipe the area with clean paper towel until the area is dry. 
• 
Wipe the area twice with Ethanol 70% (wear chemically resistant gloves). 
• 
Wipe the area with clean water and dry with a clean paper towel. 
• 
Dispose the waste in the appropriate waste bags. 
 
In case of contact with clothes or skin, remove contaminated clothing, and rinse contaminated 
skin immediately with plenty of water and soap. 
 
Materials 
• 
MEK162 15 mg film coated tablet (provided by Array BioPharma, , a wholly owned subsidiary 
of Pfizer Inc.) 
• 125 mL glass bottle or 4 ounce plastic bottle 
• Child-resistant screw cap 
• Uncarbonated potable water (from any commercial source). 
• 30 mL syringe (i.e. 30 ml accuracy ± 0.5 ml). 
• Dosing cup adapted to target administration volume (i.e. 15 to 50 ml). 
• Exacta-Med syringe type dispenser sets 
• Ethanol 70% (disinfectant and cleaning agent; used in event of spillage). 

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• Plastic bags (large enough to hold one 125 ml brown glass bottle).  
• Ora Sweet® vehicle 
• Disposable gloves 
 
Preparation of MEK162 oral suspension at 1mg/mL 
 
Note: Preparation of oral solution is to be carried out by the Pharmacy using clean glassware, 
measuring syringe, etc. Suspension, Exacta-Med syringe type dispenser sets, and dosing cups are 
provided to the patients after preparation. The suspension must be stored at room temperature 
(below 25°C) and should not be refrigerated. It should be used within 30 days after preparation. 
 
• Step 1: Measure 15 mL uncarbonated potable water using the 30 mL syringe and transfer it 
into the 125 mL brown bottle (or 4 oz plastic bottle). 
• Step 2: Add four (4) MEK162 15 mg film coated tablets into the 125mL brown bottle (or 4 
oz plastic bottle) 
• Step 3: Close the bottle using the screw cap and let the bottle sit for 10 minutes. 
• Step 4: Shake the bottle for 1-3 minutes until the tablets are completely dispersed. Remove 
the cap from the bottle. 
• Step 5: Measure 45 mL Ora Sweet using a 30 mL syringe and transfer it into the 125 mL 
brown bottle (or 4 oz plastic bottle). 
• Step 6: Shake the bottle for 1-3 minutes. Confirm the suspension is homogenous. 
 
 
Administration of MEK162 oral suspension at 1mg/mL 
 
Note: Each administration should be performed using a new Exacta-Med syringe type dispenser. 
If dosing cups are used for administration, a new dosing cup needs to be used for each 
dispensing. The suspension must be stored at room temperature (below 25°C) and should not be 
refrigerated. It should be used within 30 days after preparation. 
 
• 
Remove the screw cap from the brown bottle which contains the oral suspension. 
• 
Plug the 10 mL syringe adapter onto the bottleneck and close the brown bottle with the screw 
cap. 
• 
Gently handshake the bottle of oral suspension for 60 seconds just prior to dosing to make 
sure the content is homogeneous. 
• 
Remove the screw cap from the brown bottle and connect the syringe tip to the adapter with 
the bottle in upright position. 
• 
Hold the adapter and bottle in upside-down position, and carefully draw the required volume 
of oral suspension using the 10 mL syringe. After this is done, hold the bottle in upright 
position and remove the filled syringe from the adapter. 
• 
Transfer the content directly from the syringe into the mouth of the patient. Use a new syringe 
for each administration if more than 10mL of suspension is needed (discard the syringe after 
every use). 
 
If more than 10mL of suspension is needed, the content from the syringes can alternatively be 
transferred into a dosing cup, and administered to the patient from the cup. In this case, care has 

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to be taken to ensure all the suspension contained in the cup is administered. Use a new dosing 
cup for each administration. 
 
• 
Close the brown bottle with the cap immediately after use. 
• 
The Exacta-Med syringe type dispenser set and the dosing cup should be discarded after each 
administration. 
• 
The dosing bottle containing the remainder of the prepared suspension can be stored at room 
temperature, below 25°C, and should not be refrigerated. It should be discarded after 30 days. 
• 
The dosing bottle with any unused suspension should be returned to the pharmacy. 
 
Storage instructions 
The reconstituted suspension can be stored at room temperature no greater than 25°C and should 
not be refrigerated. It must be used within 30 days after preparation. 
 
 

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APPENDIX XIX: PEDIATRIC DOSAGE OF BINIMETINIB (MEK162) FOR LIQUID SUSPENSION  
 
 
BSA (m2) 
Level 0 
(32mg/m2) 
Level -1 
(24mg/m2) 
Level -2 
(16mg/m2) 
Level -3 
(12mg/m2) 
≤0.14 
3 
2 
2 
1 
0.15-0.24 
6 
5 
3 
2 
0.25-0.34 
10 
7 
5 
4 
0.35-0.44 
13 
10 
6 
5 
0.45-0.54 
16 
12 
8 
6 
0.55-0.64 
19 
14 
10 
7 
0.65-0.74 
22 
17 
11 
8 
0.75-0-.84 
26 
19 
13 
10 
0.85-0.94 
29 
22 
14 
11 
0.95-1.04 
32 
24 
16 
12 
1.05-1.14 
35 
26 
18 
13 
1.15-1.24 
38 
29 
19 
14 
1.25-1.34 
42 
30 
21 
16 
>1.35 
45 
30 
22 
17 
 
 
 
 
BSA should be rounded to the nearest tenth. Quantities listed are individual doses in mg 
amounts. Dose should be given twice daily (every 12 hours) 
 

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APPENDIX XX: PEDIATRIC DOSAGE OF BINIMETINIB (MEK162) FOR TABLETS  
 
 
Dosing table (15 mg tablets) 
BSA (m2)  
Level 0 
(32mg/m2) 
Level -1 
(24mg/m2)  
Level -2 
(16mg/m2)  
Level -3 
(12mg/m2)  
≤0.42 
 
* 
* 
 
* 
 
* 
 
0.43-48  
15 mg 
(1 tablet) 
* 
 
* 
 
* 
 
0.49-0.55  
15 mg 
(1 tablet) 
* 
 
* 
 
* 
 
0.55-0.63  
* 
15 mg 
(1 tablet)  
* 
 
* 
 
0.64-0.67  
* 
15 mg 
(1 tablet)  
* 
 
* 
 
0.68-0.72  
* 
15 mg 
(1 tablet)  
* 
 
* 
 
0.73-0.84  
* 
* 
 
* 
 
* 
 
0.85-0.97  
30 mg 
(2 tablets) 
* 
 
15 mg 
(1 tablet)  
* 
 
0.98-1.06  
30 mg 
(2 tablets) 
* 
 
15 mg 
(1 tablet)  
* 
 
1.07-1.12  
30 mg 
(2 tablets) 
* 
 
* 
 
* 
 
1.13-1.24  
* 
30 mg 
(2 tablets)  
* 
 
15 mg 
(1 tablet)  
>1.25 
 
45 mg 
(3 tablets) 
30 mg 
(2 tablets)  
* 
 
15 mg 
(1 tablet)  
 
*It is not permitted to use tablet form only at this BSA for this dose level. See suspension dosing in 
Appendix XIX.  Suspension OR a combination of tablets and liquid may be used to achieve the dose. For 
example, if the dose were 22 mg, and the volume of liquid was too challenging for the patient to take, they 
may take a 15 mg tablet + 7 mg liquid to achieve the dose. Dose should be given twice daily (every 12 
hours).   
 

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APPENDIX XXI:  BIOLOGICAL SPECIMEN FOR BANKING  – COLLECTION AND SHIPPING 
 
1) Blood  
Prior to the day of blood draw, the site will have arranged for a sample collection kit supplied by the 
biorepository to be shipped to the site. The Center for Data Driven Discovery in Biomedicine (D3b) at 
CHOP will be providing kits and labels. The kit will contain tubes and bar-coded labels (which include a 
specimen number) for blood collection. It will also contain shipping materials and instructions for sending 
collected blood samples to the biorepository, as well as a pre-paid shipping label. 
 
Samples 
• 
Streck tube (for plasma):  ~ 2 mL.   
• 
EDTA tube (for DNA):  ~ 5 mL.   
• 
PAXGene tube (for RNA) ~ 2.5 mL. 
 
Tubes should be inverted at least 10 times after being drawn. 
 
The samples will only be obtained if the total blood volume does not exceed 5 mL/kg.  If not enough 
blood can be drawn for all tubes, the priority order for obtaining the specimens is: 1) Streck tube, 2) 
EDTA tube, 3) PAXGene tube. 
 
Label the specimens with the specimen labels provided with the specimen kit. 
 
Blood samples must be shipped (unprocessed) same day at ambient temperature to the biorepository by 
overnight delivery using shipping container provided by the biorepository. Samples must be shipped 
Monday through Thursday. 
 
Enter the specimen numbers into the NF Consortium Operations Center eDES. 
 
For questions about shipping, kits, tubes, etc., and to confirm the shipping address prior to sending 
samples, please contact: Elizabeth Appert (apperte@email.chop.edu) and BioRc (biorc@email.chop.edu). 
 
2) Tumor Tissue 
Prior to the day of surgery, the site will have arranged for a tissue sample collection kit supplied by the 
biorepository to be shipped to the site. The Center for Data Driven Discovery in Biomedicine (D3b) at 
CHOP will be providing kits and labels. The kit will contain bar-coded cryovials (which include a 
specimen number) for tissue collection. It will also contain shipping materials and instructions for sending 
collected tissue samples to the biorepository, as well as a pre-paid shipping label. 
 
Samples 
• 
Fresh frozen tissue: 1-2 pea sized aliquots (~ 0.3 cm3, equivalent to 0.8 cm in diameter) of excess 
(left over) tumor tissue. Place each aliquot in a separate cryovial and label the specimen with 
subject’s study number. Snap freeze the aliquots in liquid nitrogen (preferred) or dry ice and then 
store in a freezer at -80°C or below until they can be sent to the biorepository. 
• 
1 H&E-stained slide cut from each submitted piece to confirm tumor is present.  
• 
If fresh frozen tissue is unavailable, please submit processed DNA (at least 3 micrograms) and 
RNA (at least 400 nanograms with optimal RIN > 7) if available.  
 
Label the specimen manifest with the subject’s study number. 
Fresh frozen tissue or DNA/RNA must be shipped on dry ice via overnight delivery using shipping 
materials provided by the biorepository. The H&E slide should be shipped at ambient temperature.  
Samples must be shipped Monday through Thursday. 
 

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Enter the specimen numbers into the NF Consortium Operations Center eDES. 
 
For questions about shipping, kits, tubes, etc., and to confirm the shipping address prior to sending 
samples, please contact: Elizabeth Appert (apperte@email.chop.edu) and BioRc (biorc@email.chop.edu).