Phase I-II Study of MEK 162 for Children With Low-Grade Gliomas and Other Ras/Raf/ERK Pathway Activated Tumors
Phase: PHASE1
Conditions: Low-Grade Gliomas, Malignant Neoplasms, Brain, Soft Tissue Neoplasms
Sponsor: Children's Hospital Los Angeles

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Protocol Title: Phase I-II Study of MEK162 for Children with Low Grade Gliomas and Other Ras/Raf/ERK 
Pathway Activated Tumors 
IND #: 124459 
Principal Investigator & Study Chair:  Nathan J. Robison, MD 
Study Co-Chair:  Karen D. Wright, MD 
Dana-Farber Cancer Institute 
Department of Pediatric Oncology 
450 Brookline Avenue, D-3150 
Boston, MA 02215 
Telephone: (617) 632-4244 
Fax: (617) 632-4897 
Email: karend_wright@dfci.harvard.edu 
Operations Center: Children’s Hospital Los Angeles 
Division of Hematology, Oncology, & BMT 
4650 Sunset Blvd, MS#54 
Los Angeles, CA 90027 
Email: mek162@chla.usc.edu 
Operations Center Coordinator:   Jasmine Pauly, CCRP 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS#54 
Los Angeles, CA 90027 
Telephone: (323) 361-7673 
Fax: (323) 361-7998 
Email: jpauly@chla.usc.edu 
Neuroimaging Center: Marvin Nelson, MD 
Children’s Hospital Los Angeles 
Department of Radiology 
4650 Sunset Blvd MS#81 
Los Angeles, CA 90027 
Telephone: (323) 361-4572 
Email: mdnelson@chla.usc.edu 
Lead Ophthalmologist: Mark Borchert, MD 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS#88 
Los Angeles, CA 90027 
Telephone: (323) 361-4510 
NCT02285439

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Email: mborchert@chla.usc.edu 
 
Lead Biostatistician: Richard Sposto, PhD 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS#54 
Los Angeles, CA 90027 
Telephone: (323) 361-8147 
Fax: (323) 361-7128 
Email: rsposto@chla.usc.edu 
 
Medical Monitor: Tom Davidson, MD 
A2-410 MDCC 
10833 Le Conte Ave 
Los Angeles, CA 90095 
Telephone: (310) 825-6708 
 
Email: tdavidson@mednet.ucla.edu 
 
Biological Correlates Laboratory: Keith Ligon, MD 
c/o Sarah Becker 
Dana Farber Cancer Institute 
450 Brookline Avenue JFB 215A 
Boston, MA 02215 
Telephone: (617) 632-6131 
Fax: (617) 582-8604 
Email: Keith_Ligon@dfci.harvard.edu 
Email: pnotissuebanking@partners.org 
 
Pratiti Bandopadhayay, PhD 
Dana Farber Cancer Institute/Broad Institute 
450 Brookline Avenue SM-1070C 
Boston, MA 02215 
Telephone: (617) 632 2018 
Email: Pratiti_Bandopadhayay@DFCI.HARVARD.EDU 
 
Nathalie Agar, PhD 
Dana-Farber Cancer Institute 
Department of Cancer Biology 
450 Brookline Avenue 
Boston, MA 02215 
Telephone: (617) 632-4668 
Email: NAGAR@PARTNERS.ORG 
 

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Mariella G. Filbin, MD 
Dana-Farber Cancer Institute 
Department of Pediatric Oncology 
450 Brookline Avenue 
Boston, MA 02215 
Telephone: (617) 582-7624 
Fax: (617) 632-4897 
Email: mariella_gruberfilbin@dfci.harvard.edu 

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SCHEMA 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase I Dose Escalation and Determination of MTD 
Phase II 
 
Stratum 1 
Phase II 
 
Stratum 2 
Phase II 
 
Stratum 3 
Phase II 
Stratum 4 
Target 
Validation 
 
Pediatric 
patients with a 
recurrent or 
progressive LGG 
containing a 3’ 
BRAF 
rearrangement  
including 
KIAA1549 and 
other similar 
translocations 
 
Pediatric 
patients with 
Neurofibromatos
is type 1 and a 
recurrent or 
progressive LGG 
 
 
Pediatric patients not 
included in strata 1 
or 2, with a recurrent 
or progressive LGG, 
NF1-related tumor, 
or BRAF, NRAS, or 
KRAS mutated tumor. 
 
Pediatric patients who 
meet criteria for strata 
1, 2, or 3 for whom 
tumor biopsy or 
resection is clinically 
indicated  
 
 
MEK162 BID 
continuous 
administration. 
 
 
MEK162 BID 
continuous 
administration. 
 
 
MEK162 BID 
continuous 
administration. 
 
MEK162 BID 
continuous 
administration 
for 7-21 days 
followed by 
surgical 
resection. Re-
institute MEK162 
BID after tumor 
resection. 
Recurrent or progressive non-hematologic malignancies with activation of the 
RAS/RAF/ERK pathway, including any tumor with a documented activating BRAF, 
NRAS, or KRAS mutation, any LGG, or any tumor in a patient with NF1.  

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TABLE OF CONTENTS 
 
SCHEMA .................................................................................................................................................... 4 
List of Abbreviations ..................................................................................................................................... 9 
Glossary of Terms........................................................................................................................................ 10 
1. 
PROTOCOL SUMMARY ........................................................................................................................ 11 
1.1 
Phase I ......................................................................................................................................... 11 
1.2 
Phase II ........................................................................................................................................ 11 
1.3 
Length of Therapy ....................................................................................................................... 11 
1.4 
Response Assessment ................................................................................................................. 11 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 12 
2.1 
Phase I ......................................................................................................................................... 12 
2.2 
Phase II ........................................................................................................................................ 12 
3. 
BACKGROUND ..................................................................................................................................... 14 
3.1 
Significance ................................................................................................................................. 14 
3.2 
Study Agent Background and Associated Known Toxicities ....................................................... 14 
3.3 
Rationale for the Current Study .................................................................................................. 18 
4. 
ELIGIBILITY CRITERIA ........................................................................................................................... 20 
4.1 
Inclusion Criteria ......................................................................................................................... 20 
4.2 
Exclusion Criteria ......................................................................................................................... 22 
4.3 
Inclusion of Women, Minorities, and Other Underrepresented Populations ............................ 23 
5. 
ENROLLMENT PROCEDURES ............................................................................................................... 24 
5.1 
Reservation ................................................................................................................................. 24 
5.2 
Enrollment................................................................................................................................... 24 
6. 
TREATMENT PLAN ............................................................................................................................... 26 
6.1 
Overview ..................................................................................................................................... 26 
6.2 
Treatment Schema ...................................................................................................................... 27 
6.3 
Agent Properties and Administration ......................................................................................... 28 
6.4 Toxicities and Dose Reductions ........................................................................................................ 29 
Table 6-1: Toxicity Table for Phase I/II DLT Period Assessment ............................................................. 29 
Table 6-2: Recommended Dose Modifications Associated with Treatment-Related Adverse Events ... 32 

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6.5 
Concomitant Medications ........................................................................................................... 37 
Table 6-3: List of inhibitors of human transporters to be used with caution ......................................... 38 
6.6 
Duration of Therapy .................................................................................................................... 40 
6.7 
Duration of Follow-Up ................................................................................................................ 40 
6.8 
Criteria for Removal from Study ................................................................................................. 41 
7. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ................................................ 43 
7.1 
Dose Delays and Modifications ................................................................................................... 43 
7.2 
Expected Toxicities for MEK162 .................................................................................................. 43 
7.3 
Management of Treatment-Related Events ............................................................................... 43 
8. 
CORRELATIVE STUDIES ........................................................................................................................ 45 
8.1 
Pharmacokinetic Studies ............................................................................................................. 45 
Table 8-1: Schedule of blood sample collections for MEK162 Pharmacokinetics (Dose Escalation Phase 
I and Phase II) .......................................................................................................................................... 45 
8.2 
Pharmacodynamic Studies .......................................................................................................... 47 
Table 8-2: Schedule of Samples .............................................................................................................. 47 
Table 8-3: Stratum 4 Target Validation Sample Schedule Cycles 0-1 ..................................................... 48 
Table 8-4: Summary of Assessments in Tumor Tissue for Participants in Strata 1, 2, and 3 .................. 48 
Table 8-4: Summary of Assessments in Tumor Tissue for Participants in Stratum 4 ............................. 49 
8.3 
Ophthalmologic Studies .............................................................................................................. 53 
Table 8-5: Visual acuity in feet and logMAR equivalents for acuity in cycles/cm .................................. 54 
8.4 
Patient Reported Outcomes (Phase II) ....................................................................................... 56 
9. 
STUDY CALENDAR ............................................................................................................................... 57 
Table 9-1: Phase I Required Observations .............................................................................................. 57 
Table 9-2: Phase I ECG Assessments ....................................................................................................... 60 
Table 9-3: Phase II Required Observations ............................................................................................. 61 
Table 9-4: Year 2 (Cycles 13-24) Required Observations ........................................................................ 62 
10. 
IMAGING PARAMETERS AND RESPONSE CRITERIA ........................................................................ 64 
10.1 General Considerations ................................................................................................................... 64 
10.2 Measurement of Effect ................................................................................................................... 64 
10.3 Imaging Sequences ......................................................................................................................... 64 
10.4 Response Assessment ..................................................................................................................... 66 
Table 10-1: Response Criteria for Target Lesions ................................................................................... 67 

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10.5 Duration of Response...................................................................................................................... 68 
10.6 Central Review ................................................................................................................................ 69 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 70 
11.1 Adverse Event (AE) .......................................................................................................................... 70 
11.2 Serious Adverse Event (SAE) ........................................................................................................... 71 
11.3 Procedures for AE and SAE Recording and Reporting .................................................................... 72 
Table 11-1 Reportable AEs ...................................................................................................................... 73 
12. DATA AND SAFETY MONITORING ......................................................................................................... 76 
12.1 Data Reporting ................................................................................................................................ 76 
12.2 Data Submission .............................................................................................................................. 76 
Table 12-1: Data Submission Timelines .................................................................................................. 76 
12.3 Weekly Safety Review ..................................................................................................................... 76 
12.4 Data Safety Monitoring Committee ................................................................................................ 77 
12.5 Monitoring ...................................................................................................................................... 77 
13. REGULATORY CONSIDERATIONS ........................................................................................................... 79 
13.1 Protocol Review and Amendments ................................................................................................ 79 
13.2 Informed Consent ........................................................................................................................... 79 
13.3 Ethics ............................................................................................................................................... 79 
13.4 Study Documentation ..................................................................................................................... 79 
13.5 Records Retention ........................................................................................................................... 80 
13.6 Multi-Center Guidelines .................................................................................................................. 80 
14. STATISTICAL CONSIDERATIONS ............................................................................................................. 81 
14.1 Primary Endpoints ........................................................................................................................... 81 
14.2 Secondary Endpoints ...................................................................................................................... 81 
14.3 Study Design for Phase I.................................................................................................................. 82 
14.4 Study Design for Phase II and Target Validation ............................................................................. 82 
14.5 Accrual Rate and Study Duration .................................................................................................... 83 
14.6 Toxicity Monitoring during Phase II ................................................................................................ 84 
Table 14-1: Phase II DLT Monitoring Rule ............................................................................................... 84 
15. PUBLICATION PLAN ............................................................................................................................... 85 
16. REFERENCES .......................................................................................................................................... 86 
Appendix I: LIST OF MEDICATIONS WITH POSSIBLE CYP INTERACTIONS TO BE USED WITH CAUTION ..... 88 

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Appendix II: MEK162 ADMINISTRATION ..................................................................................................... 89 
Appendix III: MOLECULAR ANALYSIS .......................................................................................................... 91 
Appendix IV:  SPECIMEN COLLECTION, PROCESSING AND STORAGE ......................................................... 94 
Appendix V: SPECIMEN AND DATA USE ...................................................................................................... 99 
Appendix VI: LIST OF RESEARCH USES OF TISSUE AND CLINICAL DATA ................................................... 100 
Appendix VII:  Pathology Testing Information .......................................................................................... 101 
Appendix VIII: TISSUE AND CLINICAL DATA USE OVERSIGHT COMMITTEES ............................................ 102 
Appendix IX: Dana-Farber/Boston Children’s Hospital TISSUE BANK ....................................................... 103 
Appendix X: PERFORMANCE STATUS CRITERIA ........................................................................................ 104 
Appendix XI: NORMAL BLOOD PRESSURE BY HEIGHT AND AGE .............................................................. 105 
Appendix XII: DOSAGE OF MEK162 ........................................................................................................... 108 
Appendix XIII: GUIDELINES FOR THE MANAGEMENT OF MEK162 INDUCED SKIN TOXICITY ................... 110 
Appendix XIV: GUIDELINES FOR THE MANAGEMENT OF MEK162 INDUCED DIARRHEA ......................... 112 
Appendix XV: 3+3 Dose Escalation Decision Grid ..................................................................................... 114 
Appendix XVI: Instructions for preparation of MEK162 Oral Suspension ................................................ 117 
Appendix XVIII: PedsQL Brain Tumor Modules ......................................................................................... 122 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
AE  
Adverse event 
ALT  
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT 
AST  
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase/SGOT 
AUC 
Area under the plasma concentration-time curve 
AUC0-24  
Area under the plasma concentration-time curve from 0 to 24 hours 
BID 
 bis in diem/twice a day 
CK 
Creatine kinase 
Cmax  
Maximum (peak) concentration of drug 
CNS  
Central nervous system 
CRO  
Contract Research Organization 
CSF  
Cerebral spinal fluid 
CSR  
Central serous retinopathy 
CTO 
Clinical Trials Office 
DLT  
Dose limiting toxicity 
DSMC 
Drug Safety Monitoring Committee 
ECG  
Electrocardiogram 
EGFR  
Epidermal growth factor receptor 
HFSR 
Hand-foot skin reaction 
Hr  
Hour 
IHC  
Immunohistochemical 
IRB  
Institutional Review Board 
LGG 
Low-grade glioma 
LLOQ 
Lower limit of quantification 
MRI  
Magnetic resonance imaging 
MRS 
Magnetic resonance spectroscopy 
MTD  
Maximum tolerated dose 
NF1 
Neurofibromatosis type 1 
PBL 
Peripheral blood lymphocytes 
PD  
Pharmacodynamics 
PK  
Pharmacokinetics 
QD  
Once daily 
RVO 
 Retinal vein occlusion 
RP2D 
Recommended Phase II Dose 
SAE  
Serious Adverse Event 
 
 
 

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Glossary of Terms 
Assessment 
A procedure used to generate data required by the study 
Cycle 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days) 
Enrollment/Enrolled 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Investigational 
treatment 
Drug whose properties are being testing in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational 
treatment generally does not include other study treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package that is 
linked to one of the treatment groups of a study.  
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Subject Number 
(Subject No.) 
A unique identifying number assigned to each patient who enrolls in the 
study. 
Phase 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed for 
progression and/or survival 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body 
Stop study 
participation 
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered 
to the patient (subject) as part of the required study procedures. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment  for 
any reason; may or may not also be the point/time of premature patient 
withdrawal. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points. 
 

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1. PROTOCOL SUMMARY 
 
1.1 Phase I 
Patients with non-hematologic malignancies that are recurrent, progressive, or refractory after 
standard up-front therapy receiving MEK162 will define the MTD, DLT, and toxicity profile. 
 
1.2 Phase II 
Patients with recurrent or progressive tumors signaling through the Ras/Raf pathway after standard 
up-front therapy will be treated in three strata to define the activity of MEK162. 
 
Stratum 1: Pediatric patients with recurrent or progressive low-grade glioma (LGG) characterized by 
a 3’ BRAF rearrangement (KIAA1549 fusion and similar translocations). 
Stratum 2: Pediatric patients with neurofibromatosis type 1 (NF1) and recurrent or progressive LGG.  
Stratum 3: Pediatric patients with recurrent or progressive tumors thought to involve the Ras/Raf/ERK 
pathway but not included in strata 1 or 2. This includes any LGG not included in strata 1 or 2 (i.e., any 
LGG without a BRAF rearrangement in a patient without NF1), any tumor other than LGG in a patient 
with NF1, and any other tumor with a known activating BRAF, NRAS or KRAS mutation. 
Stratum 4 (Surgical Arm, Target validation): Patient with eligible histology for whom tumor biopsy or 
resection is clinically indicated. Patients will receive MEK162 for 7 to 21 days prior to their surgery. 
Samples will be analyzed for concentration of drug and target inhibition. 
 
1.3 Length of Therapy 
Protocol treatment will last approximately 48 weeks (12 cycles) from the start of MEK162 in the 
absence of disease progression or significant toxicity. Patients deriving benefit may continue therapy 
for 12 additional cycles (up to 24 cycles total). A cycle will consist of 28 days (+/- 3 days) and 
MEK162 will be given continuously. See Section 6.6. 
 
1.4 Response Assessment 
Imaging to assess response will be performed at the end of cycle 1 (+/- 1 week; optional in phase II), 
at the end of cycle 3 (+/- 2 weeks) and after every three cycles thereafter (+/- 2 weeks).  

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2. OBJECTIVES AND ENDPOINTS 
 
2.1 Phase I  
 
Primary Objectives 
• 
To determine the MTD (or proposed phase II dose) of MEK162 suspension administered on a 
continuous, twice daily dosing schedule, in children with tumors that are recurrent, progressive, 
or refractory after standard therapy. 
 
Secondary Objectives 
• 
To characterize the safety and tolerability of MEK162 suspension in children with advanced solid 
tumors. 
• 
To assess the pharmacokinetic profile of MEK162 and its metabolite (AR00426032) when 
administered as an oral suspension in children and adolescents with recurrent, refractory or 
progressive tumors 
• 
To assess any preliminary antitumor activity of MEK162 in children with advanced solid tumors. 
 
Exploratory Objectives 
• 
To explore the PD effects of MEK162 on biomarkers of the Ras/Raf/MEK/ERK signaling pathway 
activity in PBL and tumor tissue (if available). 
 
Primary Endpoints 
• 
Frequency of DLTs associated with twice-daily administration of MEK162 suspension. 
 
Secondary Endpoints 
• 
Frequency of AEs and SAEs; changes in laboratory values 
• 
Plasma PK parameters 
• 
Tumor response 
 
Exploratory Endpoints 
• 
Post treatment changes in expression of biomarkers of Ras/Raf/MEK/ERK pathway activity (e.g. 
pERK) in peripheral blood and tumor tissue (if available) 
 
2.2 Phase II 
 
Primary Objectives 
• 
To assess preliminary efficacy of MEK162 in pediatric LGG characterized by a BRAF truncated 
fusion lesion. 
• 
To assess preliminary efficacy of MEK162 in LGG in children with NF1. 
 
Secondary Objectives 

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• 
To determine the 12-month progression-free and overall survival in pediatric patients with a 
recurrent or progressive LGG characterized by a BRAF truncated fusion lesion (KIAA1549 and 
similar translocations) (Stratum 1). 
• 
To determine the 12-month progression-free and overall survival in pediatric patients with NF1 
and recurrent or progressive LGG (Stratum 2). 
 
Exploratory Objectives 
• 
To assess response rate and 12-month progression free and overall survival in pediatric patients 
with a recurrent or progressive tumor with known or presumed signaling through the 
Ras/Raf/ERK pathway not included in strata 1 or 2, including tumors positive for BRAF V600E or 
activating NRAS or KRAS mutations, any LGG not eligible for strata 1 or 2 (i.e., any LGG without a 
BRAF truncated fusion in a patient without NF1), and any tumor other than LGG in a patient with 
NF1 (Stratum 3). 
• 
To correlate treatment response with molecular phenotype. 
• 
To quantify the intra-tumoral concentration of MEK162 after 7-21 days of twice-daily 
administration, and correlate with plasma PK assessment. 
• 
To assess downstream Ras/Raf/MEK/ERK pathway inhibition, as measured by ERK 
phosphorylation, after treatment with MEK162 for 7-21 days, and correlate with blood PD 
assessment. 
• 
To describe patient and parent-reported quality of life outcomes in children with LGG and other 
Ras/Raf/ERK pathway-activated tumors undergoing treatment with MEK162. 
 
Primary Endpoints 
• 
Response rate (strata 1 and 2). 
 
Secondary Endpoints 
• 
12-month progression-free and overall survival (strata 1 and 2). 
 
Exploratory Endpoints 
• 
Response rate, OS, and PFS in patients in stratum 3 (other tumors with known or presumed 
activation of the Ras/Raf/MEK/ERK pathway, not included in strata 1 or 2). 
• 
Tumor response as a function of BRAF tumoral genotype. 
• 
Target Validation (Surgical Arm): Intra-tumoral MEK162 concentration, and intra-tumoral 
inhibition of downstream mediators of the Ras/Raf/MEK/ERK pathway (e.g., pERK). 
• 
Patient and parent-reported outcomes as assessed using the PedsQLTM Brain Tumor Module. 
 
 
 
 
 
 

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3. BACKGROUND 
 
3.1 Significance  
The Ras pathway is implicated in a large number of tumors in adult patients and is activated in NF1-
associated tumors (1). Low-grade gliomas (LGG) are the most common brain tumor in children (2) and 
the majority have abnormal signaling through the Ras/Raf pathway (3). Complete resection is not 
feasible in many patients and incompletely resected LGG have a high rate of progression and 
recurrence (3,4)Best currently available therapies have limited efficacy, and the long-term burden of 
disease and treatment-related morbidity is significant. Results from the largest randomized phase III 
trial to date for children with LGG showed a 5-year event free survival of only 47% (5) There is clearly a 
need for more effective therapies using novel mechanisms of action. A variety of other tumor types 
are also known to have abnormal expression of the Ras/Raf and include high-grade glioma, 
pleomorphic xanthoastrocytoma,  and ganglioglioma (6); melanoma(7); thyroid carcinoma (8); and 
Langerhans cell histiocytosis (9). A number of other tumor types have abnormal signaling through this 
pathway because of upstream activation of tyrosine kinase receptors (10).   
Mitogen activated ERK kinase 1 and 2 (MEK1/2), a dual specific kinase, is a critical component of the 
Ras/Raf/MEK/ERK pathway, an important regulator of cellular survival, growth, and proliferation. 
Oncogenic dysregulation of this pathway has been described in diverse malignancies, including 
pancreatic cancer, colon cancer, lung cancer, melanoma, thyroid malignancies, histiocytosis, and 
glioneuronal tumors. Aberrant constitutive activation of this pathway via a unique BRAF tandem 
duplication has been demonstrated in 77-84% of juvenile pilocytic astrocytomas, the most common 
subtype of pediatric LGG (3,11,12).(13)  Positive immunostaining for pERK in tumors harboring the 
duplication confirms aberrant activation of this pathway (3,12). These findings suggest that the 
Ras/Raf/MEK/ERK pathway may play a critical role in the genesis of this disease and may be a 
promising therapeutic target. 
 
3.2 Study Agent Background and Associated Known Toxicities 
Preclinical data (please refer to the most recent Investigator’s Brochure for most recent data): MEK162 
(ARRY-162 / ARRY-143162) is an oral, highly selective, ATP non-competitive MEK1/2 inhibitor. The 
biological activity of MEK162 has been evaluated in vitro (both enzymatic and cell culture assays) and 
in vivo in mouse xenograft studies. MEK162 potently inhibits MEK 1/2 in both biochemical assays using 
purified protein, and in cells. MEK162 has demonstrated robust, but selective, growth inhibitory 
activity in a wide variety of cancer cell lines. In a collection of ~500 genetically annotated cell lines, 
MEK162 showed anti-proliferative activity preferentially in cells harboring activating mutations of the 
ERK pathway (e.g. BRAF, NRAS and KRAS), and in particular, activating mutations in BRAF and NRAS. In 
vivo, MEK162 has demonstrated dose dependent tumor growth inhibition in various subcutaneous 
tumor transplants harboring BRAFV600E mutations (HT29, COLO205, A-375) as well as activating 
mutations in both NRAS (Hs 944.T) and KRAS (MiaPaCa2, A549, LoVo, Calu6). These data suggest that 
MEK162 may provide a potential therapeutic benefit in cancer indications harboring these mutations. 
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. MEK162 has moderate membrane permeability and is a substrate of P-gp and BCRP. MEK162 
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 

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MEK162 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). 
The formation of active metabolite AR00426032 is mediated primarily by CYP1A2 with minor 
contributions from other cytochrome P450 enzymes (CYPs). MEK162 potently inhibits CYP2B6 and 
weakly inhibits CYP1A2 and 2C9. It is not considered a time dependent inhibitor of CYP1A2, CYP2C9, 
CYP2D6, and CYP3A. In vitro evidence also suggests that MEK162 could induce CYP3A. Acute, 
subchronic, and chronic reproductive toxicity, genotoxicity and phototoxicity studies were completed 
to support the chronic administration of MEK162 in adult and pediatric cancer patients. The clinical 
toxicity of MEK inhibitors has been more similar to that of monkeys than rats and 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 MEK162 has a very low risk of weak phototoxic potential at therapeutic doses. This is 
supported by human safety data: as of January 7, 2015, of 1945 patients who have received at least 
one dose of MEK162, there has been one reported grade I photosensitivity reaction. Given the 
embryo-lethal effects seen in rats and rabbits and the teratogenic effects seen in rabbits, MEK162 
should not be used in pregnant women and women of childbearing potential must be advised to use 
highly effective contraception methods. 
 
Clinical data (please refer to the most recent Investigator’s Brochure for most recent data): As of 
January 7, 2015, a total of 1945 subjects/patients have received at least one dose of MEK162, either 
as a single agent or in combination with PKC, CDK4/6, PI3K, RAF, EGFR or IGF-1R inhibitors or 
paclitaxel, and have been evaluated for safety, including 204 healthy subjects, 164 patients with 
rheumatoid arthritis, 6 patients with hepatic dysfunction, and 1571 patients with advanced cancer. 
The experience with MEK162 as a single agent in oncology patients includes six studies with 705 
patients enrolled as of January 7, 2015. These include two Phase I, two Phase II, and two Phase III 
studies: 
 
• 
[ARRAY-162-111]: A phase I dose escalation study in patients with solid tumors with an 
expansion phase in biliary and colorectal cancer. A total of 93 patients received at least 1 dose 
of binimetinib. Four dose levels were evaluated: 30 mg BID, 45 mg BID, 60 mg BID and 80 mg 
BID. Two of 4 patients receiving 80 mg BID experienced ocular dose-limiting toxicities (DLTs), 
thus the 80 mg BID dose was declared non-tolerable. Seven patients were enrolled at 60 mg BID 
and no DLTs were observed, therefore, 60 mg BID was declared the MTD. Following completion 
of the Dose-escalation Phase, a total of 74 patients were enrolled in the Expansion Phase. The 
dose of 45 mg BID was determined as the recommended phase II dose (RP2D) due to the higher-
than-expected frequency of ocular AEs at the 60 mg dose level. 
• 
[CMEK162X1101]: a phase I dose escalation study in Japanese patients with solid tumors and an 
expansion in patients with Ras or BRAF mutations 
• 
[CMEK162X2201]: a phase II study in patients with advanced melanoma. 
• 
[CMEK162AUS11]: a phase II study in patients with Ras/Raf/MEK activated tumors. 
• 
[CMEK162A2301]: a phase III, two-arm, randomized study in patients with advanced 
unresectable or metastatic NRAS Q61 mutation-positive melanoma. 
• 
[ARRAY-162-311]: a phase III, two-arm, randomized study in patients with recurrent or 
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The most frequently reported AEs suspected to be related to binimetinib, regardless of grade and 
binimetinib dose were skin toxicity (rash, dermatitis acneiform), GI events (nausea, vomiting, 
diarrhea), edema peripheral, fatigue and blood creatine phosphokinase (CK) increased. The majority 
of these AEs were Grade 1 or 2 with less than 5% of cases Grade 3 or 4, with the exception of 
elevation of blood CK, reported as Grade 3 or 4 in 24% in [CMEK162X2201] and 17% in 
[CMEK162X1101] studies. 
The experience with MEK162 in cancer patients in combination studies comprises 13 ongoing studies 
with 866 patients as of 07-January-2015.  
 
• 
Five studies with RAF inhibitors encorafenib and RAF265: [CMEK162X2102], phase II study of 
sequential single-agent encorafenib followed by a rational combination with targeted agents 
(including binimetinib) after progression in adults with locally advanced or metastatic BRAF 
V600 melanoma; [CMEK162X2110], phase Ib dose finding, dose escalation study of binimetinib 
in combination with encorafenib, in selected advanced solid tumors; [CLGX818X2102], phase II 
study of binimetinib in combination with encorafenib in patients with locally advanced or 
metastatic BRAF V600 melanoma;  [CMEK162B2301], phase III , randomized, 3-arm study in 
patients with BRAF V600 mutant locally advanced unresectable or metastatic melanoma; 
[CLGX818X2109], phase II study of open-label study of encorafenib and binimetinib, followed by 
a rational combination with targeted agents after progression, in adults with 
advanced/metastatic BRAF V600 melanoma. 
• 
Three studies with PIK3C/AKT pathway inhibitors BEZ235 (pan-PI3K/mTOR) buparlisib (pan-PI3K) 
and BYL719 (PIK3CA): [CMEK162X2103], [CMEK162X2101] and [CMEK162X2109], all three are 
phase Ib, dose escalation and expansion studies in selected advanced solid tumors. 
• 
One study with PKC-selective inhibitor sotrastaurin: [CMEK162X2203]: phase Ib/II study in 
patients with metastatic uveal melanoma. 
• 
One study with CDK4/6 inhibitor LEE011: [CMEK162X2114], phase Ib/II study, in patients with 
NRAS mutant melanoma. 
• 
One study with IGF-1R monoclonal inhibitor ganitumab: [CMEK162X2111], phase Ib/II dose 
escalation and expansion study in patients with selected advanced solid tumors. 
• 
One study with EGFR inhibitor panitumumab: [CMEK162X2116], phase Ib/II, dose-escalation 
study in patients with mutant RAS or wild-type RAS metastatic colorectal cancer. 
• 
One study with standard chemotherapy agent paclitaxel: [ARRAY-162-112], phase Ib, dose-
escalation and expansion study in women with platinum-resistant or refractory epithelial 
ovarian, fallopian tube or primary peritoneal cancer. 
 
Overall, the frequently reported AEs suspected to be related to binimetinib in combination studies 
were found to be similar to those found in single-agent studies, which include GI events (diarrhea, 
nausea, vomiting), skin toxicities (dermatitis acneiform, rash) CK elevation and retinal events. The 
percentage of patients that discontinued study drug due to AEs regardless of relationship to 
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observed in all combination studies, 13 (out of 52) in the [CMEK162X2101] study combining 
binimetinib with the PI3K inhibitor buparlisib. The most frequents DLTs reported were GI disorders, 
ocular disorders and skin toxicities. 
 
A total of 128 deaths were reported during the study or within 30 days of last dose of study drug in 
cancer patients, either in single agent or combination studies (45 and 46 respectively). The most 
frequent cause of treatment discontinuation was disease progression and other events not related 
to study drug. Fatal SAEs suspected to be related to study drug include the following: (single agent) 
acute hepatic failure; (in combination with BYL719) pneumonitis; (in combination with LEE001) 
intracranial hemorrhage. 
 
Based on the experience from 13 completed phase I studies and 1 completed phase II study, 
binimetinib has demonstrated an acceptable and manageable safety profile with the majority of AEs 
Grades 1 or 2 of intensity and reversible. 
 
Pharmacokinetics: In healthy subjects, MEK162 exposure (as indicated by Cmax and AUC) appeared to 
increase in a dose-proportional manner following single and multiple doses over a dose range of 5 to 
80 mg QD for single dose and 5 to 60 mg QD and 20mg BID for multiple doses.  The median apparent 
terminal elimination half-life was 5.98 hours (single dose) and 7.11 hours (multiple doses), and the 
median time of maximum plasma concentration (Tmax) was 1 hour post dose. These initial PK data 
supported a BID dosing-regimen of MEK162. The AR00426032 metabolite represented < 13% of the 
parent drug in plasma and < 5% of the parent drug was excreted renally. Accumulation of MEK162 
was < 40% following QD dosing and < 75% following BID dosing. 
 
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 (e.g., 45 mg) should provide sufficient exposure with acceptable safety and 
adequate continuous pharmacological inhibition of the primary target. 
 
The initial evaluation of the PK data of MEK162 in patients with advanced cancer (ARRAY-162-111 
and CMEK162X2201) at the doses evaluated to date (30 to 80 mg BID) indicated that both the 
plasma concentration-time profiles and PK parameters were similar to  those in healthy subjects, as 
well as in patients with rheumatoid arthritis. The inter-subject variability for AUC and Cmax was 
~40%. The mean active metabolite-to-parent ratio was less than 25% across all study days and dose 
levels tested. Steady state is reached by Day 15 and accumulation of MEK162, as estimated using 
non-compartmental methods, is around 50% (or 1.5 fold). 
 

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To integrate all the available PK information, a preliminary population PK model describing the PK of 
MEK162 was built using data from 68 subjects from the Array and Novartis studies. The model 
suggests that the PK can be adequately described using linear kinetics (2-compartmental open 
model with first order absorption and a lag time). There was extensive tissue distribution and 
clearance of MEK162 estimated as 17 L/h. For the typical individual, steady state is reached by Day 
15 and accumulation of MEK162 is around 70% (or 1.7 fold). For further information, refer to the 
Investigator’s Brochure. 
 
3.3 Rationale for the Current Study 
 
Rationale for the Current Study Population:  
Low-grade gliomas (LGG) are the most common brain tumor in children (2). Complete resection is 
not feasible in the majority of patients (3). Incompletely resected LGG have a high rate of 
progression and recurrence (3). Best currently available therapies have limited efficacy, and the 
long-term burden of disease and treatment-related morbidity is significant. Results from the largest 
randomized phase III trial to date for children with LGG showed a 5-year event free survival of only 
47% (5). There is clearly a need for more effective therapies using novel mechanisms of action. 
 
Rationale for the Current Study Design: 
Mitogen activated ERK kinase 1 and 2 (MEK1/2), a dual specific kinase, is a critical component of the 
Ras/Raf/MEK/ERK pathway, an important regulator of cellular survival, growth, and proliferation. 
Oncogenic dysregulation of this pathway has been described in diverse malignancies, including 
pancreatic cancer, colon cancer, lung cancer, melanoma, thyroid malignancies, histiocytosis, and 
glioneuronal tumors. Aberrant constitutive activation of this pathway via a unique BRAF tandem 
duplication has been demonstrated in 77-84% of sporadic pilocytic astrocytomas, the most common 
subtype of pediatric LGG (3,11,12). Positive immunostaining for pERK in tumors harboring the 
duplication confirms aberrant activation of this pathway  (3,12). Similarly, in mouse models of NF1-
associated optic pathway glioma, MEK inhibition led both to decreased tumor volume, and to a 
reduction in tumor-associated retinal nerve-fiber loss and ganglion cell reduction(14).  These 
findings suggest that the Ras/Raf/MEK/ERK pathway may play a critical role in the genesis of both 
sporadic and NF1-associated low-grade glioma, and may be a promising therapeutic target. 
 
Rationale for the Study Dosing/Treatment Plan: 
MEK162 (ARRY-162 / ARRY-143162) is an oral, highly selective, ATP non-competitive MEK1/2 
inhibitor. CNS penetration of MEK162 was assessed using a novel scanning MALDI-TOF technique 
developed at the pediatric LGG program at DFCI, which assesses extravascular and intra-vascular 
drug concentration by evaluation co-localization with heme (13). By this technique, MEK162 was 
found to have diffuse CNS extravascular penetration in the CNS. A phase I study in adults with 
advanced solid tumors suggests that it is well tolerated. The RP2D in adults is 45 mg twice daily (15). 
Phase II and phase III studies are underway. Preliminary results from one phase II study revealed 
partial responses in 20% of patients with advanced melanoma and either a V600 BRAF or an NRAS 
mutation treated with MEK162 at 45mg twice daily (16). 

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Rationale for the Pediatric Phase II Dose: 
Preliminary findings from the phase I component of this protocol 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 this study.  
 
Rationale for Correlative/Exploratory Studies: 
 The target validation component of the study will allow us to determine the ability of MEK162 to 
penetrate into the tumor as well as assess the ability of MEK162 to affect its target. A short course 
pharmacokinetics and pharmacodynamic evaluation on these patients for correlation is also 
planned. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. ELIGIBILITY CRITERIA 
 
4.1 Inclusion Criteria 
Participants must meet the following criteria on screening examination to be eligible to participate 
in the study: 
 
Phase I 
Patients with recurrent, refractory, or progressive non-hematologic malignancies (CNS or solid 
tumors) associated with activation of the RAS/RAF/ERK pathway, including any LGG, any tumor in a 
patient with NF1, or any  tumor with a documented activating BRAF, NRAS, or KRAS mutation, will 
be eligible.  LGG is defined as any WHO grade I or II (or equivalent) astrocytic, oligodendroglial, 
and/or glioneuronal tumor. 
 
Phase II 
Patients with recurrent or progressive disease, as defined in the following three strata below, will be 
eligible. For eligibility determination, tumor imaging from at least two time-points must be available 
to document radiographic progression or recurrence. Patients with non-progressive refractory 
tumors will not be eligible.  
 
• 
Stratum 1: patients with LGG with a BRAF truncated fusion that is measurable in at least two 
dimensions on imaging. 
• 
Stratum 2:  patients with NF1 and LGG that is measurable in at least two dimensions on 
imaging. 
• 
Stratum 3: Pediatric patients with a recurrent or progressive tumor thought to involve the 
Ras/Raf/ERK pathway but not included in strata 1 or 2 that is measurable in at least two 
dimensions on imaging. This includes any LGG not included in strata 1 or 2 (i.e., any LGG 
without a BRAF truncated fusion in a patient without NF1), any tumor other than LGG in a 
patient with NF1, and any other tumor with a documented activating BRAF, NRAS, or KRAS 
mutation. 
• 
Stratum 4 (surgical arm, target validation): Patients who meet criteria for stratum 1, 2, or 3 
for whom tumor biopsy and/or resection is clinically indicated. 
 
• 
Tumor tissue for correlative studies must be available for all patients except those with NF1 
and LGG (stratum 2) or any patient with optic pathway glioma (stratum 2 or 3), for whom 
tumor tissue is optional. 
 
• 
Patients must have received at least one prior chemotherapy or radiation regimen prior to 
progression. 
 

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• 
At the time of enrollment, at least 6 weeks must have elapsed since the last dose of any 
nitrosourea, and the longer of 2 weeks or 3 half-lives must have elapsed since the last dose 
of any other tumor-directed medication. or biologic therapy. 
 
• 
At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) 
at the time of enrollment. 
 
Phase I + II  
The remaining criteria apply for both phases: 
 
• 
Patients must be >1 year and <18 years old. 
 
• 
Performance Score using the Karnofsky Performance Scale (patients > 12 years old) or 
Lansky Play - Performance Scale (patients ≤ 12 years old) must be ≥ 60 assessed within two 
weeks prior to enrollment. 
 
• 
Participants must have normal organ and marrow function as defined below within two 
weeks prior to enrollment: 
o Absolute neutrophil count > 1,000/mcL 
o Platelets > 75,000/mcL and > 7 days since last platelet transfusion. Hemoglobin > 9 
gm/dL and > 7 days since last red blood cell transfusion 
o Not refractory to red cell or platelet transfusions 
o Hepatic: Total bilirubin ≤ 1.5 times the upper limit of normal; SGPT (ALT) and SGOT 
(AST) < 3 times the institutional upper limit of normal 
o Renal: Serum creatinine which is less than 1.5 time the upper limit of institutional 
normal for age or GFR > 70 ml/min/1.73m2 
o QTc interval < 450ms 
o Left ventricular ejection fraction (LVEF) > 50% as determined by an echocardiogram 
 
• 
Female patients of childbearing potential must have negative serum or urine pregnancy test 
within 72 hours of the first dose of MEK162. Patient must not be pregnant or breast-
feeding. Patients of childbearing or child-fathering potential must be willing to use a 
medically acceptable form of birth control, which includes abstinence, while being treated 
on this study and for 30 days following cessation of treatment. 
• 
Patient must be able to take oral/enteral medication. 
 
• 
Patient, parent, or legal guardian must be able to understand and willing to provide 
informed consent. 
 
• 
Patients must have recovered from the effects of prior therapy. 
 

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4.2 Exclusion Criteria 
Patients with any of the following characteristics will not be eligible: 
 
• 
Patients for whom other curative or established standard-of-care therapeutic options with 
acceptable morbidity exist. 
 
• 
Patients with any significant medical illnesses that in the investigator’s opinion cannot be 
adequately controlled with appropriate therapy or would compromise the patient’s ability 
to tolerate this therapy. 
 
• 
History of Gilbert’s syndrome 
 
• 
Patients receiving any other anticancer or experimental drug therapy. 
 
• 
Use of hematopoietic growth factors within 2 weeks prior to initiation of therapy. 
 
• 
Any other investigational agents within 2 weeks or ≤ 3 half-lives (whichever is longer) before 
start of study therapy. 
 
• 
Patients who have undergone surgery ≤ 3 weeks or who have not recovered from side 
effects of this procedure prior to receiving study drug. 
 
• 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
impaired gastrointestinal function, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
• 
History or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO 
(e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or 
hypercoagulability syndromes). 
 
• 
History of retinal degenerative disease 
 
• 
Prior therapy with a MEK inhibitor 
 
• 
Impairment of gastrointestinal function (e.g., active ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome) 
 
• 
Patients who have a neuromuscular disorder that is associated with elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
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• 
Patients with uncontrolled hypertension 
 
4.3 Inclusion of Women, Minorities, and Other Underrepresented Populations 
This protocol is open to males and females of all races.  See Inclusion Criteria above regarding 
specific eligibility requirements for female and male patients of child-bearing or child-fathering 
potential, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5. ENROLLMENT PROCEDURES 
 
5.1 Reservation 
 
Before enrolling a patient on study, a reservation must be made with the Children’s Hospital Los 
Angeles (CHLA) Operations Center. In order to make a reservation you may call the Operations 
Center at 323-361-7673 during the business hours of 8:30am- 5pm Pacific Time Monday through 
Friday, excluding holidays, and send an email to mek162@chla.usc.edu with the following 
information (when sending an email, please include “Reservation Request” in the subject line): 
 
Name of requesting institution with contact information 
Patient Initials (First, Last)  
Patient date of birth 
 
If an enrollment slot is available, you will receive an email from the CHLA study operations center to 
confirm your reservation. All reservations are active for 5 full calendar days beginning the next full 
day after the day the reservation is created. 
 
5.2 Enrollment 
 
In order to enroll a patient onto study, the following must be done: 
 
• 
Obtain written informed consent from the participant prior to the performance of any study 
related procedures or assessments. 
• 
Complete the protocol-specific eligibility checklist using the eligibility assessment documented 
in the participant’s medical record and/or research chart. To be eligible for registration and 
enrollment, the participant must meet all inclusion and exclusion criterion as described in the 
protocol and reflected on the eligibility checklist. A protocol-specific Eligibility Checklist will be 
provided to each Participating Institution by CHLA. It is the responsibility of the local investigator 
to confirm eligibility criteria and to complete the eligibility checklist. A copy of the completed 
and MD signed eligibility checklist must be submitted to the CHLA operations center on the day 
of enrollment. 
• 
Patients must be enrolled prior to beginning treatment on this study. Patients will be enrolled by 
contacting the CHLA operations center at 323-361-7673 during the business hours of 8am- 5pm 
Pacific Time Monday through Friday, excluding holidays. Sites will be asked to complete the 
eligibility form on the designated web-based DataLabs electronic data capture system prior to 
making this call. In addition, the supporting documentation, which confirms eligibility, should be 
emailed to the CHLA study operations office at mek162@chla.usc.edu. 
• 
Each patient will be assigned a unique registration and study subject number. An email 
confirming eligibility and assigned dose level (if applicable) will be sent to the treating facility, 
Study chair, and Study co-chair(s). 

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• 
Following confirmation of registration and enrollment, participants may begin protocol 
treatment. For any issues that would cause treatment delays, please contact the Study Chair. If a 
participant does not receive protocol therapy following registration, the participant’s 
registration protocol status must be changed and the study registration may be canceled. 
• 
Any patient who begins study therapy before confirmation of enrollment will be deemed 
ineligible. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6. TREATMENT PLAN 
 
6.1 Overview 
 
Phase I 
The phase I component will follow a 3+3 design. MEK162 will be administered as a suspension 
prepared by the on-site pharmacy. The starting dose will be 16 mg/m2/dose twice daily (BID) which 
is approximately 67% of the current adult RP2D (Recommended Phase II dose, 45mg bid in a 1.9m2 
adult). Doses will then be escalated in an inter-patient stepwise fashion until dose-limiting toxicities 
(DLTs) are observed (see 6.4.1). Pharmacokinetic studies will be performed on all patients in the 
phase I component of the trial. Pharmacodynamic studies, including measurement of 
phosphorylated ERK in peripheral blood mononuclear cells, will also be performed on all patients in 
the phase I component of the trial. Tissue-based pharmacodynamic studies will be performed on 
patients where tumor tissue is available. 
 
Phase II 
The primary goal of the phase II component is to determine the therapeutic efficacy, as measured by 
response rate, of MEK162 in pediatric patients. Three groups of patients will be evaluated. 
 
• 
Stratum 1 will include pediatric patients with the BRAF truncated fusion with progressive or 
recurrent LGG. 
• 
Stratum 2 will include pediatric patients with NF1 and LGG. The separation of NF1 patients with 
LGG into a separate stratum is based on the observation that LGG in this population have 
distinct biological features compared to LGG in non-NF1 patients, and follow a distinct clinical 
course. 
• 
Stratum 3 will include pediatric patients with recurrent or progressive tumors thought to involve 
the Ras/Raf/ERK pathway but not included in strata 1 or 2. This includes any LGG not included in 
strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor 
other than LGG in a patient with NF1, and any other tumor with a known activating BRAF, NRAS 
or KRAS mutation. 
• 
Stratum 4 (Target Validation) The primary goal of the target validation stratum will be to assess 
the on-target biologic effects of MEK162, and to assess the degree of tumor penetration by 
active drug. This phase will proceed concurrently with the phase II portion of the trial and will be 
open to patients with recurrent or progressive tumors for whom re-resection is clinically 
indicated. Patients who meet eligibility criteria for phase II and for whom a debulking surgery is 
planned will be eligible. Patients who elect to enroll in the target validation stratum will initially 
receive the phase II dose of MEK162 for 7-21 days pre-operatively. At the time of surgery, both 
peripheral blood and tumor sample will be obtained. Tumor tissue will be assessed for drug 
concentration and for on-target effects of MEK162, with additional correlative studies.  
 

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Once patient is sufficiently recovered post-operatively to resume study drug (determined by 
local investigator, less than 21 days in most cases), the screening evaluations (Table 9), including 
tumor imaging, will be repeated. Study calendar will be reset at the time of screening 
evaluation, and the first day that study drug is administered postoperatively will be considered 
cycle 1 day 1 of treatment. If repeat imaging shows no measurable residual disease, patient may 
resume treatment at the discretion of the local investigatory, and will be followed for toxicity 
but will be considered non-evaluable for response.  Patients enrolled in the target validation 
stratum with measurable postoperative disease will be evaluated for response in an exploratory 
fashion (see Section 14). 
 
Target accrual for both Stratum 1 and Stratum 2 is 20 response-evaluable patients, using a single 
cohort design (see Statistical Considerations, Section 14). 
 
MEK162 will be given orally twice daily, as a suspension prepared by the on-site pharmacy, or as a 
tablet. Four weeks of treatment will constitute one cycle. Patients will remain on treatment for 48 
weeks in the absence of tumor progression or development of unacceptable toxicities (see section 
6.6).  Patients deriving benefit may continue treatment for an additional 48 weeks (96 weeks or 24 
cycles total).  Responses will be determined using the Response Assessment in Neuro-Oncology 
(RANO) imaging criteria (17,18). 
 
6.2 Treatment Schema 
 
Phase I 
Treatment began at 67% of the adult RP2D (16mg/m2/dose taken twice daily). This was based on the 
following calculation: 
 
An adult RP2D of 45mg bid and an average adult m2 of 1.9m2 = 45/1.9 = 23.7mg/m2 
67% of 23.7mg/m2 = 15.9mg/m2 starting dose (which was rounded to 16mg/m2) 
 
Doses were increased as detailed below: 
Dose level -1:   
12 mg/m2/dose BID 
Dose level 1:   
16 mg/m2/ dose BID (starting dose) 
Dose level 2:   
20 mg/m2/dose BID  
Dose level 3:   
24 mg/m2/dose BID 
Dose level 4:   
28 mg/m2 /dose BID 
Dose level 5:   
32 mg/m2 /dose BID 
Phase II 
All patients in the phase II component (including those in the target validation stratum), will be 
treated at a starting dose of 32mg/ m2 /dose BID (dose level 5). This is the RP2D  determined by the 
study committee (chair and co-chairs) taking into consideration the MTD defined in the phase I 
component, any significant adverse events identified after cycle 1, and PK/PD results. 

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Continuation Treatment 
After the completion of 12 cycles of study therapy, patients deriving benefit may continue study 
drug for up to 12 additional cycles at the discretion of the investigator. See section 6.6 (Duration of 
Therapy). 
 
6.3 Agent Properties and Administration 
 
Chemical Name: 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-
1Hbenzimidazole-6-carboxamide 
 
Mechanism of Action: MEK162, generic name binimetinib, previously named ARRY 438162, is a 
potent and selective allosteric, ATP non-competitive inhibitor of MEK1/2 that is active in inhibiting 
pERK and growth of BRAF mutant cancer cells in the low nanomolar range. 
 
Classification: Small molecule inhibitor 
 
Mode of Action: Selective allosteric, ATP un--competitive inhibitor of MEK1 and MEK2 
 
Formula: C17H15BrF2N4O3 
 
Relative Molecular Mass: 441.23 
 
Appearance:  White to light tan powder or white to slightly beige powder.  Tablets are yellow to 
dark yellow capsule shaped 
 
Packaging and labeling: MEK162 will be provided by Array BioPharma as film-coated tablets for oral 
use of dosage strength 15 mg.  The film-coated tablets consist of MEK162 drug substance, lactose 
monohydrate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, 
magnesium stearate, and a commercial film coating. 
 
Dosing (see Appendix II and Appendix XII): The study drug will be administered based on body 
surface area and should be calculated approximately monthly. 
 
Route of Administration: MEK162 will be administered orally BID, as a suspension prepared by the 
on-site pharmacy (Appendix XVI), or as a tablet.  See Appendix II.  
 
Supplier: Investigational supply from Array BioPharma 
 
Supply and Receipt: Study drug must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, MEK162 should be stored according to the 

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instructions specified on the drug labels. Study medication will be dispensed by an authorized 
person at the investigator’s site. 
 
Storage: The storage conditions of the MEK162 film coated tablets are “Do not store above 25°C, 
protect from light.” Packaging is in plastic bottles acceptable for pharmaceutical use. 
 
Stability: Will be provided on the Certificate of Analysis (COA) for each lot of MEK162 distributed by 
Array BioPharma. 
 
Drug Accountability: Clinical drug supply must be accounted for and patients will be asked to return 
all unused study drug and packaging on a regular basis, at the end of the study or at the time of 
study drug discontinuation. At the conclusion of the study, and, as appropriate during the course of 
the study, the Investigator will either destroy (with permission from Array BioPharma ) or return all 
used and unused study drug, packaging, drug labels, and a copy of the completed drug 
accountability ledger to Array BioPharma. 
 
Disposal and Destruction: The drug supply may be destroyed at the investigational site according to 
site standard operating procedure.  If site procedures do not allow for destruction, the drug supply 
will be destroyed at a facility designated by Array BioPharma. 
 
6.4 Toxicities and Dose Reductions 
 
Definitions of dose limiting toxicities (DLTs): Toxicity will be assessed using the NCI CTCAE, version 
4.03, unless otherwise specified. A DLT is defined as an AE or abnormal laboratory value assessed as 
at least possibly related to the study medication, which occurs ≤ 28 days following the first dose of 
MEK162 (Cycle 1, and cycle 2 day 1), and meets any of the criteria listed in the table below. Required 
cycle 2 day 1 evaluations that are delayed for any reason should be included as part of the DLT 
assessment. Whenever a patient experiences a toxicity that fulfills the criteria for a DLT, treatment 
with the study drug will be interrupted and the toxicity will be followed up. Any dose reduction 
within the DLT period will be considered a DLT. The DLT must be reported to the Study PI, Dr. 
Robison, and the CTO Operations Center Coordinator, Jasmine Pauly, within 48 hours of the event. 
Please see section 12.2 for the reporting timeline. 
 
Table 6-1: Toxicity Table for Phase I/II DLT Period Assessment 
TOXICITY  
DLT CRITERIA 
Hematologic 
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, hand-foot skin reaction (HFSR) or photosensitivity CTCAE Grade 3 > 7 
consecutive days despite skin toxicity treatment (as per local practice)* 
Rash, HFSR or photosensitivity CTCAE Grade 4 

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Eye disorders 
CSR (Retinopathy) CTCAE Grade 2 for > 14 consecutive days confirmed by 
ophthalmologic examination* 
CSR (Retinopathy) CTCAE Grade ≥ 3, confirmed by ophthalmologic examination 
Retinal disorder other than CSR (retinal detachment/tear, retinal vascular 
disorder, retinopathy other) CTCAE Grade ≥ 2 confirmed by ophthalmologic 
examination 
Visual disturbances without ocular (retinal) changes: blurred vision, flashing lights, 
floaters CTCAE Grade ≥ 3 
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 
Pancreatitis Grade ≥ 3 
Hepato-biliary 
≥ CTCAE grade 3 total bilirubin  
≥ CTCAE grade 3 ALT, or  > CTCAE grade 2 ALT with total bilirubin > 2x ULN 
(Isolated increases in AST without concomitant increases in ALT will not be 
considered dose-limiting) 
Serum alkaline phosphatase CTCAE Grade 4 > 7 consecutive days* 
ECG QT Interval 
QTc interval > 500 msec on at least two separate ECGs  
Cardiac disorders 
Decrease of LVEF > 10% (absolute value) † compared to baseline and the LVEF is 
below the institution’s LLN 
Left ventricular systolic dysfunction Grade ≥ 3 
Other cardiac disorders Grade ≥ 3 
Renal 
Serum creatinine > 2x ULN 
Other non-hematologic 
events 
≥ CTCAE grade 3, except for the exclusions noted below 
Exceptions to DLT 
criteria 
Asymptomatic CTCAE grade 3 CK elevation 
< 5 days of CTCAE grade 3 fatigue 
< 5 days of CTCAE grade 3 edema 
Grade 3 laboratory abnormalities that are responsive to oral supplementation or 
deemed by the investigator to be clinically insignificant 
CTCAE version 4.03 will be used for all grading.  
Optimal therapy for vomiting or diarrhea will be based on institutional guidelines with consideration of the prohibited 
medications listed in this protocol. 
*Will be considered a DLT if toxicity begins within the DLT period and does not resolve within the specified time frame. 
†Changes in LVEF % refer to absolute value: e.g., a 10% decrease from 60% would be 50% (not 54%).   
 
 
Follow-Up for Toxicities 
 
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed up at least once a week (or more frequently if 

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clinically indicated) for 4 weeks, and subsequently at approximately 4 week intervals, until 
resolution or stabilization of the event, whichever comes first. Appropriate clinical experts such as 
ophthalmologist, cardiologist, dermatologist, etc., should be consulted as deemed necessary. All 
patients must be followed up for AEs and SAEs for 30 days following the last dose of MEK162. 
 
Patients exhibiting hypomagnesaemia, hypocalcaemia, and/or hypokalemia, should receive 
electrolyte replacement as indicated by national and institutional guidelines and be followed until 
laboratory values have normalized or as clinically indicated. 
 
Follow up evaluations for appearance of central serous retinopathy (CSR): Patients on the study will 
be examined regularly to monitor for the possible development of CSR, as the appearance of CSR 
has been associated with MEK162 treatment. Ophthalmologic examinations will be performed 
periodically as outlined in Tables 9-1 and 9-3. For patients developing a CSR of any grade, in addition 
to the ophthalmologic evaluations detailed in section 6.4 below, it is recommended to follow up the 
CSR with an ophthalmological exam every two weeks for 8 weeks, and subsequently at 
approximately a 4-week interval. Dose modification guidelines are outlined below. 
 
Dose Modification and Dose Delay 
 
Any dose reduction within the DLT period will be considered a DLT. Dose reductions within the DLT 
period should be undertaken in concordance with the sections below. 
 
Dose interruptions of more than 7 days per cycle must be discussed with and approved by the study 
chair. 
 
Missed/skipped doses will not be made up (i.e. the patient should not double their dose if the 
previous dose was missed).  
 
No intra-patient dose re-escalation is allowed after dose reduction due to any adverse event. 
 
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 
adverse events (AE) should be followed weekly or as clinically appropriate until stabilization or 
resolution. 
 
Skin toxicity (such as macular popular rash, acne, rash, dermatitis acneiform, etc.), visual changes 
(related to CSR), nausea, diarrhea, and asymptomatic reversible elevation of CK have been 
associated with MEK162 administration. Please refer to the table below for the study-drug dose-
adjustment recommendations for MEK162 induced toxicities. Please refer to Appendix XIII and 
Appendix XIV for additional supportive care guidelines for the management of MEK162-induced skin 
toxicity and diarrhea, respectively.  

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All dose reductions must be by 2 dose levels (e.g., from dose level 5 to dose level 3), except for 
patients at dose level 1 requiring dose reduction, who may be reduced to dose level -1.  Patients 
at dose level -1 meeting dose reduction criteria must be removed from protocol therapy.  
 
Table 6-2: Recommended Dose Modifications Associated with Treatment-Related Adverse Events  
CTCAE v4.0.3 
Grade (unless 
otherwise 
specified) 
Dose Adjustment for Study Drug MEK162 
Eye disorder – CSR like events 
Grade 1 
Maintain dose level of MEK162 and increase frequency of ophthalmologic 
monitoring to at least every 14 days.† 
Grade 2  
Maintain dose level of MEK162 and repeat ophthalmologic evaluation within one 
week: 
- If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of MEK162.  
- If not resolved to Grade ≤ 1 in ≤ 21 days, reduce dose of MEK162 or maintain dose 
of MEK162 based upon the Investigator’s discretion after consultation with the 
ophthalmologist. 
Grade 3 
Interrupt MEK162 and repeat ophthalmologic evaluation within one week:  
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce dose of MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, discontinue patient from study drug 
treatment. 
Grade 4 
Permanently discontinue MEK162, continue close ophthalmologic monitoring. 
 
Eye disorders – RVO 
Any grade 
Permanently discontinue MEK162. 
Eye disorder – Other retinal events (grading based on CTCAE grading for retinal detachment) 
Grade 1 
Repeat ophthalmologic exam including OCT and visual acuity assessment within 10 
days.  
If OCT findings are worse on follow-up exam (even if asymptomatic), interrupt 
MEK162.  Decision to resume therapy will be made on a case-by-case basis in 
discussion with the sponsor, investigator, and treating ophthalmologist. 
Grade 2  
Interrupt MEK162 and repeat ophthalmologic monitoring (including OCT and visual 
acuity assessment) within 10 days.  
-If retinal event returns to baseline or resolves ≤ Grade 1 severity, MEK162 resume 

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CTCAE v4.0.3 
Grade (unless 
otherwise 
specified) 
Dose Adjustment for Study Drug MEK162 
at the same dose level.  
-If not improved but not definitively worse, resume MEK162 at a reduced dose. 
Otherwise, continue to interrupt treatment and discuss the case with the 
investigator, ophthalmologist and Sponsor prior to resuming treatment. 
Grade 3 
Interrupt MEK162 and repeat ophthalmologic monitoring (including OCT and visual 
acuity assessment) within 10 days.  
-If retinal event returns to baseline or resolves to ≤ Grade 1 severity, MEK162 may 
be resumed at a reduced dose. Otherwise, continue to interrupt treatment and 
repeat the complete ophthalmologic assessment in 10 days. 
- If retinal event returns to baseline or resolves to ≤ Grade 1 severity after a second 
10-day period, MEK162 may be resumed at a reduced dose; otherwise, 
permanently discontinue study therapy. 
Grade 4 
Permanently discontinue MEK162.  Continue close ophthalmologic monitoring.  
 
Other eye disorders 
Grade 1 – 2 
Maintain dose level of MEK162 and increase frequency of ophthalmologic 
monitoring to at least every 14 days.† 
Grade 3 
Interrupt MEK162 and refer patient to ophthalmologist within one week: 
-If resolved to Grade ≤ 1 in ≤ 21 days, reduce dose† of MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, discontinue patient from study drug 
treatment. 
Grade 4 
Permanently discontinue MEK162. 
Liver related adverse events* 
Grade 1 
AST or ALT 
Grade 1 (> ULN – 3 x ULN) 
Maintain dose level of MEK162.  
Grade 2 
AST or ALT (> 3 – 5.0 x ULN) 
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 MEK162 until resolved to Grade ≤ 1 (or Grade ≤ 2 
in case of liver metastasis), then: 
- If resolved in ≤ 14 days, maintain dose level of MEK162.  
- If resolved in > 14 days, reduce dose level of MEK162. 
 
Interrupt dose of MEK162 until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 7 days, reduce dose level of MEK162. 
- If resolved in > 7 days, discontinue patient from study drug 

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CTCAE v4.0.3 
Grade (unless 
otherwise 
specified) 
Dose Adjustment for Study Drug MEK162 
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 MEK162 until resolved to Grade ≤ 1 (or Grade ≤ 2 
in case of liver metastasis), then: 
- If resolved in ≤ 14 days, maintain dose level of MEK162. 
- If resolved in > 14 days, reduce dose level of MEK162. 
 
Permanently discontinue MEK162. 
 
 
Permanently discontinue MEK162.  
AST or ALT Grade 4 (> 20.0 x 
ULN) 
Permanently discontinue MEK162. 
Cardiac disorders 
  
Left ventricular systolic 
dysfunction/ejection 
fraction decreased* 
Asymptomatic decrease of 
>10% (absolute value) in 
LVEF compared to baseline 
and the LVEF is below the 
institution’s lower limit of 
normal. ‡‡ 
Interrupt dose of MEK162 and repeat evaluation of LVEF within 2 weeks 
If the LVEF recovers (defined as ≥ LLN and absolute value decrease ≤ 
10% compared to baseline) ‡‡ in ≤ 4 weeks, reduce dose after approval 
of the Study Chair. Monitor LVEF 2 weeks after restarting on MEK162, 
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 
for 16 weeks). 
Grade 3 – 4 
Permanently discontinue patient from MEK162. Closely monitor LVEF 
for 16 weeks or until resolution. 
Note: Copies of ECHOs could be requested for patients with absolute 
value decrease of >10% in LVEF compared to baseline and LVEF < LLN. 
 
CK elevation  
Any grade 
- Assess hydration status.  Consider supplemental hydration if oral 
intake inadequate.   

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CTCAE v4.0.3 
Grade (unless 
otherwise 
specified) 
Dose Adjustment for Study Drug MEK162 
- Measure serum creatinine, with interval reevaluation as clinically 
appropriate.   
- If total CK > 3X ULN, measure isoenzymes and myoglobin in blood or 
urine. 
Grade 1-2 
Continue treatment on same dose level. 
 
Grade 3  
(> 5X ULN- 10X ULN) 
If asymptomatic with normal creatinine: Maintain dose of MEK162 and 
monitor closely.  
If symptomatic (muscle pain/spasms) or serum creatinine >ULN: 
Interrupt dose of MEK162 until resolved to CTCAE Grade ≤ 1 and 
monitor closely (Section 6.4), then:  
- If resolved in ≤ 21 days, reduce dose of MEK162. 
- If resolved in > 21 days, discontinue patient from study drug 
treatment. 
Grade 4 
If asymptomatic: interrupt and monitor closely . 
- If resolved in ≤ 21 days, reduce dose of MEK162. 
- If resolved in > 21 days, discontinue patient from study drug 
treatment. 
If symptomatic : permanently discontinue treatment. 
 
QTc Prolongation 
QTc > 500 msec 
(Grade 3) 
(confirmed) 
1st occurrence: Treatment with MEK162 should be temporarily suspended. 
Electrolyte abnormalities, if any, should be corrected and any concomitant 
medication that may potentially prolong QT should be discontinued. 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), MEK162 may be restarted at a reduced dose. 
2nd occurrence: If a second episode occurs that is attributed to MEK162, study drug 
must be permanently discontinued. 
 
 
 
Rash 
Grade 1 
Treatment with MEK162 should be maintained at the current dose. 

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CTCAE v4.0.3 
Grade (unless 
otherwise 
specified) 
Dose Adjustment for Study Drug MEK162 
Initiate prophylactic regimen if it was not already started and monitor closely. 
Grade 2  
1st occurrence: Treatment with MEK162 should be maintained at the current dose 
and the 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, 
interrupt dosing until improvement to Grade < 1. Resume treatment at the same 
dose level. 
 
Subsequent occurrences: Reassess within a maximum of 2 weeks. If rash worsens 
or does not improve, interrupt dosing until improvement to Grade < 1. Resume 
treatment at a reduced dose level. 
 
Grade 3 
1st occurrence: Treatment with MEK162 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 MEK162 at the same dose level 
 
Subsequent occurrences: Interrupt treatment until improvement to Grade <1. 
Resume  treatment with MEK162 at a reduced dose level 
 
Consider referral to  dermatologist  and manage rash per dermatologist’s 
recommendation 
 
Grade 4 
Permanently discontinue MEK162 
 
Diarrhea 
Uncomplicated§ 
Grade 1-2 
Consider temporary interruption of MEK162 until resolved to Grade ≤ 1. Treatment 
may then be resumed at current dose level. 
Complicated§ 
Grade 1-2 
Temporarily interrupt MEK162 treatment until resolved to Grade ≤ 1. Restart 
MEK162 at a reduced dose level. 
Grade 3 
Temporarily interrupt MEK162 treatment until resolved to Grade ≤ 1. Restart 
MEK162 at a reduced dose level. 
Grade 4 
Temporarily interrupt MEK162 treatment until resolved to Grade ≤ 1. Restart 

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CTCAE v4.0.3 
Grade (unless 
otherwise 
specified) 
Dose Adjustment for Study Drug MEK162 
MEK162 at a reduced dose level 
 
All other adverse events (suspected to be related) 
Grade 1-2 
In the event is a persistent Grade 2 AE, not responsive to a specific therapy, 
consider study drug interruption or reduction. 
Grade 3 
Interrupt study drug until resolution to Grade ≤1 or to pre-treatment/ baseline 
level. If the event resolves within 21 days then study drug may be restarted at a 
lower dose, (two levels below that previously received) based upon the 
Investigator’s discretion. 
Grade 4 
Permanently discontinue MEK162 §§ 
* Not according to CTCAE. 
† Ophthalmologic monitoring should include ocular coherence tomography (OCT) and slit lamp 
examination if feasible, in addition to visual acuity testing, visual field assessment, and indirect 
fundoscopy. Further evaluation with specialized retinal imaging (e.g. angiography) should be 
performed as indicated. 
‡ Refers to total bilirubin. 
‡‡ Change in LVEF % refers to absolute value: e.g., a 10% decrease from 60% would be 50% (not 54%).   
§ The determination of whether grade 1-2 diarrhea is uncomplicated or complicated will be made by 
the investigator.  Complicated diarrhea will typically be characterized by one or more of the following: 
moderate to severe cramping, fever, neutropenia, sepsis, bleeding, dehydration, decrease in 
performance status, or nausea and vomiting. 
 §§ A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to 
Grade ≤1 within 21 days of discontinuing drug and, if in the opinion of the Investigator and Study 
Chair, the event is not life-threatening, and the patient can be managed and monitored for recurrence 
of AE. Any patients requiring a treatment interruption of longer than 21 days must discontinue study 
drug permanently. 
 
6.5 Concomitant Medications 
 
All medications (other than the study drugs) taken within 4 weeks of study treatment initiation and 
all concomitant therapy and significant non-drug therapies (including physical therapy and blood 
transfusions) administered during the study, with reasons for use, should be recorded. Medications 
include not only physician prescribed medications, but also all over-the counter medications, herbal 
medications and nutritional or vitamin supplements. 
 

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The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after starting study drug.  
 
Patients taking medication chronically should be maintained on the same dose and schedule 
throughout the study period, as medically feasible. The days of full pharmacokinetic blood sampling 
should be representative of the other study days with regard to the use of the chronically 
administered concomitant medications. However, if a concomitant medication is used intermittently 
during the study, this medication should be avoided on the days of full pharmacokinetic sampling, if 
medically feasible. 
 
Permitted Concomitant Therapy 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted. Please refer to MEK162 IB for possible interactions with other drugs. 
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases and 
supportive care agents, such as PRBCs, pain medications, anti-emetics, short courses of steroids, and 
anti-diarrheals are allowed. Oral contraceptive pills are permitted. The use of any other potential 
new concomitant medications may be discussed between the investigator and the sponsor on a 
case-by-case basis. Please refer to Table 6-3 and Appendix I for a list of drugs to be used with 
caution. 
 
Transfusions or growth factor support for white cell counts, platelets, or red blood cells are not 
permitted during Cycle 1, unless the patient has already experienced a DLT. Transfusions and growth 
factor support should not be used prophylactically during Cycle 1. 
 
Patients taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible. 
 
The investigator should instruct the patient to notify the study site about any new medications 
including vitamins, supplements, and herbal supplements he/she takes after the start of the study 
drug. All medications (other than study drug) including vitamins, supplements and herbal 
supplements and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with study drug must be noted. 
 
Permitted concomitant therapy requiring caution and/or action 
The solubility of MEK162 is pH dependent and a 10-fold decrease in solubility is observed between 
pH 1 and 2. Patients receiving concomitant treatments that could potentially modify the gastric pH 
(i.e. PPI) should be instructed to take them at least two hours after the administration of MEK162. 
In vitro data showed that MEK162 is a substrate of P-gp and BCRP and thus the use of drugs that are 
known to inhibit these transporters should be used with caution. Please refer to Table below for a 
list of these drugs. 
 
Table 6-3: List of inhibitors of human transporters to be used with caution 

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Transporters  
Category 
Substrate 
P-gp 
Calcium Channel Blockers 
felopidine, verapamil, diltiazem, mibefradil, nifedipine, 
nitrendipine 
 
Protease inhibitors 
indinavir, ritonavir, lopinavir, telaprevir, saquinavir, nelfinavir 
Antibiotics 
Fexofenadine, clarithromycin, azithromycin, erythromycin, 
rifampin 
Antiarrhythmics 
quinidine, dronedarone, amiodarone 
Adrenergic Antagonist 
carvedilol, talinolol 
Herbal Medications 
Schisandra chinensis, St. John’s wort, milk thistle (silybum 
marianum), ginkgo biloba 
Others 
valspodar (PSC 833), elacridar (GF120918), ranolazine, 
fluvoxamine, itraconazole, quercetin, captopril, conivaptan, 
paroxetine, ticagrelor, telmisartan, tolvaptan 
BCRP 
Others 
elacridar (GF120918) 
* This table was compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies”; and from 
the University of Washington’s Drug Interaction Database. 
For further information, please see the FDA’s website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093606.htm 
 
 
MEK162 showed relatively potent inhibitory potency for CYP2B6 (unbound Ki of 1.67 µM). Based on 
these in vitro findings, MEK162 may inhibit the metabolic clearance of co-medications metabolized 
by CYP2B6, if sufficiently high concentrations are achieved in vivo. Caution should be used in 
patients receiving concomitant treatment with other drugs that are substrates of this enzyme.  
Please refer to Appendix I for a list of CYP2B6 substrates. 
Drugs with a known, a conditional or a possible 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. For further information, please visit the website of the QTdrugs.org Advisory Board of the 
Arizona CERT. 
The impact of UGT1A1 inhibitors or inducers on PK of MEK162 in vivo is unknown; therefore, inhibitors 
or inducers of UGT1A1 should be co-administered with caution. 
 
The effect of inhibitors or inducers of CYP1A2 or CYP2C19 in vivo is unknown; therefore, strong 
inhibitors or inducers of CYP1A2 or CYP2C19 should be used with caution.  Please refer to Appendix I. 
 
Prohibited concomitant therapy 
• 
Medications that carry a strong risk for QT prolongation are prohibited 
• 
Concurrent anti-neoplastic therapy, including radiotherapy are prohibited 
 

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Growth Factors: Routine use of growth factors (i.e. G-CSF, GM-CSF, erythropoietin) is not permitted. 
However, therapeutic use of G-CSF or GM-CSF in patients with serious neutropenic conditions, such 
as sepsis, may be considered at the investigator’s discretion. 
 
Anti-emetics: The use of anti-emetics will be at the investigator’s discretion. Use of anti-emetics 
should be recorded in the concomitant medication diary. 
 
Febrile neutropenia: Febrile neutropenia should be managed according to the local institutional 
guidelines. Measures include laboratory testing, blood and urine cultures, and institution of broad-
spectrum antibiotics. 
 
Pneumocystis carinii pneumonia (PCP) prophylaxis: The use of medication (i.e., 
trimethoprim/sulfamethoxazole, dapsone, atovaquone, or pentamidine) for PCP prophylaxis in 
patients on chronic steroids is recommended, but is at the investigator’s discretion. 
 
Surgical Procedures: If a surgical procedure is required for a reason other than tumor progression 
(i.e. the onset of hydrocephalus), these procedures should be documented, but will not constitute 
criteria for declaring the patient “off therapy.” 
 
Central Venous Catheters: Treatment via central venous catheters is not needed. 
 
6.6 Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue for 
approximately 48 weeks or until one of the following criteria applies:  
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Participant decides to withdraw from the study 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
After the completion of 12 cycles, patients deriving benefit may continue investigational drug for up 
to 12 additional cycles (up to 24 cycles or 96 weeks total) at the investigator’s discretion. 
 
6.7 Duration of Follow-Up 
Participants will be followed for AEs for 30 days after discontinuation of study therapy or until 
death, whichever occurs first. Participants who discontinue study therapy due to unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. For all patients 
that complete therapy or come off therapy for any other reason, toxicity assessment (for new SAEs 
and unresolved prior AEs) will continue for 30 days or until the events return to baseline. Patients 

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that start new therapy will not be evaluated for new SAEs. After the 30 days, survival data and MRI 
scans (if available) will be requested for all patients. 
 
Recommended follow-up for patients that complete therapy will occur every 3 months (+/- 2 weeks) 
for the first year (can be more or less frequent) and then approximately annually until progression 
or change of therapy. Frequency of disease assessment in patients receiving continuation therapy is 
at the discretion of the investigator. 
 
6.8 Criteria for Removal from Study 
Participants will be removed from treatment when any of the criteria listed in Section 6.6 applies. 
The reason for study removal and the date the participant was removed must be documented in the 
study-specific case report form (CRF). Alternative care options will be discussed with the participant. 
Reasons for study removal include: death, patient lost to follow-up, or patient withdrawal of 
consent. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator (or Protocol Chair), Dr. Nathan Robison at (323) 
361-8147 or Dr. Mark Kieran at (617) 632-4907. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 Dose Delays and Modifications 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4, which is identified and located on the CTEP website at: 
http//ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If possible, appropriate supportive and symptomatic care should be provided, include anti-emetics, 
antidiarrheals, etc., as indicated. In the case of toxicity, appropriate medical treatment should be 
used (including anti-emetics, antidiarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
7.2 Expected Toxicities for MEK162 
Please refer to the most recent Investigators Brochure for a list of the current known and suspected 
MEK162 toxicities. 
 
7.3 Management of Treatment-Related Events 
For rash-like events, institutional standard of care treatment should be initiated promptly upon 
occurrence of such events. Treatment of rash may include, but is not limited to, topical or oral 
antibiotics, topical or oral anti-inflammatory, topical or oral corticosteroids, and oral antihistamines. 
Sun avoidance or careful use of sunscreen is recommended. Emollients may be used prophylactically 
or as treatment for rash (see Appendix XIII). 
 
For elevated CK levels, patients may remain on MEK162 per investigator discretion if asymptomatic. 
Patients may be treated symptomatically for nausea, vomiting, and diarrhea with standard anti-emetic 
and anti-diarrheal medications (see appendix XIV). Prophylactic treatment for nausea should be 
considered.  Prophylactic treatment for diarrhea is not required. 
 
Patients with edema may be treated with diuretic medications if indicated. 
 
For stomatitis/mucositis-like events, institutional standard of care treatment should be initiated 
promptly upon occurrence of such events. 
Patients with a history or current evidence of CSR, RVO or ophthalmopathy present at baseline that 
would be considered a risk factor for CSR or RVO should not be treated with MEK162 (see exclusion 
criteria). 

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The decrease of cardiac ejection fraction has been reported with other MEK inhibitors in clinical 
development. The review of all cardiac SAEs across all studies administering MEK162, either as a single 
agent or in combination with other antineoplastic drugs, suggests that these side effects are also 
observed with the Array/Novartis compound MEK162. Therefore, in order to ensure patient safety in 
all ongoing clinical studies with MEK162, monitoring of cardiac function and stringent 
inclusion/exclusion criteria are included and followed.  
Although there was one fatal case of liver failure in study MEK2201 at 60 mg BID, thorough review of 
liver abnormalities observed across the different studies, revealed that most of the changes in liver 
parameters (transaminases, bilirubin) have been Grade 1-2. To ensure an adequate and prospective 
monitoring of liver toxicities stringent guidelines for inclusion criteria and dose modifications were 
included in the protocols. 
 
 
 
 
 
 
 
 
 

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8. CORRELATIVE STUDIES 
 
8.1 Pharmacokinetic Studies 
The blood sampling regimens for determining the pharmacokinetics of MEK162 and its primary 
active metabolite AR00426032 are given in Table 8-1. Blood samples for MEK162/AR00426032 
concentration measurements will be collected on all patients in the study from both the phase I and 
phase II component. Exact dates and clock times of drug administration and actual PK blood draw 
should be recorded on the appropriate eCRF. If a patient experiences an AE that results in an 
unscheduled visit or fits the criteria of a SAE as determined by the Investigator, a blood sample 
should be collected for measurement of drug concentrations at or around that time. Additionally, if 
a patient experiences an ocular event of any grade, a blood sample should be collected. 
 
If vomiting occurs within 4 hours following study-drug administration on the day of PK blood 
sampling (Cycle 1 Day 1 and Day 15), the time (using the 24-h clock) of vomiting should be recorded 
on the transmittal forms, which accompanies the sample. No additional trial medication should be 
taken that day in an effort to replace the material that has been vomited. 
If a patient withdraws prematurely from the study, a PK blood sample for MEK162 analysis (2 mL of 
sample) should be obtained whenever possible. Sample should be collected as soon as possible after 
the last dose of MEK162, and the date and time of last dose should be recorded. 
Whenever an ECG with a QTc change from baseline > 60 msec or a new absolute QTc ≥ 500 msec 
result is known, a blood sample to assess the concentrations of MEK162/AR00426032 should be 
obtained and the time of sample collection noted.  
 
A detailed description of the planned pharmacokinetic analyses is given below. 
 
Pharmacokinetic blood sample collection and handling 
All blood samples will be taken either by direct venipuncture or from an indwelling venous cannula. 
Blood should be collected in accordance with institutional guidelines. All samples must be carefully 
packed in suitable material containing sufficient dry ice to keep them frozen during shipment. A list 
of samples, including the date, subject number, and the time of sampling should be included in the 
shipment. Any missing samples should be notified on the list. 
 
Complete instructions for sample processing, handling and shipment is provided in Appendix IV. Any 
sampling problems should be noted on the eCRF and on appropriate source documentation. 
 
Table 8-1: Schedule of blood sample collections for MEK162 Pharmacokinetics (Dose Escalation Phase 
I and Phase II) 
Cycle 
Day 
PK 
1 
1 
Pre-dose 

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1 
1 
0.5hr 
1 
1 
1hr 
1 
1 
2hr 
1 
1 
4hr 
1 
1 
6hr 
1 
2 
Pre-dose 
1 
15 
Pre-dose 
1 
15 
0.5hr 
1 
15 
1hr 
1 
15 
2hr 
1 
15 
4hr 
1 
15 
6hr 
Phase I: Cycles 2-12 
Phase II: Cycles 2-4 
1 
Pre-dose 
At the time off study or associated with 
toxicity 
 
 
Take pre-dose sample immediately prior to the start of study drug (MEK162) administration. 
In the event of difficulty scheduling sampling for PK, the samples may be obtained ± 3 day from the 
scheduled date (except for Day 1 of Cycle 1). There is a +/- 15 minute window for any samples taken 
from 0.5 hr – 2hr and +/- 30 minute window for >2hr. For Cycle 2+ pre-dose samples the previous 
dose time must be recorded. 
 
At the specified time points, 2.0 mL of blood will be collected in tubes containing EDTA (purple top). 
The tubes will be kept in an ice water bath after blood collection. Within 30 minutes, the tubes will 
be centrifuged at between 3°C and 5°C for 10 minutes at approximately 1500g to separate plasma. 
Immediately after centrifugation, transfer at least 0.5 mL of plasma into 2-mL polypropylene screw-
cap tube (MEK162/AR00426032). The tubes will be placed in a freezer set at < -70ºC until shipment. 
 
Assay for Plasma MEK162: Plasma concentrations of MEK162 and its metabolite, ARR00426032, will 
be measured at QPS, LLC using a validated liquid chromatography-tandem mass spectrometry assay 
with an LLOQ of 5.0 ng/mL for both analytes. 
All plasma pharmacokinetic samples should be shipped Monday through Wednesday to the 
following address: 
QPS Sample Coordination 
3 Innovation Way 
Suite 240 
Newark, DE 19711 
Phone: 302-369-5120 
Fax: 302-369-5602 
Email: sample@qps.com 
 
 

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8.2 Pharmacodynamic Studies 
As outlined in the Table 8-2 below, tumor, blood, and urine (Phase II) samples will be collected in 
cryovials, in BD 367863 Vacutainer EDTA tubes, and sterile urine collection containers, respectively 
before and during treatment with the MEK162 to investigate the effect of the drug at the molecular 
and cellular level as well as to determine how baseline values/levels and changes from baseline in 
the markers may relate to exposure, clinical outcomes, and resistance. Details are outlined in 
Appendices III, IV, V, VI, VII, VIII, and IX. 
 
 
Table 8-2: Schedule of Samples 
Sample Type 
Time Point 
Format 
Collection Tube 
Shipment 
Tube 
Shipment 
Conditions/ 
Temperature 
Label 
Tumor  
  
Pre-treatment  
FFPE  
N/A 
Block or H&E 
slide, 20-40 
unstained 
slides  
Ambient (room 
temperature)  
Subject ID, CTO 
registration ID, 
patient initials, date 
sample obtained 
Pre-treatment  
Frozen  (not 
fixed) 
1.5 ml Cryovial  
1.5 mL 
Cryovial  
Dry Ice or -80°C 
Subject ID, CTO 
registration ID, 
patient initials, date 
sample obtained 
Post-treatment  
Frozen  (not 
fixed) 
1.5 ml  Cryovial  
1.5 mL 
Cryovial 
Dry Ice or -80°C 
Subject ID, CTO 
registration ID, 
patient initials, date 
sample obtained 
Pharmacodynamic 
Blood (6mL) 
  
Tube 1: Pre-
treatment 
Whole Blood, 
Frozen  
BD 367863 
Vacutainer 
EDTA 
1.5 mL 
Cryovials 
(aliquoted 
from 
Vacutainer) 
Dry Ice or -80°C 
Subject ID, CTO 
registration ID, 
subject initials, date & 
time sample obtained, 
PD #1 
Tube 2:   
Phase I Cycle 3 
Phase II Cycle 4  
Day 1, 4-6 hours 
after dose  
Whole Blood, 
Frozen  
BD 367863 
Vacutainer 
EDTA 
1.5 mL 
Cryovials 
(aliquoted 
from 
Vacutainer) 
Dry Ice or -80°C 
Subject ID, CTO 
registration ID, 
subject initials, date & 
time sample obtained, 
PD #2 
Tube 3: Time of 
progression, end 
of treatment, or 
end of cycle 12  
Whole Blood, 
Frozen  
BD 367863 
Vacutainer 
EDTA 
1.5 mL 
Cryovials 
(aliquoted 
from 
Vacutainer) 
Dry Ice or -80°C 
Subject ID, CTO 
registration ID, 
subject initials, date & 
time sample obtained, 
PD #3 

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Before shipment, please confirm with Sarah Becker via email (pnotissuebanking@partners.org) that 
proper materials are sent. 
All materials from Table 8-2 should be sent to: 
Keith Ligon C/O Sarah Becker 
450 Brookline Ave JFB215A 
Boston, MA 02215 
 
Table 8-3: Stratum 4 Target Validation Sample Schedule Cycles 0-1 
Sample Type 
Cycle 0 
Day of Surgery 
Cycle 1 
PK 
None 
Single Collection 
Full Panel 
6mL Blood PD 
Pre-treatment 
Single Collection 
None 
9-10 mL Streck Blood PD 
Pre-treatment 
Single Collection 
None 
Urine PD 
Pre-treatment 
None 
None 
 
Biomarker Assessments in Tumor Samples 
A representative baseline tumor tissue sample (archival or fresh) will be requested from all patients 
to perform the assessments as described in Tables 8-4 and 8-5. 
 
Table 8-4: Summary of Assessments in Tumor Tissue for Participants in Strata 1, 2, and 3 
Tumor markers 
Archival tissue 
Frozen tissue (if available) 
Streck 
BiomarkerBlood 
(9mL-10mL) 
 
 
 
Phase I: Any time 
(Pre-treatment 
preferred) 
 
Phase II: 
Pretreatment, 
and day 1 of 
cycles  2, 4, 7, and 
at end of 
treatment or end 
of cycle 12.   
Whole blood at 
room 
temperature  
9mL or 10mL 
Cell-Free DNA 
BCT Streck tube 
9mL or 10mL 
Cell-Free 
DNA BCT 
Streck tube 
Ambient (room 
temperature) 
Subject ID, CTO 
registration ID, 
subject initials, date 
sample obtained, PD 
and time point  
Urine (10mL-
45mL) 
Phase II: 
Pretreatment and 
day 1 of cycles 2, 
4, 7 and at end of 
treatment or end 
of cycle 12 
Urine with 
urine preserve 
at room 
temperature 
added 
Sterile, screw 
top urine 
collection cup 
50 mL sterile 
conical tube 
(transferred 
from 
collection 
cup) 
Ambient (room 
temperature) 
Subject ID, CTO 
registration ID, 
subject initials, Date 
& Time Obtained, 
Urine and time point 
CSF (1mL-10mL 
When clinically 
indicated 
CSF at room 
temperature 
10mL Cell-Free 
DNA BCT Streck 
tube 
10mL Cell-
Free DNA 
BCT Streck 
tube 
Ambient (room 
temperature) 
Subject ID, CTO 
registration ID, 
subject initials, date 
sample obtained, CSF 
and time point 

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pS6(Ser240/244, 235/236) 
X 
X 
pERK (T202/Y204) CST #4370 
X 
X 
pMEK1/2 (S221) CST #2338 
X 
X 
BRAF V600E Roche #790-4855 
X 
X 
Duplication/fusion BRAF FISH 
X 
X 
 
Table 8-4: Summary of Assessments in Tumor Tissue for Participants in Stratum 4 
Tumor markers 
Pre-Treatment Tissue 
Post- Treatment Tissue  
Cleaved Caspase 3  IHC 
X 
X 
pS6(Ser240/244, 235/236) IHC 
X 
X 
pERK(T202/Y204) CST #4370 IHC 
X 
X 
pMEK1/2 (S221) CST #2338 IHC 
X 
X 
Oncopanel (which assesses 
BRAF V600E) 
X 
X 
Array CGH (which assesses 
duplicated/fusion BRAF) 
X 
X 
KI67 IHC 
X 
X 
 
Fresh Frozen Post-Dose Tumor Biopsies 
These will be requested if tissue acquisition is clinically indicated. Tumor tissue samples are 
important to investigate the effects of MEK162 on molecular signaling and may aid identification of 
markers predictive of efficacy, of pharmacodynamics markers, or of markers related to 
resistance/early resistance to treatment. 
 
• 
One “green pea sized” specimen from previously banked snap frozen primary tumor 
material, regardless of time from surgery, should be rapidly transferred (without thawing) 
from long term frozen storage to a Styrofoam box (minimum suggested internal dimensions 
of 30cm x 30cm x 30cm) filled with as much dry ice as possible. Samples should be 
submitted in 1.5ml standard size Cryovials containing the tumor material and labeled with 
the MEK162 Subject ID, site name, and subject initials. 
 
Collection of Archival Tumor Samples 
Archival tumor samples representing current disease status are required at baseline for all patients 
for whom an archival sample is available. If tissue is available from several surgeries, the most 
recent tissue should be sent. 
 
 
• 
The local pathologist should select the “best block” which contains viable tumor with 
greater than 50% tumor nuclei, less than 30% necrosis, and the tissue fragment size in total 
~0.5cm in diameter for advanced studies. The block should contain sufficient tissue to 
provide 20-40 standard 5-micron FFPE slides for the planned advanced studies. If you are 
unable to send a block, please send an H&E slide and 20- 

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• 
40 unstained slides (no heat treatment, “plus” type charged slides).  
 
Pharmacodynamic and Biomarker Assessments in Blood 
 
Pharmacodynamic: The pharmacodynamic effects of MEK162 on MEK signaling will be assessed by 
measuring pMEK and pERK in  serum. Other methods of pathway signaling quantitation may also be 
used. A whole blood sample (approximately 6 mL in an EDTA tube) will be obtained Cycle 1 Day 1 
pre-dose and at Cycle 3 (Phase I) or Cycle 4 (Phase II) Day 1 4-6 hours post-dose in order to provide a 
normal (non-tumor) control tissue sample for DNA sequencing as a normal genomic control. This 
sample will be used to identify tumor-specific gene alterations by comparing DNA from tumor 
samples with DNA from normal-non-tumor cells. 
 
Biomarker: Samples of blood will be requested at the time of venipuncture for additional biomarker 
studies (see Appendices III, IV, V, VI, VII, VIII, and IX). These samples may be used to support 
analyses of potential tumor mutations versus polymorphisms. These samples will be drawn into a 
purple top EDTA tube with anticoagulant/preservative, inverted a few times to mix, and placed on 
wet ice temporarily Whole blood must be aliquoted into as many 1.5mL standard cryovials (~1mL 
per tube) as needed. Blood should not be processed further and placed in a freezer -80°C until 
shipment. Samples should be shipped in a Styrofoam box with 7-10lbs of dry ice to Dr. Keith Ligon's 
laboratory at the address above.  
 
Processing for the  ambient blood PD sample is as follows: 
 
Streck PD Blood Sample Processing Protocol 
1. Collect 9-10mL whole blood in Cell-Free DNA BCT Streck Tube  
2. Gently invert tube 8 times 
3. De-identify tube by removing all patient identifiers 
4. Label the tube with: 
a. Subject ID  
b. CTO registration ID 
c. Subject initials 
d. Date and time sample obtained  
e. Sample and Time point (ex: Streck PD C1D1)  
5. Send sample and transmittal form at room temperature within 72 hours of collection to Dana-
Farber Cancer Institute in Boston. 
 
Urine Sample Processing Protocol 
1. Collect 10mL-45mL urine in sterile collection cup and add 10-20% volume of Streck Cell-Free 
DNA Urine Preservative to sample  
a. Note time of addition of preserve on transmittal form  
2. Gently invert container 5 times to make sure it is well mixed  
3. Transfer urine with added preservative to 50 mL conical tube 
4. De-identify tube by removing all patient identifiers 
5. Label the tube with: 

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a. Subject ID 
b. CTO registration ID 
c. Subject initials 
d. Date and time sample obtained  
e. Sample and Time point (ex: Urine C7D1) 
6. Send sample and transmittal form at room temperature within 72 hours of collection to Dana-
Farber Cancer Institute in Boston. 
 
CSF Sample Processing Protocol 
1. Collect 1mL-10 mL CSF in Streck Cell-Free DNA BCT Streck Tube 
2. Gently invert tube 10 times to ensure proper mixing of stabilization agent 
3. De-identify tube by removing all patient identifiers 
4. Label the tube with: 
a. Subject ID  
b. CTO registration ID 
c. Subject initials 
d. Date and time sample obtained  
e. Sample and Time point (ex: CSF C1D1)  
5. Send sample and transmittal form at room temperature within 72 hours of collection to Dana-
Farber Cancer Institute in Boston. 
 
 
After receipt at Dana-Farber Cancer Institute in Boston, biomarker blood, urine, and CSF samples 
will be processed and sent to the BROAD Institute via courier for Cell-Free DNA analysis. This will 
include next generation sequencing to identify genomic events associated with the cancer cells.  
 
Other Exploratory Biomarker Assessments Performed during the Study: During the study, in 
addition to the biomarkers specified above, exploratory biomarkers research may be conducted on 
any tumor and blood (including PK) samples. These studies would extend the search for other 
potential biomarkers relevant to the effects of the MEK162 drug and/or prediction of these effects 
and/or resistance to the treatment, and/or safety, and these additional investigations would be 
dependent upon clinical outcome, reagent and sample availability. While the goal of the biomarkers 
is to provide supportive data for the clinical study, there may be circumstances when a decision is 
made to stop a collection, or not perform or discontinue an analysis due to either practical or 
strategic reasons (e.g., inadequate sample number, issues related to the quality of the sample or 
issues related to the assay that preclude analysis, impossibility to perform correlative analyses, etc). 
Therefore, depending on the results obtained during the study, sample collection/analysis may be 
omitted at the discretion of the PI. 
 
Optional Additional Biomarker Assessments Using Remaining Tumor and/or Blood Samples: If the 
patient agrees, any remaining samples (tumor and blood) may be stored indefinitely and further 
analyzed to address scientific questions and/or development of biological tests related to MEK162 
and/or cancer. The decision to perform such exploratory biomarker research studies would be based 

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on outcome data from this study or from new scientific findings related to the drug class or disease, 
as well as reagent and assay availability (see appendices III, IV, V, VI, VII, VIII and IX). 
 
Pharmacodynamic and Biomarker Studies: Guidelines for Processing Biopsy Tumor Tissue Samples 
Tissue Handling:  The tissue should be kept frozen whenever possible by snap freezing via placement 
of tubes containing the tumor into a  -700C freezer or placement onto dry ice within 1 hour (sooner 
is better) and shipped immediately to Dr. Keith Ligon for molecular analysis (see address above). 
 
Immunohistochemistry will be performed at the lead site through Dr. Keith Ligon: pERK, pMEK, pS6 
expression will be determined by immunohistochemistry (IHC). If sufficient tissue is available, 
additional IHC studies will be performed. Oncopanel sequencing and copy array assays will be 
performed to test for v600E and BRAF rearrangements, respectively. Oncopanel sequencing will be 
performed at the CLIA-certified BWH CAMD Molecular Diagnostics Laboratory (Dr. Neal Lindeman, 
Director) and copy array testing will be performed in the CLIA-certified BWH CAMD Clinical 
Cytogenetics Lab (Dr. Azra Ligon, Director).  
 
Immunohistochemical Assay: Tissue will be fixed in 10% neutral buffered formalin for 6 to 24 hours 
(standard clinical fixation conditions). Samples will then be paraffin embedded, sectioned at a 
thickness of 5 microns, and adhered to Superfrost Plus slides (Fisher). The slides will be heated at 
37° overnight in a dry oven. Antigen retrieval will be performed by incubation of the sections in 
10ug/ml proteinase K in PBS for 10 minutes at room temperature. Antibodies to the specific target 
based on the vendor recommendations will be used. Appropriate controls as specified in the clinical 
laboratory will be included. Negative controls will be incubated with blocking serum alone. 
 
Sample Reporting: Results from the Oncopanel and Array CGH tests are CLIA certified and will be 
reported to the institution. Confirmation of receipt of the email containing these reports from CHLA 
is required. Non-CLIA certified laboratory results (e.g. IHC, cell free DNA, PD studies) will be 
maintained with unique codes to ensure that none of this information is returned to the patient’s 
medical record as per CHLA policy. 
 
Molecular Profiles: Additional molecular profiling will be performed if sufficient material remains. 
Results of all molecular studies below as well as results from the matched normal blood will be 
maintained with unique codes to ensure that none of this information is returned to the patient’s 
medical record as per CHLA policy. 
 
If additional material becomes available, repeat molecular analyses will be performed and compared 
to the original baseline studies. A comparison will be made to the original tumor sample to study the 
effect the treatment had on the tumor. 
 
If there is any tissue leftover after the optional analyses have been performed, the tissue will be 
stored and archived by Dr. Keith Ligon at DFCI within his research laboratory. This tissue may be 
used in the future if new molecular analyses tests become available. All samples will be stored in the 

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laboratory of Dr. Keith Ligon at the address above. Please see appendices III, IV, V, VI, VII, VIII, and IX 
for details regarding sample collection and storage. 
 
Samples for cell free DNA analysis will be shipped to Dr. Ligon centrally and the testing will be 
performed in the laboratory of Dr. Mimi Bandopadhayay at the Broad Institute. 
 
Samples for mass spectrometry imaging of drug in tumor tissue (0.3 cm3/300 mg sample) will be 
shipped to Dr. Ligon centrally and then testing will be performed in the laboratory of Dr. Nathalie 
Agar at the Brigham and Women’s Hospital. 
 
8.3 Ophthalmologic Studies 
 
For patients with tumors involving the optic pathway (including suprasellar/hypothalamic tumors) 
all of the assessments in this section are mandatory.  For patients with tumors not involving the 
optic pathway, the retinal evaluation assessments are mandatory, but institutional standard of care 
procedures may be substituted for visual acuity. 
 
Retinal Evaluation  
As retinal events and intra-ocular hypertension are well-described toxicities of MEK inhibition, all 
study participants must go regular ophthalmologic evaluation for the duration of study treatment. 
Examination will include visual acuity testing and indirect fundoscopy with attention to retinal 
abnormalities, especially RPED-like events and RVO. Slit lamp examination, visual field testing, 
intraocular pressure (IOP) measurement and ocular coherence tomography should be performed if 
feasible. Age appropriate methods of evaluation are permitted. Ophthalmologic examination must 
be performed by a pediatric ophthalmologist for all patients <12 years old. For patients with clinical 
suspicion of retinal abnormalities (i.e. photopsia, metamorphopsia, impairment of visual acuity, etc.) 
or RVO, additional assessments of fluorescein angiography and/or optical coherence tomography 
(OCT) should be performed. Images of OCT and fluorescein angiography should be sent to the 
investigative site along with the results of the exam and maintained in the patient’s source 
documentation file. 
 
Visual Acuity (best corrected) 
Teller acuity testing and/or ATS-HOTV must be attempted at each ophthalmology visit.  For patients 
able to cooperate with HOTV, both Teller acuity testing and HOTV must be performed together 
(same visit) at least once.  For patients who are literate and able to cooperate with Snellen visual 
acuity testing and whose tumors do not involve the optic pathway, Snellen may be performed in 
place of ATS-HOTV.   
 
If the VA data at a particular visit is felt to be unreliable due to poor cooperation, testing should 
be repeated in 1-2 weeks.  Only the visit believed to have yielded the most reliable data should be 
reported. 
 

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Teller acuity testing using TAC II cards will be performed in each eye separately at a distance of 
55cm in all subjects.   The tester will utilized the “Two down, one up” protocol to achieve the best 
visual acuity.  Acuity will be reported in cycles/cm by the site and converted by the operations 
center to logMAR.  Reasons for VA testing not being completed will be recorded. 
 
 
Table 8-5: Visual acuity in feet and logMAR equivalents for acuity in cycles/cm 
Card @ 55 cm 
(Cycles/cm) 
VA equivalent 
logMAR 
38 
20/16 
-0.10 
26 
20/24 
0.06 
19 
20/32 
0.20 
13 
20/47 
0.36 
9.8 
20/63 
0.49 
6.5 
20/94 
0.66 
4.8 
20/130 
0.80 
3.2 
20/190 
0.97 
2.4 
20/260 
1.10 
1.6 
20/380 
1.27 
1.3 
20/470 
1.36 
0.86 
20/710 
1.54 
0.64 
20/960 
1.67 
0.43 
20/1400 
1.84 
0.32 
20/1900 
1.97 
 
HOTV will be attempted on subjects who are old enough.  HOTV will be performed using the PEDIG 
ATS-HOTV computerized protocol in each eye separately at a distance of 3 meters in all subjects.26  
For subjects with severe visual impairment at baseline (20/400 or less) HOTV may be performed at a 
distance of 1 meter, with appropriate refractive correction.  Acuity will be reported in logMAR.  
Reasons for VA testing not being completed will be recorded. 
 
For primary analysis, the VA endpoint will be the difference between best-corrected VA and age-
based normal values (i.e. the age adjusted VA). 
 
Visual Fields 
Visual field testing will be performed by confrontation and reported as the number of quadrants (0, 
1, 2, 3, or 4) with VF deficits.  In addition, if feasible, Goldmann perimetry should be performed at 
baseline at the end of cycle 12 or at conclusion of therapy (whichever occurs first). 
 
Optic Discs 

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Optic discs will be assessed for the presence or absence of pallor and edema. 
 
 

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8.4 Patient Reported Outcomes (Phase II) 
For all subjects age > 24 months at the time of visit with at least one English or Spanish-speaking 
parent, an age-specific Parent Report PedsQLTM Brain Tumor Module (attached as Appendix XVIII) 
will be administered to one parent at the time points below. 
 
For all English or Spanish-speaking subjects age  > 5 years at the time of visit, an age-specific Self 
Report PedsQLTM Brain Tumor Module will be administered to the subject at the time points below. 
 
The appropriate PedsQLTM Brain Tumor Module will be administered at the cycle 1 day 1 visit  (or at 
a screening visit), on the day 1 visit of cycles 2, 4, and 7, and at end of cycle 12 or end of study 
therapy visit, whichever occurs first. 
 
The module should be selected based on the age of the subject at the time of module 
administration.   (For example, if a child reaches her eighth birthday during study participation, the 
“Parent Report for Young Children” and “Young Child Report” should be administered at the 
appropriate visits before her 8th birthday, and the “Parent Report for Children” and “Child Report” 
should be administered at the appropriate visits on or after her 8th birthday.) 
• Age ≥2 and <5 at the time of administration: Parent Report for Toddlers 
• Age ≥5 and <8: Parent Report for Young Children and Young Child Report. 
• Age ≥8 and <13: Parent Report for Children and Child Report 
• Age ≥13: Parent Report for Teens and Teen Report.   
 
 

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9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within the 2 weeks prior to start of protocol therapy. Scans 
and baseline ophthalmologic exam must be done ≤4 weeks prior to enrollment. In the event that the 
participant's condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
All study assessments and medications should be administered within +/-3 days of the protocol-
specified date, unless otherwise noted. 
 
Tumor samples should be submitted to the biological correlates laboratory within one week of 
enrollment 
Additional assessments may be required to monitor for AEs (see section 6.4) or as clinically indicated. 
 
Table 9-1: Phase I Required Observations  
See section 6.4 for toxicity monitoring observations 
 
Screening1 
Cycle 1 
Subsequent 
Cycles 
End of Tx 
30 day f/u 
Day of cycle16 
-28 to -1 
1 2 
8 
15 
22 
1 
Within 14 days 
of last dose 
 
Demographics2/informed 
consent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
Tumor sample 
X 
 
 
 
 
 
 
 
 
Medical history3 / current 
medical conditions 
X 
X  
 
 
 
X 
X 
 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
 
 
Height, weight 
X 
X  
 
 
 
X 
X 
 
Vital signs4 
X 
X  
X  
 
X 
X 
 
Physical examination5 
X 
X  
X  
 
X 
X 
 
Ophthalmologic 
examination6  
X 
 
 
 
 
 
X6 
X6 
X6 
Pregnancy test (females of 
child-bearing potential 
only)7 
X 
X  
 
 
 
X 
X 
 
Lansky/Karnofsky 
performance status 
(appendix X) 
X 
X  
 
 
 
X 
X 
 
ECG8 and table 9-2 
X 
X  
X X 
X 
X   
(table 9-2) 
X 
 
ECHO9 
X 
 
 
 
 
 
X9 
X 
 
 
Blood15 
Hematology10 
X 
X  
X X 
X 
X 
X 
 
Biochemistry 11, 
12, 13 
X 
X  
X X 
X 
X 
X 
 

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Screening1 
Cycle 1 
Subsequent 
Cycles 
End of Tx 
30 day f/u 
Day of cycle16 
-28 to -1 
1 2 
8 
15 
22 
1 
Within 14 days 
of last dose 
 
Coagulation 
profile 
(PT/PTT/INR) 
X 
X  
X X 
X 
X 
X 
 
Thyroid Function  
Tests14 
X 
 
 
 
 
 
X14 
X 
 
Urinalysis 
X 
X  
X X 
X 
X 
 
 
Radiologic tumor 
response/assessment 17 
X 
 
 
 
 
 
X17 
X17 
 
Pharmacokinetics  
 
Refer to Table 8-1 for detailed timeline 
 
 
Pharmacodynamic Studies 
/Biomarkers  
 
Refer to Table 8-2 for detailed timeline 
 
 
1 The screening examination should start with the Informed Consent procedure. The investigator is obliged to give the patient 
thorough information about the study and the study related assessments, and the patient should be given ample time to 
consider his or her participation. The investigator must not start any study related procedure before ICF is signed and dated by 
patient and/or parents (and impartial witness, if applicable) and investigator. 
2 Demographic data includes age, sex, ethnicity and race as well as other background or relevant medical history. Additionally, 
cancer characteristics; diagnosis, history, extent of cancer, prior anticancer treatments including surgery, radiotherapy, 
adjuvant and/or first-line metastatic immunotherapy, date of progression prior to study entry will also be collected.  
3 Significant findings that were present prior to the signing of informed consent must be included in the Relevant Medical 
History/Current Medical Conditions. Significant new findings that begin or worsen after informed consent must be recorded. 
4 Vital signs (heart rate, blood pressure (see appendix XI) and temperature) will be obtained in the same position, either sitting 
or supine, as appropriate prior to any blood collection. 
5 A full physical examination (PE) that evaluates all major organ systems will be performed at baseline. This should include a 
complete ophthalmologic and dermatologic exam. Subsequent PEs should be focused on sites of disease, clinical signs and 
symptoms, and include eye and skin exams.  
6 Ophthalmologic examination will be performed prior to initiation of therapy and at day 28 (+/- 1 week), and approximately 
every 8 weeks thereafter unless symptomatic or new abnormalities identified (see section 6.4). Patients completing all 12 cycles 
will have a 30 day follow-up examination while patients ending early will have an examination within 14 days of their last dose.  
Examination will include visual acuity testing and indirect fundoscopy with attention to retinal abnormalities, especially RPED-
like events and RVO. Slit lamp examination, visual field testing, intraocular pressure (IOP) measurement and ocular coherence 
tomography should be performed if feasible. Age appropriate methods of evaluation are permitted. For patients with clinical 
suspicion of retinal abnormalities (i.e. photopsia, metamorphopsia, impairment of visual acuity, etc.) or RVO, additional 
assessments of fluorescein angiography and/or optical coherence tomography (OCT) and electroretinogram (ERG) are 
mandatory. Images of OCT and fluorescein angiography should be sent to the investigative site along with the results of the 
exam and maintained in the patient’s source documentation file.  Ophthalmologic examination must be performed by a 
pediatric ophthalmologist for all patients <12 years old. 
7 To ensure patient safety, each pregnancy in a patient on study drug must be reported to Array BioPharma and the IRB within 
24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
8 A standard 12-lead ECG will be performed after the patient has been resting for 5-10 min. On cycle 1 day 1 (pre-dose) the ECG 
will provide a baseline value for each patient. If an abnormal ECG is obtained at any time, patient’s electrolytes must be 
reviewed and repeat ECG measurements must be done after correction of electrolyte abnormalities. Each ECG tracing should 
be labeled with the patient number, date, and kept in the source documents at the study site. Clinically significant 
abnormalities at screening should be recorded.   

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9 ECHO will be performed to determine cardiac ejection fraction at 4 and 8 weeks after initiation of therapy and every 12 weeks 
thereafter.  
10 Complete blood count (CBC) with differential - white blood count (WBC), absolute neutrophil count, lymphocyte, 
hemoglobin, hematocrit, and platelet count. 
11 Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, glucose, AST (SGOT), ALT (SGPT), total bilirubin (if 
abnormal, then direct and indirect bilirubin should be measured), LDH, albumin, calcium, magnesium, phosphate, alkaline 
phosphatase, and CK. 
12 CK and troponin will be performed at the same time points as the hematology collections as outlined above. Follow up for 
total creatine kinase (CK) ≥3 X ULN will include weekly assessment of isoenzymes and myoglobin in blood/or urine, and 
troponin as applicable. 
13 Bilirubin can be reported as direct and indirect, the sum of which will be counted as total. If only total bilirubin is reported to 
be within normal limits, reporting of direct and indirect fractions is not necessary. 
14 TSH level is recommended. If TSH abnormal, free T4 may be performed. For patients with known central hypothyroidism 
receiving thyroid supplementation, free T4 may be substituted for TSH level. Additional endocrinologic testing should be 
performed as clinically indicated 
15 Laboratory tests will be collected and analyzed as per institutional standards. Examinations may be performed more  
frequently at the investigator’s discretion if medically indicated; results should be recorded. At any time during the study, 
abnormal laboratory parameters which are clinically relevant (e.g., require dose modification and/or interruption of study drug, 
lead to clinical symptoms or signs, or require therapeutic intervention), whether specifically requested in the protocol or not, 
must be recorded. 
 
16 For all visits, there is a ± 3 days window on assessments to take into account scheduling over public or religious holidays if not 
explicitly specified otherwise. Laboratory assessments that were completed within 72 hours of Cycle 1, Day 1 (C1D1) do not 
need to be repeated. 
 
17 Imaging to assess response will be obtained on day 1 of the following cycles (+/- 1 week for cycle 2, +/- 2 weeks thereafter): 
cycle 2, cycle 4, cycle 7, and cycle 10, and within 28 days following completion of study treatment. Recommended follow-up for 
patients that complete therapy, including medical evaluation and MRI, will occur approximately every 3 months (can be more 
or less frequent) for the first year and then approximately yearly until progression or change of therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 9-2: Phase I ECG Assessments 
Scheduled time points (hours) 
Screening 
Anytime during the screening period 
Cycle 
Day 
Sampling time  
1 
1 
pre-dose 
1 
1 
2h post-dose (± 1hr) 
1 
1 
4h post-dose (± 1hr) 
1 
8 
pre-dose  
1 
15 
pre-dose  
1 
15 
2h post-dose (± 1hr) 
1 
22 
pre-dose 
1 
22 
2h post-dose (± 1hr) 
1 
22 
4h post-dose (± 1hr) 
2 
1 
pre-dose 
2 
15 
Anytime during visit 
C3-6 
1 
Anytime during visit 
End of Tx 
Within 14 days of last dose 
Other 
 
As clinically indicated 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 9-3: Phase II Required Observations 
See section 6.4 for toxicity monitoring observations 
 
 
Screening
1 
Cycle 1 
Subsequent Cycles 
(Through end of cycle 12; 
see Table 9-4 for 
participants receiving 
continuation therapy) 
End of Treatment 
(see Table 9-4 for 
participants receiving 
continuation therapy) 
Disease 
Progressio
n f/u  
Day of cycle14, 15 
-28 to -1 
1 2 15 
1 
Within 14 days of last 
dose, unless 
otherwise noted 
 
Demographics2/informed 
consent 
X 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
Tumor sample 
X 
 
 
 
 
 
 
Medical history3 / current 
medical conditions 
X 
X  
 
X 
X 
X 
Prior antineoplastic therapy 
X 
 
 
 
 
 
 
Height, weight 
X 
X  
 
X 
X 
 
Vital signs4 
X 
X  
 
X 
X 
 
Physical examination5 
X 
X  
 
X 
X 
 
Ophthalmologic examination6  
X 
 
 
 
X6 
X6 
 
Pregnancy test (females of 
child-bearing potential only)7 
X 
X  
 
X 
X 
 
Lansky/Karnofsky performance 
status (appendix X) 
X 
X  
 
X 
X 
 
ECHO and EKG8,9 
X 
 
 
 
X9 
X 
 
 
Blood12 
Hematology10 
X 
X  
X 
X 
X 
 
Biochemistry 11 
X 
X  
X 
X 
X 
 
Urinalysis 
X 
X  
X 
X 
 
 
Radiologic tumor 
response/assessment 13 
X 
 
 
 
X13 
X13 
X 
Pharmacokinetics 
 
Refer to Table 8-1 for detailed timeline 
 
 
Pharmacodynamic Studies 
/Biomarkers  
 
Refer to Table 8-2 for detailed timeline 
 
 
PedsQL Brain Tumor Module 16 
X 
Refer to Section 8.4 
X 
 
 
1 The screening examination should start with the Informed Consent procedure. The investigator is obliged to give the patient 
thorough information about the study and the study related assessments, and the patient should be given ample time to 
consider his or her participation. The investigator must not start any study related procedure before ICF is signed and dated by 
patient and/or parents (and impartial witness, if applicable) and investigator. 
2 Demographic data includes age, sex, ethnicity and race as well as other background or relevant medical history. Additionally, 
cancer characteristics; diagnosis, history, extent of cancer, prior anticancer treatments including surgery, radiotherapy, 
adjuvant and/or first-line metastatic immunotherapy, date of progression prior to study entry will also be collected.  
3 Significant findings that were present prior to the signing of informed consent must be included in the Relevant Medical 
History/Current Medical Conditions. Significant new findings that begin or worsen after informed consent must be recorded. 
4 Vital signs (heart rate, blood pressure (see appendix XI) and temperature) will be obtained in the same position, either sitting 
or supine, as appropriate prior to any blood collection. 

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5 A full physical examination (PE) that evaluates all major organ systems will be performed at baseline. This should include a 
complete ophthalmologic, neurologic and dermatologic exam. Subsequent PEs should be focused on sites of disease, clinical 
signs and symptoms, and include neurologic, eye and skin exams.  
6 Ophthalmologic examination will be performed prior to initiation of therapy and at the end of cycle 1 (+/- 1 week), on day 1 of 
cycle 4 (+/- 2 weeks), and approximately every 12 weeks thereafter unless symptomatic or new abnormalities identified (see 
section 6.4). Patients completing all 12 cycles and discontinuing therapy will have a follow-up examination within 30 days of  
cycle 12 day 28, while patients ending early will have an examination within 14 days of their last dose. For patients continuing 
past 12 cycles see Table 9-4.  See section 8.3 for details of the ophthalmologic evaluation.  
7 To ensure patient safety, each pregnancy in a patient on study drug must be reported to Array BioPharma  and the IRB within 
24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
8 A standard 12-lead ECG will be performed at baseline and at the end of cycles 1, 3, 6 and 12, and/or within 30 days of 
discontinuing study treatment. If an abnormal ECG is obtained at any time, patient’s electrolytes must be reviewed and repeat 
ECG measurements must be done after correction of electrolyte abnormalities. Each ECG tracing should be labeled with the 
patient number, date, and kept in the source documents at the study site. Clinically significant abnormalities should be 
recorded.   
9 ECHO will be performed to determine cardiac ejection fraction at baseline and at the end (+/- 7 days) of cycles 1, 3, 6, 9 and 
12, and/or within 30 days of discontinuing study treatment.   
10 Complete blood count (CBC) with differential - white blood count (WBC), absolute neutrophil count, lymphocyte, 
hemoglobin, hematocrit, and platelet count. 
11 Sodium, potassium, chloride, bicarbonate, urea or BUN, creatinine, glucose, AST (SGOT), ALT (SGPT), total bilirubin (if 
abnormal, then direct and indirect bilirubin should be measured), LDH, albumin, calcium, magnesium, phosphate, alkaline 
phosphatase, and CK.  See section 6.4 for follow-up evaluation if CK > 3X ULN.   
12 Laboratory tests will be collected and analyzed as per institutional standards. Examinations may be performed more 
frequently at the investigator’s discretion if medically indicated; results should be recorded. At any time during the study, 
abnormal laboratory parameters which are clinically relevant (e.g., require dose modification and/or interruption of study drug, 
lead to clinical symptoms or signs, or require therapeutic intervention), whether specifically requested in the protocol or not, 
must be recorded. 
13 Imaging to assess response will be obtained on day 1 of the following cycles (+/- 1 week for cycle 2, +/- 2 weeks 
thereafter): cycle 2, cycle 4, cycle 7, and cycle 10, and within 30 days following completion of study treatment. 
Cycle 2 imaging assessment is optional. Recommended follow-up for patients that complete therapy, including 
medical evaluation and MRI, will occur approximately every 3 months (can be more or less frequent) for the first 
year and then approximately yearly until progression or change of therapy. 
14 For all visits, there is a ± 3 days window on assessments to take into account scheduling over public or religious holidays if not 
explicitly specified otherwise. Laboratory assessments that were completed within 72 hours of Cycle 1, Day 1 (C1D1) do not 
need to be repeated.   
15 For patients enrolled on the target validation stratum, all screening evaluations should be repeated prior to beginning post-
operative cycle 1.  If eligibility criteria (excluding surgical time windows) are not met, postoperative cycle 1 day 1 should be 
delayed up to 30 days until all eligibility criteria are met.   
16 PedsQL brain tumor module will be administered at screening on day 1 of cycles 1, 2, 4, and 7each subsequent cycle, and at 
the end of cycle 12 or aton the off therapy visit (whichever occurs first).  See section 8.4. 
 
 
 
 
Table 9-4: Year 2 (Cycles 13-24) Required Observations 
  

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Cycle 13 
Cycle 16 
Cycle 19 
 
Cycle 22 
End of Treatment 
See Table 9-3 or 
Table 9-1 
 
 
 
Day 1 of cycle (+/- 2  weeks) 
1 
1 
1 
1 
 
Medical history / current medical conditions 
X 
X 
X 
X 
 
Height, weight 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
 
Ophthalmologic examination (section 8.3) 
X 
 
X 
 
 
Pregnancy test (females of child-bearing 
potential only) 
X 
X 
X 
X 
 
Lansky/Karnofsky performance status (appendix 
X) 
X 
X 
X 
X 
 
ECHO  
X 
X 
X 
X 
 
CBC, differential, platelets 
X 
X 
X 
X 
 
BUN, creatinine, glucose, albumin, total protein, 
alkaline phosphatase, AST, ALT, bilirubin, CK 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
 
Radiologic tumor response/assessment  
X 
X 
X 
X 
 
 
 
 

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10. IMAGING PARAMETERS AND RESPONSE CRITERIA 
 
10.1 General Considerations 
The overall response assessment takes into account response in the target lesion, and the 
appearance of new lesions, where applicable, according to the criteria described in the table below. 
The overall response assessment is shown in the last column, and depends on the assessments of 
target, non-target, and new lesions in the preceding columns. 
 
For this study, comparison of maximal 2-dimensional measurements, TxW (product of the longest 
diameter [width (W)] and its longest perpendicular diameter [transverse (T)] will be used for 
Response Criteria for Target Lesions. 
 
Imaging: Standard MRI evaluation is required for disease evaluation as per institutional imaging 
parameters. Both 1.5T and 3.0 T magnets are acceptable. 
 
Additional Imaging Studies:  MR diffusion-weighted imaging (DWI), dynamic contrast-enhanced 
(DCE), and T1 permeability perfusion MRI, and MR spectroscopy (MRS) are recommended as part of 
standard of care at each evaluation period. The data obtained from these studies will be correlated 
with patient response and outcome in an exploratory analysis. 
 
10.2 Measurement of Effect 
Methods for Evaluation of Measurable Disease: Whole Brain MRI With and Without Contrast.   For 
target tumors outside the brain, clinically appropriate imaging modalities may be added or 
substituted. 
 
The following sequences incorporate the standard CNS imaging protocol. Institutional brain tumor 
or solid tumor imaging protocols can be substituted as long as similar disease evaluation is possible. 
 
10.3 Imaging Sequences 
Imaging Sequences 1.5 T 
Sequence 
Slice 
Thickness 
TR  
(ms) 
TE  
(ms) 
TI  
(ms) 
Directions 
B0 
FOV (cm) 
Matrix 
Sagittal T1 
5 mm skip 1 
400 
9 
  
  
  
22 
256 x 256 
Axial FSE T2 
2 mm skip 0  
3800 
102 
  
  
  
20 
256 x 256 
Axial T2 FLAIR 
4 mm skip 0 
10000 
160 
2200 
  
  
20 
256 x 224 
Axial diffusion 
2.5 mm skip 0 
  
  
  
12-30 
1000 
26 
128 x 128 
single shot 
Sagittal T2 
3 mm skip 1 
3800 
102 
  
  
  
22 
256 x 256 
Axial MPGR 
4 mm skip 0 
  
  
  
  
  
  
  

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Axial T1 
4 mm skip 0  
500 
min 
  
  
  
20 
320 x 224 
Axial T1  
with contrast 
4 mm skip 0 
500 
min 
  
  
  
20 
320 x 224 
Sagittal T1 FSPGR 
with contrast 
1.5 mm skip 0 
  
min, flip 
angle 
15 
  
  
  
24 
256 x 256 
T1 permeability 
perfusion 
sequence 
5 mm skip 0  
(See below) 
  
  
  
  
  
  
  
Single-voxel MR 
Spectroscopy 
PRESS 
Volume: 
15x15x15 
mm3 
1500
ms 
35ms 
 
 
 
 
 
Imaging Sequences 3.0 T 
Sequence 
Slice Thickness 
TR 
(ms) 
TE 
(ms) 
Directions 
Sagittal T1 MPRAGE 
1.0 mm skip 0 
2530 
    
Sagittal T2 
3.0 mm skip 1.0 mm 
  
    
Axial T2 
2.5 mm no skip 
11730 
91   
Axial T2 FLAIR 
4 mm, no skip 
9000 
137   
Axial diffusion 
2 skip 0 
9100 
88 
30 
Sagittal MPRAGE  
1.0 mm no skip 
  
    
Axial T1 post contrast 
4.0 mm skip 0 
650 
9.7   
Axial SWI 
1.25 mm no skip  
  
    
T1 permeability  
perfusion sequence 
5 mm skip 0 (See Below) 
  
    
Single-voxel MR Spectroscopy 
PRESS 
Volume: 15x15x15 mm3 
2000
ms 
35ms  
 
T1 Permeability Imaging 
T1 permeability should begin with a set of T1 maps with flip angles of 2, 5, 10, and 15 followed by 
the T1 permeability sequence. After the T1 map sequence with 15-degree flip angle, start the T1 
permeability series and 20 seconds into it inject 0.1 mmol/kg of intravenous contrast. See below. 
 
3D T1W Specifications for T1 Maps and Dynamic Series 
Sequence type 
Spoiled gradient echo 
Imaging mode 
3D 
Slice orientation 
Axial 
Frequency direction 
A/P 
Phase direction 
R/L 
FOV - frequency 
220 mm 

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FOV - phase 
220 mm 
Matrix - frequency 
256 
Matrix - phase 
160-192 
In-plane resolution 
≤ 1 mm 
Fat-suppression 
No Fat Sat 
TR 
~4 msec  
TE 
Less than 2 msec or min full 
TI (STIR sequence) 
N/A 
Flip Angle 
DCE -15 degrees; T1 maps - 2, 5, 10 and 15 
Slice thickness (acquired, not interpolated) 
5mm, maximum 6mm  
Number of slices 
Minimum 10  prior to zero fill 
Slice Gap 
No gap 
Parallel imaging factor 
≤ 2 
Number of averages  
1 for DCE, 2 for T1 maps 
k-space ordering 
standard, non-centric  
Temporal Resolution of “T1 DCE”: (seconds per 
phase/measurement) 
≤ 6 seconds 
“T1 DCE” imaging duration 
≥ 5 minutes  
 
 
 
10.4 Response Assessment 
The overall response assessment takes into account response in the target lesion(s), and the 
appearance of new lesions, where applicable, according to the criteria described in the table below. 
The overall response assessment is shown in the last column, and depends on the assessments of 
target, non-target, and new lesions in the preceding columns. 
 
 
 
 
 
 
T1 Maps / DCE 
Series Name 
Sequence 
Flip Angle 
Notes 
T1 map15 
3D fast GRE 
15 degrees 
Axial, 2 NEX 
T1 map10 
3D fast GRE 
10 degrees 
Axial, 2 NEX 
T1 map05 
3D fast GRE 
5 degrees 
Axial, 2 NEX 
T1 map02 
3D fast GRE 
2 degrees 
Axial, 2 NEX 
T1 DCE 
Dynamic Series, 3D 
fast GRE 
15 degrees 
Axial, 1 NEX,  
inject 20 sec into this 

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Table 10-1: Response Criteria for Target Lesions 
Target Lesion(s) 
New Lesions* 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
MR (phase II only) 
No 
MR 
SD 
No 
SD 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as "symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): The disappearance of all abnormal signal 
• 
Partial Response (PR): x≥50% decrease in the sum of the products of the two perpendicular 
diameters of the target lesion(s), taking as reference the initial baseline measurements. 
• 
Minor Response (MR) Phase II only: ≥25% and <50% decrease in the sum of the products of 
the two perpendicular diameters of the target lesion(s), taking as reference the initial 
baseline measurements. 
• 
Stable Disease (SD): Neither sufficient decrease in the products of the two perpendicular 
diameters of the target lesion(s) to qualify for PR or minor response, taking as reference the 
initial baseline measurements, nor sufficient increase in the target lesion(s) to qualify for PD, 
taking as reference the smallest disease measurement since the treatment started. 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products of the two 
largest perpendicular diameters of the target lesion(s), taking as reference the smallest 
product observed since the start of treatment; or the appearance of one or more new 
lesions; or (for the phase II study only) new clinical symptoms that are clearly related to 
disease progression.  For progressive disease by clinical criteria, confirmatory imaging 
studies should be obtained when feasible. 
• 
Unevaluable (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
Note: If tumor response data is missing for target lesions, the overall assessment must 
be UN unless there is new disease that would result in an overall assessment of PD. 
However, if there is missing or unevaluable data for non-target lesions, but data is 

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available for all target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment of CR cannot be 
made if there is missing or unevaluable data for non-target lesions. In this case, the 
overall assessment would be PR. 
 
*Definition of New Lesion 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, 
imaging modality, or findings thought to represent something other than tumor (ex: new bone 
lesions may be healing or flare of pre-existing lesions). However, a lesion identified on a follow-up 
scan in an anatomical location that was not scanned at baseline is considered new and will indicate 
PD. If a new lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the date of the 
initial scan on which the lesion was discovered. 
 
10.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started. 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
 
Progression-Free and Overall Survival: Progression-Free Survival (PFS) is defined as the duration of time 
from patient enrollment to time of objective disease progression or death from any cause.x 
 
Overall Survival (OS): Overall survival is defined as the duration of time from patient enrollment to 
time of death from any cause. 
 
 
 

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10.6 Central Review 
All responses will be reviewed at the end of the trial. Optional imaging studies will also be reviewed 
at the end of the trial. Images should be loaded onto CDs and forwarded to the data-imaging center 
at: 
  
Children’s Hospital Los Angeles 
c/o Jasmine Pauly 
Clinical Trials Office 
4650 Sunset Boulevard, MS#54 
Los Angeles, CA 90027 
 
All images (DICOM) should be saved on a CD and mailed to Children’s Hospital Los Angeles. Data 
must be anonymized and the appropriate study identifier must be added. Studies will be stored in 
an anonymized form on the secure hospital PACS system research site. For diffusion images, raw 
images and ADC maps should be sent. T1 permeability T1 maps and sequence should be sent. For 
MR spectroscopy, the raw data should be sent. Also, the position of the region of interest (ROI) used 
for the MRS acquisition should be documented. At the end of the study, images will be evaluated by 
central review including assessments of standard MR imaging parameters such as tumor signal 
intensity, absence or presence of blood products, size of tumor, and size of enhancement. 
Assessment of tumor cellularity will be done by diffusion imaging analyses of the tumor assessing 
ADC (both 2D and 3D), fractional anisotropy values, and involvement of key white matter tracts. 
Perfusion analyses will assess cerebral blood volume and permeability coefficient (ktrans) within the 
tumor. MRS data will be analyzed at CHLA using LCModel software. Association between imaging 
parameters and outcome will be assessed. 
 
 

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11. ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 Adverse Event (AE) 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.  
The severity rating of an AE refers to its intensity. The severity of each AE will be determined by the 
Investigator using the NCI CTCAE. For any term that is not specifically listed in the CTCAE scale, 
intensity should be assigned a Grade of 1 through 5 using the following CTCAE guidelines: 
 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Fatal 
Expectedness: Adverse events can be “Expected” or “Unexpected.” An assessment of causal 
relationship of study drug to each AE must be performed by the Investigator. Medical judgment 
should be used to determine the cause of the AE, considering all relevant factors such as (but not 
limited to) the underlying study indication, coexisting disease, concomitant medication, relevant 
history, pattern of the AE, temporal relationship to the study medication and de-challenge or re-
challenge 
 
Expected adverse event: Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk. 
 
Unexpected adverse event: For the purposes of this study, an adverse event is considered 
unexpected when it varies in nature, intensity or frequency from information provided in the 
current adverse event list, the Investigator’s Brochure, the package insert or when it is not included 
in the informed consent document as a potential risk.   
 

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Attribution: Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows: 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment.  
 
Unlikely - The AE is doubtfully related to the study treatment. 
 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
11.2 Serious Adverse Event (SAE) 
An AE is considered “serious” if it results in any of the following outcomes: 
 
• 
Results in Death: Death is an outcome of an SAE and not an SAE in itself. Death should only be 
reported as an SAE term when no additional information is known about a fatal event. When 
death is an outcome, the event(s) resulting in death should be reported (e.g., “pulmonary 
embolism” with a fatal outcome) and assigned severity Grade 5. 
• 
Is immediately life-threatening (its occurrence places the patient at immediate risk of death. It 
does not include an event that, had it occurred in a more severe form, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalization includes any hospital admission, even if for less than 24 hours. The following do 
not meet hospitalization serious criteria:  
 
A visit to the emergency room, or outpatient observation that does not result in 
admission 
 
Elective surgery, planned prior to signing consent 
 
Routine health assessment requiring admission 
 
• 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
Is a congenital anomaly/birth defect. 
• 
Based upon appropriate medical judgment, represents an important medical event that may 
jeopardize the patient or may require intervention to prevent one of the outcomes described 
above. 

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11.3 Procedures for AE and SAE Recording and Reporting 
All SAEs occurring in patients from the first dose of Array study drug until 30 days after the last dose 
of study drug must be reported to Array BioPharma Inc. within 24 hours of the Investigator’s 
knowledge by faxing a completed SAE form to Array BioPharma Inc. at the number provided on the 
SAE form or fax cover sheet.  SAEs occurring greater than 30 days after the last dose of Array study 
drug should be reported to Array BioPharma Inc. only if considered related to the Array product. 
 
If new information becomes available for a previously reported SAE, a follow-up SAE report should 
be sent within 24 hours. The follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, and whether the patient continued or withdrew from study 
participation. 
 
Suspected unexpected serious adverse reactions (SUSARs) will be collected and reported by the 
Sponsor and/or designee to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
Reporting: Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time-points during the study. 
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded in 
the participant’s medical record and on the appropriate study-specific case report forms.  
 
The descriptions and grading scales found in the CTEP Version 4.03 of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. The CTEP Version 4.03 of the 
CTCAE is identified and located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE. 
Monitoring will occur before the clinical phase of the protocol begins and continue during protocol 
performance and completion.    
 
Each participating investigator is required to abide by the reporting requirements set by CHLA. The 
study must be conducted in compliance with FDA regulations, local safety reporting requirements, 
and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious adverse 
events to the study sponsor and/or others as described below.  
 
All serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the CHLA Study Chair on the local 

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institutional SAE form. This includes events in the table below. Investigators at CHLA will report SAEs 
directly to the CHLA IRB. Other investigative sites will report SAEs to their respective IRB according 
to the local IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the CHLA Study Chair within the timeframes detailed 
in the table below.  
 
Table 11-1 Reportable AEs 
 
 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE  
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days 
 
5 calendar days 
 
24 hours* 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of 
the last intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
The CHLA Study Chair will submit SAE reports from outside institutions to the CHLA IRB according to 
CHLA IRB policies and procedures in reporting adverse events. 
 
Report serious adverse events by telephone, email, or facsimile to: 
 
 
Nathan J. Robison, MD 
Tel (323) 361-8147 
nrobison@chla.usc.edu 
Fax (323) 361-7128 
 
Within the following 48 hours, the participating investigator must provide follow-up information on 
the serious adverse event. Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will continue or 
discontinue study participation. 
 
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the CHLA Study Chair on the toxicity Case Report 
Forms.   
 
Reporting to the Institutional Review Board (IRB) 

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Investigators at CHLA will report all serious adverse events directly to the CHLA IRB. 
 
Other investigative sites should report serious adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to: 
 
 
Nathan J. Robison, MD 
 
Tel (323) 361-8147 
 
nrobison@chla.usc.edu 
 
Fax (323) 361-7128 
 
The CHLA Principal Investigator will submit SAE reports from outside institutions to the CHLA IRB 
according to CHLA IRB policies and procedures in reporting adverse events.  
 
Reporting to the Food and Drug Administration (FDA) 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event that 
meets the FDA’s criteria for expedited reporting following the reporting requirements and timelines 
set by the FDA. Events will be reported to the FDA by mail using Form FDA 3500A (Mandatory 
Reporting Form for investigational agents) or FDA Form 3500 (Voluntary Reporting Form for 
commercial agents). Forms are available at http://www.fda.gov/medwatch/getforms.htm. 
 
Reporting to Study Investigators 
All multicenter site investigators will be notified in a timely fashion of any SAE reported to the FDA.  
In most cases this will be no later than 24 hours after communication with the FDA.   
 
Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
 
Pregnancy or Drug Exposure during Pregnancy 
Pregnancies (both those of female patients and female partners of male patients) must be reported 
to Array BioPharma Inc. or designee within 24 hours of the Investigator’s knowledge. All pregnancies 
should be followed through to outcome and the outcome must be reported to Array BioPharma Inc.  
Pregnancies themselves are not considered AEs or SAEs. However, any AEs or SAEs occurring during 
pregnancy are to be reported following AE and SAE reporting guidelines. 
 
Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of 
study intervention, throughout the study, and within 30 days of the last study intervention should 
be followed to their resolution, or until the participating investigator assesses them as stable, or the 
participating investigator determines the event to be irreversible, or the participant is lost to follow-

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up. The presence and resolution of AEs and SAEs (with dates) should be documented on the 
appropriate case report form and recorded in the participant’s medical record to facilitate source 
data verification. 
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring 
visit to obtain additional case details deemed necessary to appropriately evaluate the SAE report 
(e.g., hospital discharge summary, consultant report, or autopsy report). 
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. Participating investigators should notify the CHLA Study Chair 
and their respective IRB of any unanticipated death or adverse event occurring after a participant 
has discontinued or terminated study participation that may reasonably be related to the study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12. DATA AND SAFETY MONITORING 
 
12.1 Data Reporting 
The CHLA Clinical Trials Office (CTO) will collect, manage, and monitor data for this study.  
 
12.2 Data Submission 
The schedule for completion and submission of case report forms is as follows: 
 
Table 12-1: Data Submission Timelines 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration 
On Study Forms 
Within 14 days of registration 
Baseline Assessment Forms 
Within 14 days of registration 
Treatment Forms 
Within 10 days of the last day of the cycle 
Adverse Event Report Forms 
Within 10 days of the last day of the cycle 
DLT reporting  
Within 48 hours of the event 
Response Assessment Forms 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Forms 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Forms 
Within 14 days of the protocol defined follow up 
visit date or call 
All study data will be submitted via electronic data capture forms using the DataLabs Website. 
Please refer to the DataLabs user manual or contact the CHLA Operations Center if you need 
assistance.  
 
12.3 Weekly Safety Review 
The CHLA Study Operations Center conducts weekly (as needed) patient safety and review meetings 
with the protocol chair, research coordinators and other administrative team members to review all 
data submitted, non-serious adverse events and other correspondence pertaining to patients. 
Serious adverse events will be immediately evaluated by the study team and determination 
regarding notification of participating site will be made. All serious events will be sent to the CHLA 
IRB and DSMC if required. Any interim results that would affect patient safety would be immediately 
communicated to all participating sites. All correspondence with sites will be done via email. 
 
 

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12.4 Data Safety Monitoring Committee 
An independent four member Data and Safety  Monitoring Committee (DSMC) will review and 
monitor toxicity and accrual data from this trial. The committee is composed of clinical specialists 
who have no direct relationship with the study. Standing meetings will occur every 6 months. 
Information that raises any questions about participant safety will be addressed with the Principal 
Investigator and study team. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 
days, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request. After DSMC review, the DSMC will issue a 
confidential report to the study PI and the CHLA operations center.  
 
No more than 8 weeks after the DSMC meeting, a DSMC public review report will be created after 
approval of the confidential report and resolution of any issues by the PI. The public report will then 
be emailed to the participating sites for each study. These can be filed at the IRB at each site, in 
accordance with local IRB guidelines and requirements.  
 
12.5 Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the CHLA Study 
Chair (or Protocol Chair) or CHLA. The purpose of these audits or inspections is to examine study-
related activities and documents to determine whether these activities were conducted and data 
were recorded, analyzed, and accurately reported in accordance with the protocol, institutional 
policy, and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements.  
 
Tom-Belle Davidson, MD, will the Medical Monitor for this study. She is a qualified physician and is 
not associated with this particular protocol. She will work closely with the Principal Investigator to 
monitor the participants’ treatment while on this study.  
 
For research determined to be greater than minimal risk, DODI 3216.02 requires that the IRB 
approve, by name, an independent medical monitor with expertise consonant with the nature of 
risk(s) identified within the research protocol. The IRB must approve a written summary of the 
research/medical monitors’ duties, authorities, and responsibilities. The medical monitor’s duties 
should be based on specific risks or concerns about the research. The medical monitor may perform 
oversight functions and report their observations and findings to the IRB or a designated official. The 
medical monitor may be identified from within or outside the PI’s institution. 
 

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Medical 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 medical 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 medical 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 medical 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 medical 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 
medical monitor should also indicate whether he/she concurs with the details of the report 
provided by the study investigator. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. REGULATORY CONSIDERATIONS 
 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed, and approved by a properly constituted IRB governing each study 
location.  
 
Any changes made to the protocol must be submitted as amendments and must be approved by 
the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The 
CHLA Study Chair (or Protocol Chair) will disseminate protocol amendment information to all 
participating investigators.  
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
13.2 Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained before 
the participant is involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and by the person 
obtaining the consent. The participant must be given a copy of the signed and dated consent 
document. The original signed copy of the consent document must be retained in the medical 
record or research file.  
 
13.3 Ethics 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
• 
State laws 
• 
CHLA research policies and procedures  
• 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
 
13.4 Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 

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Original source documents supporting entries in the case report forms include but are not limited to 
hospital records, clinical charts, laboratory and pharmacy records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
 
13.5 Records Retention 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. Study-related documents will be stored in 
a secured location accessible only to the investigators and formally designated study personnel.  
 
13.6 Multi-Center Guidelines 
This protocol will adhere to the policies and requirements of Children’s Hospital Los Angeles (CHLA).  
 
The CHLA Study Chair/Coordinating Center is responsible for distributing all IND Action Letters or 
Safety Reports to all participating institutions for submission to their individual IRBs. 
 
Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse event 
reporting at each site.  
 
Except in very unusual circumstances, each participating institution will order the agent(s) directly 
from the supplier. A participating site may order the agent(s) only after the initial IRB 
approval for the site has been forwarded to the Coordinating Center.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14. STATISTICAL CONSIDERATIONS 
 
14.1 Primary Endpoints 
The primary endpoint for the Phase I portion of the study is dose limiting toxicity during the first 
course of therapy, as defined in section 6.4. 
 
The primary endpoint for the Phase II portion of the study is best overall response (BOR) during the 
first 12 cycles (nominally 48 weeks) of treatment.  BOR will be assessed through the time of the 
post-12th cycle tumor assessment, or through the last tumor assessment time during this nominal 
period for patients in follow-up  but who have withdrawn from protocol therapy, or through the last 
available tumor assessment for patients who are lost to follow-up during this time.  The percent 
change in tumor sizes compared to baseline will be recorded at each evaluation time and will be 
used to define the categorical BOR as described below, per the definition of CR, PR, MR, SD, and PD 
in section 10.4. 
• 
For tumors that regress compared to baseline during the assessment period without first 
satisfying the criteria for progressive disease (PD), BOR will be defined at the nadir of the 
tumor size compared to baseline provided that the percent reduction at the nadir satisfies 
the definition of CR, PR, or MR per section 10.4, with the BOR value of CR, PR, or MR 
determined by the percent reduction at this time. The associated time of BOR will also be 
recorded. 
• 
For tumors that progress compared to baseline and satisfy the definition of PD without first 
satisfying the criterion at least for minor response (MR), BOR will be defined at the first time 
at which the percent increase in tumor size compared to baseline satisfies the criterion for 
PD. The BOR value will be PD.  The associated time of BOR will also be recorded. 
• 
For tumors that neither regress sufficient to satisfy the criterion for MR nor progress 
sufficiently to satisfy the criterion for PD during the assessment period, the BOR value will 
be SD. The time associated with BOR will be the last evaluation time during the 48 week 
evaluation period.  
 
Patients will be considered evaluable for BOR if they have received at least one dose of treatment 
and have at least one post baseline tumor assessment.  
 
14.2 Secondary Endpoints 
Secondary endpoints for Phase I include the grade and duration of CTCAE toxicities observed during 
treatment. 
The concentration of MEK162 and its metabolite (AR00426032) in blood drawn at specified time-
points (Table 8-1).   
 
Secondary endpoints for Phase II include: 
• 
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• 
Time to event, defined as the time from start of treatment to the first occurrence of tumor 
recurrence, tumor progression, occurrence of a second malignancy, or death from any 
cause. Patients event-free at last follow-up will be censored in analysis. 
• 
Time to tumor recurrence/progression, defined as the time from start of treatment to the 
first occurrence of tumor recurrence, tumor progression, or death from disease. Patients 
without tumor recurrence at last follow-up, or who experience a second malignancy, or who 
die for causes unequivocally unrelated to tumor recurrence, will be censored in analysis. 
• 
The concentration of investigational compound in tumor tissue after treatment with 
MEK162.  
• 
Immunohistochemical assessment of PD effects on Ras/Raf/MEK/ERK pathway inhibition 
within tumor tissue (Strata 4 only) as measured by ERK phosphorylation before and after 
treatment with MEK162 for 7-14 days. Blood pharmacodynamic assessment will also be 
performed and correlated with tumor results. 
 
14.3 Study Design for Phase I 
Dose levels and starting dose are described in section 6.2. Patients  will  be  enrolled  according  to  a 
3+3  dose  escalation  design. In brief, three patients will initially be enrolled and treated at starting 
dose level 1. If no DLTs are observed, dose will be escalated to dose level 2. If 1 DLT is observed, 
three additional patient will be enrolled to dose level 1. If at most 1 DLT is observed in six patients 
during course 1 of treatment then the dose will be escalated to dose level 2. If 2 or more DLTs are 
observed at a dose level, then the dose will be de-escalated. The MTD will be the maximum dose at 
which 6 patients have been treated and no more than 1 DLT has been observed. Refer to Appendix 
XV for a detailed description of the escalation rules.  
 
To be considered DLT-evaluable, a patient must either have experienced an adverse event meeting 
DLT criteria during the first cycle of treatment, or have received at least 85% of doses in the first 
cycle. Only DLT-evaluable patients will be considered for dose escalation determinations.   
 
14.4 Study Design for Phase II and Target Validation 
For Strata 1 through 3, the Phase II study is viewed as three distinct Phase II studies, one 
corresponding to each of the three strata described in section 1. Each will be a single cohort study 
using best overall response (BOR – section 14.1) as the primary endpoint. While the primary analysis 
will be in the intent-to-treat (ITT) cohort – i.e., including all patients who are BOR evaluable per 
section 14.1, target accrual will be in terms of BOR -evaluable patients with sufficient treatment 
(BORwST), defined as receiving at least 12 weeks of treatment or experiencing disease progression 
or death prior to 12 weeks. For the Target Validation Stratum 4, tumor resection prohibits 
evaluation of BOR as described above, so that analysis tumor response in this stratum will be 
descriptive. 
 
Each of Stratum 1 and Stratum 2, target minimum accrual is 20 eligible BORwST patients, with  up to 
30 eligible patients allowed to ensure that at least 20 BORwST are accrued. Accrual to strata 1 and 2 

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will be halted once it is reasonably certain that this 20-patient target will be achieved.  In the 
unlikely case that minimum of 20 BORwST patients is not reached, the study committee will 
consider whether an amendment to increase accrual is warranted.  The accrual rate to Stratum 1 
and Stratum 2 is estimated at approximately 1 per month. 
 
For Stratum 3, target minimum accrual is also 20 eligible BORwST patients, with up to 30 eligible 
patients allowed. Accrual to this stratum will be halted once it is reasonably certain that the target 
of 20 BORwST patients will be achieved, or once both stratum 1 and stratum 2 have met accrual 
goals, whichever occurs first.   
 
For Target Validation Stratum 4, accrual will be halted once it is reasonably certain that 20 patients 
are enrolled with pre- and post-treatment tumor specimens, or once both Stratum 1 and Stratum 2 
have met accrual goals, whichever occurs first.   
   
There will be no statistical monitoring rules for halting the study early either for lack of efficacy or 
futility.   
 
The primary analyses in Strata 1 and 2 will include all patients who are evaluable for BOR per 
section 14. The primary method of analysis will be an exact one-sided, one-sample test of the 
proportion of patients who achieve BOR of at least minor response (MR). With Type I error no 
greater than 10% at a response rate of 0.05, with a minimum of 20 patients there will be at least 
85% power to detect a BOR CR/PR/MR rate of 25%. Hence, in each of Strata 1 and 2 there is 
sufficient power to discriminate between an unacceptable BOR rate of ≤0.05 and an achievable 
and clinical relevant BOR rate of ≥0.25. Secondary analyses in these strata will include analysis of 
BOR in the BORwST cohort, as well as estimation of 12-month event-free survival (EFS) and 
recurrent/progression free survival (PFS) via the product limit estimator, and summarization of 
rates of toxicities in both the ITT and BORwST cohorts.  
 
Analysis in Strata 3 and 4 (target validation) will be descriptive, in the former comprising 
estimation of the BOR rate, EFS, PFS, and in the latter comprising analysis of MED162 tumor 
concentration, ERK phosphorylation as an indicator of Ras/Raf/MEK/ERK pathway inhibition, and 
other related endpoints.  Rates of toxicities will also be summaries for both strata.  
 
 
 
14.5 Accrual Rate and Study Duration 
The Phase I portion of the study will require a minimum 4 patients and at maximum 36 patients. The 
Phase I portion will require 12 to 18 months to complete. 
 
Phase II portion of the study will require 20-30 months to complete at an expected accrual rate of 1 
per month in each of strata 1 and 2. 
 

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14.6 Toxicity Monitoring during Phase II 
A minimum of 40 and possibly as many as 90 patients will be enrolled in strata 1, 2 and 3 combined 
during Phase II.  Toxicity monitoring will continue during Phase II as described below, with patients 
in strata 1 through 3 combined in this analysis.   
 
The primary endpoint for toxicity monitoring will be the occurrence of DLT during the first course of 
treatment.    If the number of DLTs occurring in the first course of treatment equals or exceeds the 
number in the table below, the study will be suspended to accrual pending review of toxicities by 
the study committee, in consultation with the DSMC, to determine whether the study should 
continue as planned, be amended, or be terminated.  This monitoring rule has at most 14% Type I 
error for true DLT rates of 15% or lower, which are considered acceptable, at least 80% power to 
detect DLT rates of 25% or more, and at least 95% power to detect DLT rates of 30% or more.  The 
average numbers of patients that would be treated under these three scenarios are 75, 42, and 41 if 
the study were halted when the boundary was reached.   
 
Table 14-1: Phase II DLT Monitoring Rule 
# Patients Treated 
# DLTs 
# Patients Treated 
# DLTs 
1 – 5 
- 
 
 
6 – 9 
6 
52 – 56 
13 
10 – 18 
7 
57 – 61 
14 
19 – 26 
8 
62 – 66 
15 
27 – 33 
9 
67 – 70 
16 
34 – 39 
10 
71 – 75 
17 
40 – 45 
11 
76 – 79 
18 
46 – 51 
12 
80 
19 
 
Toxicity monitoring for Stratum 4 will be independent of that for Strata 1 through 3.  The primary 
endpoint will be DLT occurring any time pre-surgery through the end of the first course following 
surgery.  The monitoring bounds describe in Table 14-1 will be used.  If the number of DLTs 
equals or exceeds the number in the table, or if at least 5 patients have been treated on stratum 
4 and the nominal rate of DLT exceeds that currently observed in strata 1 through 3 combined, 
the stratum will be suspended to accrual pending review of toxicities by the study committee, in 
consultation with the DSMC, to determine whether the stratum should continue as planned, be 
amended, or be terminated. 

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15. PUBLICATION PLAN 
Timely publication will be the responsibility of the principal investigator. No data should be 
submitted for presentation at public meetings or in abstract form without approval of the principal 
investigator. Guidelines will follow the rules for publication for the University of Southern California 
and Children’s Hospital Los Angeles. 
 
The results should be made public within 24 months of the end of data collection, sooner if possible. 
If a report is planned to be published in a peer-reviewed journal, then that initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors. A 
full report of the outcomes should be made public no later than three (3) years after the end of data 
collection. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16. REFERENCES  
 
1.  
Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev 
Cancer. 2007 Apr;7(4):295–308.  
2.  
CBTRUS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed 
in the United States in 2004-2006. Hinsdale, IL: Central Brain Tumor Registry of the United States; 
2010.  
3.  
Bergthold G, Bandopadhayay P, Bi WL, Ramkissoon L, Stiles C, Segal RA, et al. Pediatric low-grade 
gliomas: How modern biology reshapes the clinical field. Biochim Biophys Acta BBA - Rev Cancer. 
2014 Apr;1845(2):294–307.  
4.  
Tihan T, Ersen A, Qaddoumi I, Sughayer MA, Tolunay S, Al-Hussaini M, et al. Pathologic 
characteristics of pediatric intracranial pilocytic astrocytomas and their impact on outcome in 3 
countries: a multi-institutional study. Am J Surg Pathol. 2012 Jan;36(1):43–55.  
5.  
Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, et al. Randomized Study of Two 
Chemotherapy Regimens for Treatment of Low-Grade Glioma in Young Children: A Report From 
the Children’s Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol [Internet]. 2012 Jun 4 [cited 
2012 Jul 3]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/22665535 
6.  
Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, et al. Analysis of BRAF 
V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic 
xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 
(Berl). 2011 Jan 29;121(3):397–405.  
7.  
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-
RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16;468(7326):973–7.  
8.  
Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High Prevalence of BRAF 
Mutations in Thyroid Cancer. Cancer Res. 2003 Apr 1;63(7):1454–7.  
9.  
Badalian-Very G, Vergilio J-A, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent 
BRAF mutations in Langerhans cell histiocytosis. Blood. 2010 Jan 1;blood-2010-04-279083.  
10.  Jones DTW, Hutter B, Jäger N, Korshunov A, Kool M, Warnatz H-J, et al. Recurrent somatic 
alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013 Aug;45(8):927–32.  
11.  Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, et al. BRAF gene duplication 
constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 
2008 May;118(5):1739–49.  
12.  Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, Resnick AC, et al. Duplication of 7q34 in 
pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based 
genotype arrays results in a novel BRAF fusion gene. Brain Pathol Zurich Switz. 2009 Jul;19(3):449–
58.  

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13.  Liu X, Ide JL, Norton I, Marchionni MA, Ebling MC, Wang LY, et al. Molecular imaging of drug transit 
through the blood-brain barrier with MALDI mass spectrometry imaging. Sci Rep. 2013;3:2859.  
14.  Kaul A, Toonen JA, Cimino PJ, Gianino SM, Gutmann DH. Akt- or MEK-mediated mTOR inhibition 
suppresses Nf1 optic glioma growth. Neuro-Oncol. 2015 Jun 1;17(6):843–53.  
15.  Ascierto PA, Berking C, Agarwala SS, Schadendorf D, Herpen CV, Queirolo P. Efficacy and safety of 
oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous 
melanoma harboring BRAFV600 or NRAS mutations. J Clin Oncol. 2012;30:suppl; abstr 8511.  
16.  Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for 
patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-
randomised, open-label phase 2 study. Lancet Oncol. 2013 Mar;14(3):249–56.  
17.  van den Bent MJ, Wefel JS, Schiff D, Taphoorn MJB, Jaeckle K, Junck L, et al. Response assessment 
in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-
grade gliomas. Lancet Oncol. 2011 Jun;12(6):583–93.  
18.  Warren KE, Poussaint TY, Vezina G, Hargrave D, Packer RJ, Goldman S, et al. Challenges with 
defining response to antitumor agents in pediatric neuro-oncology: A report from the response 
assessment in pediatric neuro-oncology (RAPNO) working group. Pediatr Blood Cancer. 2013 Sep 
1;60(9):1397–401.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix I: LIST OF MEDICATIONS WITH POSSIBLE CYP INTERACTIONS TO BE USED WITH CAUTION 
CYP2C19 Inhibitors 
CYP2C19 Inducers 
cimetidine 
esomeprazole 
felbamate 
fluoxetine 
fluvoxamine 
isoniazid 
ketoconazole 
lansoprazole 
omeprazole 
oral contraceptives 
pantoprazole 
ticlopidine 
voriconazole 
efavirenz 
rifampin 
ritonavir 
St. John's Wort 
 
 
CYP1A2 Inhibitors 
CYP1A2 Inducers 
aminodarone * 
cimetidine 
efavirenz 
fluoroquinolones 
fluvoxamine* 
ticlopidine 
carbamazepine 
tobacco 
rifampin 
char-grilled meats 
CYP 2B6 Substrates 
 
artemisinin 
bupropion 
cyclophosphamide 
efavirenz 
ifosfamide 
ketamine 
meperidine 
methadone 
nevirapine 
propofol 
selegiline 
 
*Indicates strong/moderate inhibitor. Refer to the following website for a complete list:    
http://medicine.iupui.edu/clinpharm/ddis/clinical-table 
 
 
 
 
 

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Appendix II: MEK162 ADMINISTRATION 
Dosing: The study drug will be administered based on body surface area and should be calculated 
approximately monthly.   
 
Premedication: None required. 
 
Route of Administration: MEK162 will be administered orally BID, as a suspension prepared by the on-
site pharmacy (Appendix XVI), or as a tablet.  Co-administration of both tablet and suspension is not 
permitted, but patients may switch from one form to the other at beginning of a cycle, or at the time of 
a dose-level change. Administration of suspension via nasogastric or gastrostomy tube is permitted. 
Prescribed doses should be taken twice daily, approximately 12 ± 2 hours apart. 
 
If a patient vomits at any time after dosing, the dose of study drug should not be re-administered. Doses 
of study drug omitted for AEs or any other reason should not be made up later in the day, or at the end 
of the dosing period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix III: MOLECULAR ANALYSIS 
Due to the rapid development of techniques for protein, lipid and DNA/RNA analysis, newer approaches 
to those discussed below will be incorporated or substituted where appropriate. All samples should be 
shipped to Dr. Keith Ligon.  
 
Keith Ligon, MD, PhD 
C/O Sarah Becker 
Dana-Farber Cancer Institute 
450 Brookline Avenue JFB 215A 
Boston, MA 02215 
Dr. Ligon Telephone: (617) 632-2357 
Sarah Becker: (617)632-6131 
Fax: (617) 582-8760 
Email: Keith_Ligon@dfci.harvard.edu 
Email: pnotissuebanking@partners.org 
 
Tissue Analysis: Required  Tissue Analysis:  
• 
Oncopanel sequencing 
• 
OncoPanel sequences ~500  genes known to be associated with cancer and includes 
the ability to detect selected translocations and copy number variation. This assay 
requires 10 formalin fixed paraffin embedded (FFPE) unstained slides with a 
minimum of 50% viable tumor nuclei and mean depth of coverage is 200X. 
• 
OncoScan copy array 
• 
OncosScan copy arrays will be used to survey the DNA copy-number variations across 
the genome. This requires a minimum of 80ng of genomic DNA. Please send 10 
unstained slides with at least 50% viable tumor, and more cellular areas are 
preferred. 
 
 
Exploratory Tissue Analysis (if enough tissue available):  
• 
Agilent Array CGH (substitute for Oncoscan if needed):  
Array CGH analysis will be performed using paraffin tissue. This array analysis will be directed by 
Dr. Keith Ligon from the Department of Neuropathology and will be performed at  Brigham and 
Women’s Hospital CAMD.  
• 
OncoPanel: 
OncoPanel analysis will be conducted at the Brigham and Women’s Hospital Center for 
Advanced Molecular Diagnostics using DNA derived from paraffin archival tissue. This unique 
technology allows rapid identification of known mutation within tumor suppressor genes, 
oncogenes and other major regulators of cellular proliferation.. Results from the OncoPanel may 
be returned to the patient’s chart only if performed in a CLIA-certified lab; this information will 
be maintained with linkers to the database containing an abstraction of the patient’s medical 
record and the database containing the results of the histopathologic analysis. 
 

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• 
Additional Sequencing:  
Sequencing, such as whole genome, whole exome, and RNA sequencing to form a more 
comprehensive view of the genomic changes in tumor tissue may be performed. If tissue is 
available for this testing such whole genome, whole exome, or RNA sequencing will be 
conducted at the Broad Institute, in the lab of Dr. Mimi Bandopadhayay. 
 
• 
FISH Analysis:  
FISH analysis has become a routine method for the rapid evaluation of areas of chromosomal 
region gain or loss. This method uses standard paraffin sections and can be used to examine any 
chromosomal region that has been identified in the screens above. 
• 
Methylation Array:  
Methylation array is a new technology that examines the regulation of gene expression at the 
chromosomal level rather than the DNA, RNA or protein level. Some pediatric tumors may result 
from the maintenance of gene expression that should have been silenced, or conversely as a 
result of the failure of an inhibitory gene product to be expressed at the correct time or location 
rather than by mutation. Methylation array survey the genome for regions that are differentially 
regulated compared to normal controls. This methodology for methylation analysis or just now 
becoming available and will be performed if tissue permits. 
• 
RNA Analysis: 
The frozen tissue obtained will be processed using standard techniques for nucleic acid isolation. 
Total RNA will be processed for labeling and hybridization to the Affymetrix U133 Plus 2.0 array 
that contains probes for over 47,000 transcripts and variants including 38,500 well-characterized 
human genes. For limited amounts of starting material, less than 5 µg of RNA and less than 500 
ng of DNA, an amplification step will precede labeling. As new chips become available, they may 
be substituted for those listed above. 
 
Blood Analysis:  
• 
Genomic Blood 
• 
Blood will be used as genomic normal control to compare to  OncoPanel, whole 
exome, whole genome and gene expression arrays.  
• 
Peripheral blood serum will be used for exploratory analysis of proteins, lipids, and 
DNA/RNA 
 
CSF Analysis 
 CSF Sample Preparation and Analysis: 
• 
In order to assess the molecules in the CSF of patients with tumors, cell-free DNA analysis will be 
conducted at the Broad Institute. 
 
Material from the Buffy coat will be used as controls for the molecular and genomic analyses 
including sequencing, whole exome, whole genome and gene expression arrays. Plasma will be used 
for exploratory analysis of proteins, lipids, and DNA/RNA.  
 e laboratory of Dr on Monday through Thursday at the following  

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Keith Ligon, MD, PhD 
C/O Sarah Becker 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue JFB 215A 
Boston, MA 02215 
Telephone: (617) 632-6131 
Fax: (617) 582-8760 
Email: Keith_Ligon@dfci.harvard.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix IV:  SPECIMEN COLLECTION, PROCESSING AND STORAGE 
 
Specimen collection and shipment 
 
Patients enrolled on this study may provide specimens and/or clinical information. All specimens will be 
collected and processed according to site-specific banking procedures. All samples collected under this 
protocol/consent document will be tracked in the ODQ Neuro-Oncology database at Dana-Farber Cancer 
Institute. 
 
It is mandatory to contact Jasmine Pauly and Sarah Becker prior to shipment to confirm proper materials 
are sent.  
 
Tumor Tissue: Fresh Frozen Tumor Material 
Collection: Tissue will be collected from any patient undergoing neurosurgical procedures as 
defined in this protocol with patient consent.  One “green pea sized” specimen from 
previously banked snap frozen primary tumor material, regardless of time from surgery, 
should be rapidly transferred (without thawing) from long term frozen storage to a 
Styrofoam box filled with 7-10lbs of dry ice for shipment.  
Shipment:   Samples should be submitted in 1.5mL standard size Cryovials containing the 
tumor material and labeled according to table 8-2. Please ship in a Styrofoam box (minimum 
suggested internal dimensions of 30 cm x 30 cm x 30 cm) with 7-10lbs of dry ice. Please 
include all items on transmittal form including de-identified pathology report from current 
surgery and any prior surgeries, along with any additional molecular or genetic testing 
results previously generated. Ship to Dr. Keith Ligon's laboratory in Boston. .Follow 
instructions on transmittal form and confirm shipment with Sarah Becker and Jasmine Pauly. 
 
 
Tumor Tissue: FFPE 
Collection: The “best block” should be identified for advanced studies by the local 
pathologist. The block must contain viable tumor with greater than 50% tumor nuclei, less 
than 30% necrosis, and the tissue fragment size in total ~0.5cm in diameter. The block 
should contain sufficient tissue to provide 40 standard 5 micron FFPE slides for the planned 
advanced studies. If you are unable to send a block, please send 20-40 unstained slides and 
1 H&E.  
Shipment: Slides and blocks should be sent at room temperature in secure slide or block 
containers in a padded envelope. Please label according to table 8-2. Please include all items 
on transmittal form including de-identified pathology report from current surgery and any 
prior surgeries, along with any additional molecular or genetic testing results previously 
generated. Ship to Dr. Keith Ligon's laboratory in Boston. Follow instructions on transmittal 
form and confirm shipment with Sarah Becker and Jasmine Pauly. 
 
 

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Blood 
Pharmacokinetic Blood  
Collection: 2ml of blood collected in EDTA as indicated in Table 8-1. The tubes will be 
kept in an ice water bath after blood collection. Within 30 minutes, the tubes will be 
centrifuged between 3°C and 5°C for 10 minutes at approximately 1500g. Immediately 
after centrifugation, transfer at least 0.5ml of plasma into a 2ml polypropylene screw-
cap tube. Place the tube in a freezer ≤-70°C until shipment. 
Shipment: Samples should be submitted in 2ml polypropylene screw-cap tubes as per 
Section 8.0. Please ship in a Styrofoam box with 7-10lbs of dry ice to QPS Sample 
Coordination in Delaware, following the instructions on the transmittal form. 
 
Biomarker Blood  
Collection: 10ml of blood collected in Cell-Free DNA BCT Streck tube as indicated in 
Table 8-2 and processed per Section 8.0.  
Shipment: Samples should be submitted in 10mL BCT Streck tubes labeled as per table 
8-2.   Store at room temperature up to 72 hours before shipping. Ship in a padded 
envelope or other secure packaging at room temperature within 72 hours of collection 
to Dr. Keith Ligon's laboratory in Boston. Follow instructions on transmittal form and 
confirm shipment with Sarah Becker and Jasmine Pauly.  
 
Pharmacodynamic Blood  
Collection: 6ml of blood collected in EDTA at time-points as indicated in Table 8-2. 
Whole blood must be aliquoted into as many 1.5mL standard cryovials (~1mL per tube) 
as needed. Blood should not be processed further and placed in a freezer -80°C until 
shipment. 
Shipment: Samples should be submitted in 1.5mL standard cryovials labeled as per table 
8-2. Samples should be shipped in a Styrofoam box with 7-10lbs of dry ice to Dr. Keith 
Ligon's laboratory in Boston. Follow instructions on transmittal form and confirm 
shipment with Sarah Becker and Jasmine Pauly. 
 
CSF 
Collection: CSF can be collected per institutional standards in a sterile, screw top tube and 
then transferred to a 10mL Cell-Free DNA BCT Streck tube. Store at room temperature up to 
72 hours and shipment. 
Shipment: in secure package at room temperature to Dr. Keith Ligon’s laboratory in Boston. 
Follow instructions on transmittal form and confirm shipment with Sarah Becker and 
Jasmine Pauly. Ensure tubes are de-identified and labeled with protocol number, patient ID, 
and draw date. Make note of time at which CSF was collected. 
 
 
 
 

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Urine 
Collection:  in sterile collection cup adding 10-20% volume of Streck Cell-Free DNA Urine 
Preservative to sample (i.e. 3mL preservative to 30mL urine),  Secure cap tightly and gently 
invert container 5 times to make sure it is well mixed.  Transfer to 50 mL conical tube. Stor 
at room temperature up to 72 hours. 
Shipment: in secure package at room temperature to Dr. Keith Ligon’s laboratory in Boston. 
Follow instructions on transmittal form and confirm shipment with Sarah Becker and 
Jasmine Pauly. Ensure tubes are de-identified and labeled with protocol number, patient ID, 
and draw date. Make note of time at which urine was collected and at which preservative 
was added.   
 
 
Blood sample volume 
The maximum blood volume drawn for all research studies should be no more than 2mL/kg in any one 
24-hour period, and 4mL/kg in any one 30-day period, unless otherwise specified by institutional 
guidelines. In small children for whom the required sample volume would exceed the maximum 
allowance, the volume of individual samples should be reduced. Questions regarding sample size 
reduction can be discussed on a case by case basis with the study chair.  
 
Specimen processing, storage, and coding 
All specimens will be processed according to site-specific banking procedures; exceptions are made for 
samples that are required to go directly to the researcher and/or laboratory for immediate processing. 
The amount of each of the following samples will be tracked in the ODQ Neuro-Oncology database at 
the Dana-Farber Cancer Institute or other in-house tracking system. All biological samples will be coded 
with an internal numbering system to ensure patient confidentiality. The samples will be stored and 
distributed to researchers with this numbering code as the only identifier. 
 
Specimen that circumvent the tissue bank and go directly to the researcher or laboratory 
Samples that are required to go directly to the researcher and/or laboratory for immediate processing 
can be collected and not be entered in the bank: i.e. blood and tissue that requires immediate 
processing beyond the scope of the bank, such as for the creation of cell lines, if it is codified. All 
samples, including those that go for immediate processing outside the bank, are to be logged into and 
out of the ODQ Neuro-Oncology database.  
 
Specimen tracking of all samples collected and distributed under this protocol 
All samples collected and distributed for the use of future research studies are to be tracked, and logged 
into and out of ODQ DFCI database. The database will be able to generate reports of what is available in 
storage, and provide a history of samples obtained and distributed.  
If the formal tissue bank wishes to track samples using an internal tracking system with similar 
features, this will be noted with the description of the bank in Appendix XII. If this option is chosen by 
a facility, it should be noted that samples obtained using this protocol that are not logged into the 
bank’s internal tracking system, for instance samples which circumvent the tissue bank are to be tracked 

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in this database. The internal tracking system must track not only what is in store, but provide a history 
of samples obtained and distributed. The ODQ Neuro-Oncology database also has the useful capability 
of allowing samples to be reserved, succeeding permission from the respective oversight committee. 
 
Samples after a patient withdraws from the study 
Should a participant or his/her legally authorized representative or his/her next of kin withdraw consent 
from the study, any unused tissue specimens will be removed from the tissue bank and will be 
discarded. Tissue, its derivatives, and results from samples previously obtained and distributed to third 
parties (outside of the respective main tissue bank) will not be recalled or destroyed. 
 
Coding of samples given to investigators 
All biological samples will be coded with a numbering system to ensure patient confidentiality. 
The samples will be stored and distributed to researchers with this numbering code as the only identifier 
on the sample. 
 
QPS (Pharmacokinetic Blood):  
QPS Sample Coordination 
3 Innovation Way 
Suite 240 
Newark, DE 19711 
 
Dr Ligon's Laboratory (all other samples):  
Keith Ligon C/O Sarah Becker 
Dana-Farber Cancer Institute 
450 Brookline Ave JFB215A 
Boston, MA 02215 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix V: SPECIMEN AND DATA USE 
 
Research uses of Tissue and Clinical Data 
Any leftover tissue samples will be banked for future analyses that are not yet available.  
Clinical data and tissue samples, independently and together, will be used for non-therapeutic research 
that advances the diagnosis, evaluation, etiology, prevention, and outcome improvement of nervous 
system diseases. Research on tissue samples may include detailed genetic and molecular analysis and 
cell line development. In general, these findings will be linked to clinical care and outcome to maximize 
research findings. Studies may include tumor biology studies, biomarker identification studies, drug 
target studies, genomics and proteomics studies, genetic susceptibility studies, drug development 
efforts, epidemiological studies, and outcomes studies. 
 
Retrospective analysis on clinical data performed outside of prospective formal clinical trial data will be 
linked with outcomes to create research findings and provide preliminary data to support further 
investigations. 
 
For a comprehensive list of research use of tissue and clinical data, see Appendix VI.  
 
Commercial uses of Tissue and Clinical Data 
Tissue samples collected and/or stored in the bank may be made available to commercial or corporate 
scientific collaborators only as part of a scientific collaboration. Derivative products from the participant 
tissues including cell lines, diagnostics tests, or other items may arise from study of these tissues. 
Participants will not have any ownership or financial benefit from their tissue samples and derivatives. 
 
Uses which may affect determination of treatment (clinical care) and/or eligibility onto clinical trials 
In rare circumstances, findings from tissue testing may be clinically relevant and affect treatment 
decisions. All testing results communicated back to the participant’s treating clinician and/or placed into 
the participant’s medical record must be CLIA compliant. If the testing is first done in a lab that does not 
meet these criteria, yet the results are felt to be clinically significant, the testing will be repeated in a 
CLIA environment prior to informing the participant’s clinician and/or placement in the participant’s 
medical record. The participant’s treating clinician is responsible for treatment decisions including 
whether and how to inform the participant of any results. 
 
 
 

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Appendix VI: LIST OF RESEARCH USES OF TISSUE AND CLINICAL DATA 
 
  
 
 

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Appendix VII:  Pathology Testing Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix VIII: TISSUE AND CLINICAL DATA USE OVERSIGHT COMMITTEES 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix IX: Dana-Farber/Boston Children’s Hospital TISSUE BANK 
 
 
 
 

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Appendix X: PERFORMANCE STATUS CRITERIA 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
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 XI: NORMAL BLOOD PRESSURE BY HEIGHT AND AGE 
 
The normal blood pressure by height and age tables are included in this Appendix. In order to use these 
tables, 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.  
 
Standards for systolic and diastolic BP for infants younger than 1 year are available in the second task 
force report. Recently, additional data has been published. In children younger than 1 year, systolic BP 
has been used to define hypertension.  
 
Source: 
DHHS, PHS, NIH, National Heart, Lung, and Blood Institute. Update on the Task Force Report (1987) on 
High Blood Pressure in Children and Adolescents: A Working Group Report from the National High Blood 
Pressure Education Program. NIH Publication 96-3790; 1996; 7-9. 
The entire NIH document can be viewed at: 
 http://www.nhlbi.nih.gov/health/prof/heart/hbp/hbp_ped.pdf. 
 
 

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90th and 95th Percentile BP for Girls 1-17 Years 
 
 

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90th  and 95th  Percentile BP For BOYS  1-17 Years 
 
 
 
 

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Appendix XII: DOSAGE OF MEK162 
Dosing table (15 mg tablets) 
BSA (m2) 
Level -1 
(12mg/m2) 
Level 1 
(16mg/m2) 
Level 2 
(20mg/m2) 
Level 3 
(24mg/m2) 
Level 4 
(28mg/m2) 
Level 5  
(32mg/m2) 
≤0.42 
* 
* 
* 
* 
* 
* 
0.43-48 
* 
* 
* 
* 
* 
15 mg 
(1 tablet) 
0.49-0.55 * 
* 
* 
* 
15 mg 
(1 tablet) 
15 mg 
(1 tablet) 
0.55-0.63 * 
* 
* 
15 mg 
(1 tablet) 
15 mg 
(1 tablet) 
* 
0.64-0.67 * 
* 
* 
15 mg 
(1 tablet) 
* 
* 
0.68-0.72 * 
* 
15 mg 
(1 tablet) 
15 mg 
(1 tablet) 
* 
* 
0.73-0.84 * 
* 
15 mg 
(1 tablet) 
* 
* 
* 
0.85-0.97 * 
15 mg 
(1 tablet) 
* 
* 
* 
30 mg 
(2 tablets) 
0.98-1.06 * 
15 mg 
(1 tablet) 
* 
* 
30 mg 
(2 tablets) 
30 mg 
(2 tablets) 
1.07-1.12 * 
* 
* 
* 
30 mg 
(2 tablets) 
30 mg 
(2 tablets) 
1.13-1.24 
15 mg 
(1 tablet) 
* 
* 
30 mg 
(2 tablets) 
30 mg 
(2 tablets) 
* 
1.25-1.35 
15 mg 
(1 tablet) 
* 
* 
30 mg 
(2 tablets) 
* 
45 mg 
(3 tablets) 
1.36-1.44 
15 mg 
(1 tablet) 
* 
30 mg 
(2 tablets) 
30 mg 
(2 tablets) 
* 
45 mg 
(3 tablets) 
1.45-1.66 * 
* 
30 mg 
(2 tablets) 
* 
45 mg 
(3 tablets) 
45 mg 
(3 tablets) 
1.67-1.87 * 
* 
* 
45 mg 
(3 tablets) 
45 mg 
(3 tablets) 
60 mg 
(4 tablets) 
≥1.88 
* 
* 
* 
45 mg 
(3 tablets) 
60 mg 
(4 tablets) 
60 mg 
(4 tablets) 
 
*Tablet form not permitted at this BSA for this dose level. See suspension dosing table below.   
Dose should be given twice daily (every 12 hours).   
 
 
 

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Dosing table (suspension) 
BSA (m2) 
Level -1 
(12mg/m2) 
Level 1 
(16mg/m2) 
Level 2 
(20mg/m2) 
Level 3 
(24mg/m2) 
Level 4 
(28mg/m2) 
Level 5  
(32mg/m2) 
≤0.14 
1 
2 
2 
2 
3 
3 
0.15-0.24 
2 
3 
4 
5 
6 
6 
0.25-0.34 
4 
5 
6 
7 
8 
10 
0.35-0.44 
5 
6 
8 
10 
11 
13 
0.45-0.54 
6 
8 
10 
12 
14 
16 
0.55-0.64 
7 
10 
12 
14 
17 
19 
0.65-0.74 
8 
11 
14 
17 
20 
22 
0.75-0-.85 10 
13 
16 
19 
22 
26 
0.85-0.94 
11 
14 
18 
22 
25 
29 
0.95-1.04 
12 
16 
20 
24 
28 
32 
1.05-1.14 
13 
18 
22 
26 
31 
35 
1.15-1.24 
14 
19 
24 
29 
34 
38 
1.25-1.34 
16 
21 
26 
31 
36 
42 
1.35-1.44 
17 
22 
28 
34 
39 
45 
1.45-1.54 
18 
24 
30 
36 
42 
48 
1..55-1.64 
19 
26 
32 
38 
45 
51 
1.65-1.74 
20 
27 
34 
41 
48 
54 
1.75-1.84 
22 
29 
36 
43 
50 
58 
≥1.85 
23 
30 
38 
45 
53 
61 
Quantities listed are individual doses in mg amounts.   
Dose should be given twice daily (every 12 hours).   
 
 
 
 
 

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110 
 
 
Appendix XIII: GUIDELINES FOR THE MANAGEMENT OF MEK162 INDUCED SKIN TOXICITY 
Clinical judgment and experience of the treating physician should guide the management plan of each 
patient. In general, the following interventions are in addition to the MEK162 induced rash dosing 
guidelines, Recommended Dose Modifications Associated with Treatment Related Adverse Events, in 
section 6.4.  
Prophylactic treatment for skin toxicity is recommended. Prophylaxis of skin toxicity to be initiated   24 
hours prior to the first treatment with MEK162 or later as needed. Apply topical agents to the mostly 
common affected areas such as face, scalp, neck, upper chest, upper back. 
• 
Non oily sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection)  
• 
Topical steroid (e.g., mometasone cream, applied sparingly daily) 
• 
Topical erythromycin  
• 
Consider low-dose oral doxycycline for the first 2-3 weeks of study drug administration. 
Topical agents should be applied on a daily basis starting on Day 1 of study treatment or 24 hours prior 
to first treatment, and more often as needed. 
Effective medications also include antihistamines, other topical corticosteroids, other topical antibiotics, 
and low-dose systemic corticosteroids.  
The treatment algorithm based on CTCAE grade is as follows: 
Mild Rash (CTCAE Grade 1) 
• 
Consider prophylactic rash treatment as described above if not already started 
• 
Topical mometasone cream or other topical corticosteroid and/or topical antibiotic (erythromycin 
(2%)) are recommended. 
• 
The patient should be reassessed after 2 weeks or sooner if rash worsens or as per investigator 
opinion. 
Moderate Rash (CTCAE Grade 2) 
• 
Although there has been no evidence of phototoxicity or photosensitivity in patients being treated 
with MEK162, doxycycline (or minocycline as second-line) should be used with careful UV protection 
(i.e., avoid direct exposure to sunlight, use sunglasses, use sunscreen, etc.).  
• 
Use of topical erythromycin or clindamycin (1%) plus mometasone or pimecrolimus (1% cream) plus 
oral antibiotics such as oral doxycycline or minocycline. 
Severe Rash (CTCAE Grade 3-4) 
CTCAE Grade 3 
• 
 In addition to the interventions recommended for moderate rash, consider oral prednisolone at a 
dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise manner. 
• 
 Alternatively, in addition to the interventions recommended for moderate rash, consider oral 
isotretinoin (low doses, i.e. 0.3 to 0.5 mg/kg) (Lacouture et al 2011). 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
111 
 
CTCAE Grade 4 
• 
Immediately discontinue the patient from study drug and treat the patient with oral and topical 
medications (see recommendation CTCAE Grade 3). 
Symptomatic treatment: 
It is strongly recommended that patients who develop rash/skin toxicities receive symptomatic 
treatment: 
• 
For pruritic lesions,  use of cool compresses and oral antihistamine agents 
• 
For fissuring, use of Monsel’s solution, silver nitrate, or zinc oxide cream is. If not sufficient, use mild 
steroid ointments or combination of steroids and antibiotics such as Fucicort. 
• 
For desquamation, use emollients with   mild pH 5/ (best containing urea 10%) 
• 
For paronychia, antiseptic bath and local potent corticosteroids, use  oral antibiotics  and, if no 
improvement is seen,  refer to a dermatologist or surgeon  
• 
For infected lesions, obtain bacterial and fungal cultures and treat with topical or systemic 
antibiotics based on sensitivity of culture 
References 
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, et al (2011) Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer; 19: 
1079–95 
 
 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
112 
 
Appendix XIV: GUIDELINES FOR THE MANAGEMENT OF MEK162 INDUCED DIARRHEA 
Proactively investigate for occurrence of diarrhea 
Educate patient 
1. Remind patients at each visit to contact the site immediately upon the first sign of loose stool or 
symptoms of abdominal pain. Additionally, at each study visit, each patient should be specifically 
asked regarding occurrence of diarrhea or diarrhea-related symptoms. If the patient had symptoms, 
the patient should be asked regarding the actions taken for these symptoms and re-instruct if 
indicated. 
2. In addition to dietary modification, the patients should be instructed on early warning signs of 
diarrhea and potentially life-threatening illnesses (e.g. severe cramping → severe diarrhea, fever 
with diarrhea → infection and dizziness on standing might be a sign for shock). 
3. Patients should be instructed on what to report to the investigator if possible (i.e. number of stools, 
stool composition, stool volume)  
Anti-diarrhea therapy 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of diarrhea, 
patient education, as well as proper management of diarrhea is mandatory.  
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose stools, or 
overt diarrhea. All concomitant therapies used for treatment of diarrhea must be recorded on the 
Concomitant Medications eCRF. It is recommended that patients be provided loperamide tablets and 
are instructed on the use of loperamide on the first day of MEK162 treatment.  In addition to the 
MEK162 induced diarrhea dosing guidelines, Recommended Dose Modifications Associated with 
Treatment Related Adverse Events, in section 6.4 the protocol, these instructions should be provided at 
each visit and the site should ensure that the patient understands the instructions.  
Explain the frequency of diarrhea and its relationship to NCI CTCAE grading  
Determine if diarrhea is complicated versus uncomplicated (section 6.4) 
Rule out other or concomitant causes. 
These may include: 
• 
Infection by Candida spp, Salmonella spp., Clostridium difficile, Campylobacter spp. Giardia, 
Entamoeba, Cryptosporidium which can lead to opportunistic infections in immunosuppressed 
patients, 
• 
Medication-induced diarrhea  
• 
Malabsorption/lactose intolerance 
• 
Fecal impaction, partial bowel obstruction 
For uncomplicated Grade 1 to Grade 2 diarrhea 
• 
Stop all lactose-containing products and alcohol and eat frequent small meals that include bananas, 
rice, applesauce or toast) 
• 
Stop laxatives, bulk fiber (i.e. Metamucil®) and stool softeners (e.g. docusate sodium; Colace®) 

MEK162 Pediatric Phase I/II 
 
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23Jul2018 
113 
 
• 
Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus (with fiber) 
• 
Drink 8 to 10 large glasses of clear liquids per day (e.g. water, Pedialyte®, Gatorade® or broth) 
• 
Consider administration of standard dose loperamide. 
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of the physician. 
For complicated Grade 1 to Grade 2 diarrhea or Grade 3 to 4 diarrhea 
• 
The patient must call the investigator immediately 
• 
If loperamide has not been initiated, initiate standard dose loperamide immediately.  
• 
Administer IV fluids and electrolytes as needed. In case of severe dehydration, replace loperamide 
by octreotide. 
• 
Monitor/Continue IV fluids and antibiotics as needed. Intervention should be continued until the 
patient is diarrhea free for at least 24 hours. 
• 
Hospitalization may need to be considered. 
 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
114 
 
Appendix XV: 3+3 Dose Escalation Decision Grid 
 
# of Eligible 
Patients at 
Dose Level 
#  of DLTs 
Observed to 
Date 
# of Patients 
Pending DLT 
evaluation 
3 + 3 
Decision 
1 
0 
0 
Continue enrollment 
1 
1 
0 
Continue enrollment 
1 
0 
1 
Continue enrollment 
2 
0 
0 
Continue enrollment 
2 
1 
0 
Continue enrollment 
2 
2 
0 
De-escalate 
2 
0 
1 
Continue enrollment 
2 
1 
1 
Continue enrollment 
2 
0 
2 
Continue enrollment 
3 
0 
0 
Escalate 
3 
1 
0 
Continue enrollment 
3 
2 
0 
De-escalate 
3 
3 
0 
De-escalate 
3 
0 
1 
Suspend enrollment 
3 
1 
1 
Suspend enrollment 
3 
2 
1 
De-escalate 
3 
0 
2 
Suspend enrollment 
3 
1 
2 
Suspend enrollment 
3 
0 
3 
Suspend enrollment 
4 
0 
0 
Continue enrollment 
4 
1 
0 
Continue enrollment 
4 
2 
0 
De-escalate 
4 
3 
0 
NA 
4 
4 
0 
NA 
4 
0 
1 
Continue enrollment 
4 
1 
1 
Continue enrollment 
4 
2 
1 
NA 
4 
3 
1 
NA 
4 
0 
2 
NA 
4 
1 
2 
NA 
4 
2 
2 
NA 
4 
0 
3 
NA 
4 
1 
3 
NA 
4 
0 
4 
NA 
5 
0 
0 
Continue enrollment 
5 
1 
0 
Continue enrollment 
5 
2 
0 
De-escalate 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
115 
 
# of Eligible 
Patients at 
Dose Level 
#  of DLTs 
Observed to 
Date 
# of Patients 
Pending DLT 
evaluation 
3 + 3 
Decision 
5 
3 
0 
De-escalate 
5 
4 
0 
NA 
5 
5 
0 
NA 
5 
0 
1 
Continue enrollment 
5 
1 
1 
Continue enrollment 
5 
2 
1 
De-escalate 
5 
3 
1 
NA 
5 
4 
1 
NA 
5 
0 
2 
Continue enrollment 
5 
1 
2 
Continue enrollment 
5 
2 
2 
NA 
5 
3 
2 
NA 
5 
0 
3 
NA 
5 
1 
3 
NA 
5 
2 
3 
NA 
5 
0 
4 
NA 
5 
1 
4 
NA 
5 
0 
5 
NA 
6 
0 
0 
Escalate 
6 
1 
0 
Escalate 
6 
2 
0 
De-escalate 
6 
3 
0 
De-escalate 
6 
4 
0 
De-escalate 
6 
5 
0 
NA 
6 
6 
0 
NA 
6 
0 
1 
Escalate 
6 
1 
1 
Suspend enrollment 
6 
2 
1 
De-escalate 
6 
3 
1 
De-escalate 
6 
4 
1 
NA 
6 
5 
1 
NA 
6 
0 
2 
Suspend enrollment 
6 
1 
2 
Suspend enrollment 
6 
2 
2 
De-escalate 
6 
3 
2 
NA 
6 
4 
2 
NA 
6 
0 
3 
Suspend enrollment 
6 
1 
3 
Suspend enrollment 
6 
2 
3 
NA 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
116 
 
# of Eligible 
Patients at 
Dose Level 
#  of DLTs 
Observed to 
Date 
# of Patients 
Pending DLT 
evaluation 
3 + 3 
Decision 
6 
3 
3 
NA 
6 
0 
4 
NA 
6 
1 
4 
NA 
6 
2 
4 
NA 
6 
0 
5 
NA 
6 
1 
5 
NA 
6 
0 
6 
NA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
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117 
 
Appendix XVI: Instructions for preparation of MEK162 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  
General remarks  
Utmost care must be exercised while handling (preparation and dosing) MEK162 oral suspensions. Follow the 
“Disposition of hazardous waste procedure” 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.  
 
Consideration of events  
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 )  
•  125 mL glass bottle or 4oz 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).  
•  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 on-site 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.  

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
118 
 
•  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 4oz 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 
brown bottle.  
•  Step 5: Measure 45 mL Ora Sweet using a 30 mL syringe and transfer it into the 125 mL brown bottle (or 4oz 
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 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 remaining 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 on-site 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. 

MEK162 Pediatric Phase I/II 
Protocol Version 4.0 
23Jul2018 
119 
Appendix XVII: Patient Diary 
INSTRUCTIONS 
•
Suspension Administration: Use a new or rinsed clean syringe and/or dosing cup (provided by your site Pharmacy) for each dose
o
Remove the screw cap from the bottle which contains the oral suspension
o
Plug the syringe adapter onto the bottleneck and close the bottle with the screw cap
o
Gently handshake the bottle of oral suspension for 60 seconds just prior to dosing to make sure the content is evenly mixed
o
Remove the screw cap from the bottle and connect the syringe tip to the adapter with the bottle in upright position.
o
Hold the adapter and bottle in upside down position and carefully draw the required volume of oral suspension using the syringe. After this is
done, hold the bottle in upright position and remove the filled syringe from the adapter.
o
Transfer the content directly from the syringe into the mouth of the patient. Use a new or rinsed clean syringe for each administration if
more suspension is needed (discard or rinse clean syringe after every use).

If more 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 to be taken to ensure all the suspension contained in the cup is administered. Use a
new dosing cup for each administration.
o
Close the bottle with the cap immediately after use.
o
The syringe dispenser set and the dosing cup should be discarded or rinsed clean after each administration.
o
Doses should be taken 12 hours apart (+/- 2 hours) with a glass of water
o
Do not retake dose if vomiting occurs or make up missed doses
•
Storage: Room temperature (below 25°C or 77°F), do NOT refrigerate. Suspension must be used within 30 days of Pharmacy preparation.
•
Return: Bottle with any unused suspension, these completed drug diary forms
•
Diary: Please complete this document in pen, include comments regarding missed doses or side effects experienced and sign at the end
Cycle _____ 
Week 1 
Date: 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
AM 
 _ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
PM 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
MEK162 Subject ID: 
CTO Registration Number: 
Dose Volume:    
 BID (twice a day) 

MEK162 Pediatric Phase I/II 
Protocol Version 4.0 
23Jul2018 
120 
Week 2 
Date: 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
AM 
 _ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
PM 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
Week 3 
Date: 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
AM 
 _ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
PM 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 

MEK162 Pediatric Phase I/II 
Protocol Version 4.0 
23Jul2018 
121 
Week 4 
Date: 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
       /       / 
AM 
 _ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
PM 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
_ _ : _ _  
Missed Dose 
Comments  
(Missed Dose or  
Side Effects) 
Parent/Participant Signature: _________________________________________________________ Date: _________________________________ 
Reviewed by Treating Physician: ______________________________________________________ Date: _________________________________ 

MEK162 Pediatric Phase I/II 
 
Protocol Version 4.0 
 
 
23Jul2018 
122 
 
Appendix XVIII: PedsQL Brain Tumor Modules 

PedsQL 1.0 Parent (2-4) Brain Tumor           Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
PARENT REPORT for TODDLERS (ages 2-4) 
 
 
 
 
 
 
DIRECTIONS 
 
       Children with brain tumors sometimes have special problems. On the following   
      page is a list of things that might be a problem for your child. Please tell us 
      how  much of a problem each one has been for your child during the past 7 
      days by circling: 
 
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 Parent (2-4) Brain Tumor          Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
In the past 7 days, how much of a problem has your child had with … 
 
PAIN AND HURT (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Aches in joints and/or muscles 
0 
1 
2 
3 
4 
2. Having a lot of pain 
0 
1 
2 
3 
4 
3. Getting headaches 
0 
1 
2 
3 
4 
 
MOVEMENT AND BALANCE (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty keeping his/her balance 
0 
1 
2 
3 
4 
2. Difficulty using his/her legs 
0 
1 
2 
3 
4 
3. Difficulty using his/her hands 
0 
1 
2 
3 
4 
 
PROCEDURAL ANXIETY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Needle sticks (i.e. injections, blood tests, IV’s) 
causing him/her pain 
0 
1 
2 
3 
4 
2. Getting anxious about having blood drawn 
0 
1 
2 
3 
4 
3. Getting anxious about having needle sticks (i.e. 
injections, blood tests, IV’s) 
0 
1 
2 
3 
4 
 
NAUSEA (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Becoming nauseated during medical treatments 
0 
1 
2 
3 
4 
2. Food not tasting very good to him/her 
0 
1 
2 
3 
4 
3. Becoming nauseated while thinking about medical 
treatments 
0 
1 
2 
3 
4 
4. Feeling too nauseous to eat 
0 
1 
2 
3 
4 
5. Some foods and smells making him/her nauseous 
0 
1 
2 
3 
4 
 
WORRY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
2. Worrying about whether or not his/her medical 
treatments are working 
0 
1 
2 
3 
4 
3. Worrying that the cancer will reoccur or relapse 
0 
1 
2 
3 
4 
 

PedsQL 1.0 (5-7) Brain Tumor           
                      Not to be reproduced without permission             Copyright © 1998 JW 
Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
           All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
YOUNG CHILD REPORT (ages 5-7) 
 
 
Instructions for interviewer: 
 
I am going to ask you some questions about things that might be a problem for some 
children.  I want to know how much of a problem any of these things might be for you. 
  
Show the child the template and point to the responses as you read. 
 
If it is not at all a problem for you, point to the smiling face  
 
If it is sometimes a problem for you, point to the middle face  
 
If it is a problem for you a lot, point to the frowning face 
 
I will read each question. Point to the pictures to show me how much of a problem it is for 
you. Let’s try a practice one first. 
 
 
 Not at all 
Sometimes       A lot 
Is it hard for you to snap your fingers 
  
 
 
 
 
 
 
 
 
 
 
 
Ask the child to demonstrate snapping his or her fingers to determine whether or not the question 
was answered correctly.  Repeat the question if the child demonstrates a response that is 
different from his or her action. 
 
 
 
 
Think about how you have been doing for the past 7 days. Please listen carefully to each 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (5-7) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                 All rights reserved 
sentence and tell me how much of a problem this is for you. 
 
After reading the item, gesture to the template. If the child hesitates or does not seem to understand how to 
answer, read the response options while pointing at the faces. 
 
COGNITIVE PROBLEMS (problems with…) 
Not at all 
Some-
times 
A lot 
1. Is it hard for you to know what to do when something bothers  
     you 
0 
2 
4 
2. Is it hard for you to work with numbers or do math 
0 
2 
4 
3. Is it hard for you to pay attention to things 
0 
2 
4 
4. Is it hard for you to remember what is read to you 
0 
2 
4 
5. It is hard for you to learn new things 
0 
2 
4 
6. Do you get mixed up easily 
0 
2 
4 
 
 
PAIN AND HURT (problems with…) 
Not at all 
Some-
times 
A lot 
1. Do you ache or hurt in your bones and/or muscles 
0 
2 
4 
2. Do you hurt a lot 
0 
2 
4 
3. Do you have headaches 
0 
2 
4 
 
 
MOVEMENT AND BALANCE (problems with…) 
Not at all 
Some-
times 
A lot 
1. It is hard for you to keep your balance 
0 
2 
4 
2. It is hard for you to use your legs 
0 
2 
4 
3. It is hard for you to use your hands 
0 
2 
4 
 
 
 
PROCEDURAL ANXIETY (problems with…) 
Not at all 
Some-
times 
A lot 
1. Do needle sticks (i.e. shots, blood tests, IV’s) hurt you 
0 
2 
4 
2. Do you get scared when you have to have blood tests 
0 
2 
4 
3. Do you get scared about having needle sticks (i.e. shots, blood 
tests, IV’s) 
0 
2 
4 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (5-7) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                 All rights reserved 
Think about how you have been doing for the past 7 days. Please listen carefully to each 
sentence and tell me how much of a problem this is for you. 
 
 
NAUSEA (problems with…) 
Not at all 
Some-
times 
A lot 
1. Does your medicine make you sick to your stomach 
0 
2 
4 
2. Does food taste bad to you 
0 
2 
4 
3. Do you get sick to your stomach when you think about your 
medicine 
0 
2 
4 
4. Do you feel too sick to your stomach to eat 
0 
2 
4 
5. Do some foods and smells make you sick to your stomach 
0 
2 
4 
 
 
WORRY (problems with…) 
Not at all 
Some-
times 
A lot 
1. Do you worry about how medicines make you feel 
0 
2 
4 
2. Do you worry about whether or not your medicine is working  
0 
2 
4 
3. Do you worry that your cancer illness will come back 
0 
2 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (5-7) Brain Tumor           
                      Not to be reproduced without permission             Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
           All rights reserved 
 
 
 
 
 
How much of a problem is this for you? 
 
 
 
 
         Not at all 
 
 
   Sometimes    
 
 
  A lot 
       
     
 

PedsQL 1.0 Parent (5-7) Brain Tumor           Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
PARENT REPORT for YOUNG CHILDREN (ages 5-7) 
 
 
 
 
 
 
DIRECTIONS 
 
       Children with brain tumors sometimes have special problems. On the following   
      pages is a list of things that might be a problem for your child. Please tell us 
      how  much of a problem each one has been for your child during the past 7 
      days by circling: 
  
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 Parent (5-7) Brain Tumor          Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
In the past 7 days, how much of a problem has your child had with … 
 
COGNITIVE PROBLEMS (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty figuring out what to do when something 
bothers him/her 
0 
1 
2 
3 
4 
2. Difficulty working with numbers or doing math 
0 
1 
2 
3 
4 
3. Difficulty paying attention to things 
0 
1 
2 
3 
4 
4. Difficulty remembering what is read to him/her 
0 
1 
2 
3 
4 
5. Difficulty learning new things 
0 
1 
2 
3 
4 
6. Getting mixed up easily 
0 
1 
2 
3 
4 
 
 
PAIN AND HURT (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Aches in joints and/or muscles 
0 
1 
2 
3 
4 
2. Having a lot of pain 
0 
1 
2 
3 
4 
3. Getting headaches 
0 
1 
2 
3 
4 
 
 
MOVEMENT AND BALANCE (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty keeping his/her balance 
0 
1 
2 
3 
4 
2. Difficulty using his/her legs 
0 
1 
2 
3 
4 
3. Difficulty using his/her hands 
0 
1 
2 
3 
4 
 
 
 
PROCEDURAL ANXIETY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Needle sticks (i.e. injections, blood tests, IV’s) 
causing him/her pain 
0 
1 
2 
3 
4 
2. Getting anxious about having blood drawn 
0 
1 
2 
3 
4 
3. Getting anxious about having needle sticks (i.e. 
injections, blood tests, IV’s) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 Parent (5-7) Brain Tumor          Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
In the past 7 days, how much of a problem has your child had with … 
 
 
NAUSEA (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Becoming nauseated during medical treatments 
0 
1 
2 
3 
4 
2. Food not tasting very good to him/her 
0 
1 
2 
3 
4 
3. Becoming nauseated while thinking about medical 
treatments 
0 
1 
2 
3 
4 
4. Feeling too nauseous to eat 
0 
1 
2 
3 
4 
5. Some foods and smells making him/her nauseous 
0 
1 
2 
3 
4 
 
 
WORRY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
2. Worrying about whether or not his/her medical 
treatments are working 
0 
1 
2 
3 
4 
3. Worrying that the cancer will reoccur or relapse 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (8-12) Brain Tumor           
Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
CHILD REPORT (ages 8-12) 
 
 
 
 
 
 
DIRECTIONS 
 
       Children with brain tumors sometimes have special problems. Please tell us 
      how  much of a problem each one has been for you during the past 7 days 
      by circling: 
 
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
 
 
 
 
 
 
 
 
 
In the past 7 days, how much of a problem has this been for you … 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (8-12) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
COGNITIVE PROBLEMS (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. It is hard for me to figure out what to do when  
     something bothers me 
0 
1 
2 
3 
4 
2. I have trouble solving math problems 
0 
1 
2 
3 
4 
3. I have trouble writing school papers or reports 
0 
1 
2 
3 
4 
4. It is hard for me to pay attention to things 
0 
1 
2 
3 
4 
5. It is hard for me to remember what I read 
0 
1 
2 
3 
4 
6. It is hard for me to learn new things 
0 
1 
2 
3 
4 
7. I get mixed up easily 
0 
1 
2 
3 
4 
 
 
PAIN AND HURT (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. I ache or hurt in my joints and/or muscles 
0 
1 
2 
3 
4 
2. I hurt a lot 
0 
1 
2 
3 
4 
3. I get headaches 
0 
1 
2 
3 
4 
 
 
MOVEMENT AND BALANCE (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. It is hard for me to keep my balance 
0 
1 
2 
3 
4 
2. It is hard for me to use my legs 
0 
1 
2 
3 
4 
3. It is hard for me to use my hands 
0 
1 
2 
3 
4 
 
 
 
PROCEDURAL ANXIETY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Needle sticks (i.e. injections, blood tests, IV’s) hurt 
me 
0 
1 
2 
3 
4 
2. I get scared when I have to have blood tests 
0 
1 
2 
3 
4 
3. I get scared about having needle sticks (i.e. 
injections, blood tests, IV’s) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (8-12) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
In the past 7 days, how much of a problem has this been for you … 
 
 
 
NAUSEA (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. I become sick to my stomach when I have medical 
treatments 
0 
1 
2 
3 
4 
2. Food does not taste very good to me 
0 
1 
2 
3 
4 
3. I become sick to my stomach when I think about 
      medical treatments 
0 
1 
2 
3 
4 
4. I feel too sick to my stomach to eat 
0 
1 
2 
3 
4 
5. Some foods and smells make me sick to my 
stomach 
0 
1 
2 
3 
4 
 
 
WORRY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. I worry about side effects from medical treatments 
0 
1 
2 
3 
4 
2. I worry about whether or not my medical treatments 
are working 
0 
1 
2 
3 
4 
3.  I worry that my cancer will come back or relapse 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 Parent (8-12) Brain Tumor          Not to be reproduced without permission      Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
PARENT REPORT for CHILDREN (ages 8-12) 
 
 
 
 
 
 
DIRECTIONS 
 
       Children with brain tumors sometimes have special problems. On the following   
      pages is a list of things that might be a problem for your child. Please tell us 
      how  much of a problem each one has been for your child during the past 7 
      days by circling: 
 
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 Parent (8-12) Brain Tumor         Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
In the past 7 days, how much of a problem has your child had with … 
 
COGNITIVE PROBLEMS (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty figuring out what to do when something 
bothers him/her 
0 
1 
2 
3 
4 
2. Trouble solving math problems 
0 
1 
2 
3 
4 
3. Trouble writing school papers or reports 
0 
1 
2 
3 
4 
4. Difficulty paying attention to things 
0 
1 
2 
3 
4 
5. Difficulty remembering what he/she reads 
0 
1 
2 
3 
4 
6. Difficulty learning new things 
0 
1 
2 
3 
4 
7. Getting mixed up easily 
0 
1 
2 
3 
4 
 
 
PAIN AND HURT (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Aches in joints and/or muscles 
0 
1 
2 
3 
4 
2. Having a lot of pain 
0 
1 
2 
3 
4 
3. Getting headaches 
0 
1 
2 
3 
4 
 
 
MOVEMENT AND BALANCE (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty keeping his/her balance 
0 
1 
2 
3 
4 
2. Difficulty using his/her legs 
0 
1 
2 
3 
4 
3. Difficulty using his/her hands 
0 
1 
2 
3 
4 
 
 
 
PROCEDURAL ANXIETY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Needle sticks (i.e. injections, blood tests, IV’s) 
causing him/her pain 
0 
1 
2 
3 
4 
2. Getting anxious about having blood drawn 
0 
1 
2 
3 
4 
3. Getting anxious about having needle sticks (i.e. 
injections, blood tests, IV’s) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 Parent (8-12) Brain Tumor         Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
In the past 7 days, how much of a problem has your child had with … 
 
 
NAUSEA (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Becoming nauseated during medical treatments 
0 
1 
2 
3 
4 
2. Food not tasting very good to him/her 
0 
1 
2 
3 
4 
3. Becoming nauseated while thinking about medical 
treatments 
0 
1 
2 
3 
4 
4. Feeling too nauseous to eat 
0 
1 
2 
3 
4 
5. Some foods and smells making him/her nauseous 
0 
1 
2 
3 
4 
 
 
WORRY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
2. Worrying about whether or not his/her medical 
treatments are working 
0 
1 
2 
3 
4 
3. Worrying that the cancer will reoccur or relapse 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (13-18) Brain Tumor           
Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
TEEN REPORT (ages 13-18) 
 
 
 
 
 
 
DIRECTIONS 
 
       Teens with brain tumors sometimes have special problems. Please tell us 
      how  much of a problem each one has been for you during the past 7 days 
      by circling: 
 
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
 
 
 
 
 
 
 
 
 
In the past 7 days, how much of a problem has this been for you … 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (13-18) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
COGNITIVE PROBLEMS (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. It is hard for me to figure out what to do when  
     something bothers me 
0 
1 
2 
3 
4 
2. I have trouble solving math problems 
0 
1 
2 
3 
4 
3. I have trouble writing school papers or reports 
0 
1 
2 
3 
4 
4. It is hard for me to pay attention to things 
0 
1 
2 
3 
4 
5. It is hard for me to remember what I read 
0 
1 
2 
3 
4 
6. It is hard for me to learn new things 
0 
1 
2 
3 
4 
7. I get mixed up easily 
0 
1 
2 
3 
4 
 
 
PAIN AND HURT (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. I ache or hurt in my joints and/or muscles 
0 
1 
2 
3 
4 
2. I hurt a lot 
0 
1 
2 
3 
4 
3. I get headaches 
0 
1 
2 
3 
4 
 
 
MOVEMENT AND BALANCE (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. It is hard for me to keep my balance 
0 
1 
2 
3 
4 
2. It is hard for me to use my legs 
0 
1 
2 
3 
4 
3. It is hard for me to use my hands 
0 
1 
2 
3 
4 
 
 
 
PROCEDURAL ANXIETY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Needle sticks (i.e. injections, blood tests, IV’s) hurt 
0 
1 
2 
3 
4 
2. I get scared when I have to have blood tests 
0 
1 
2 
3 
4 
3. I get scared about having needle sticks (i.e. 
injections, blood tests, IV’s) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
In the past 7 days, how much of a problem has this been for you … 

PedsQL 3 
PedsQL 1.0 (13-18) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
 
 
NAUSEA (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. I become sick to my stomach when I have medical 
treatments 
0 
1 
2 
3 
4 
2. Food does not taste very good to me 
0 
1 
2 
3 
4 
3. I become sick to my stomach when I think about 
      medical treatments 
0 
1 
2 
3 
4 
4. I feel too sick to my stomach to eat 
0 
1 
2 
3 
4 
5. Some foods and smells make me sick to my 
stomach 
0 
1 
2 
3 
4 
 
 
WORRY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. I worry about side effects from medical treatments 
0 
1 
2 
3 
4 
2. I worry about whether or not my medical treatments 
are working 
0 
1 
2 
3 
4 
3.  I worry that my cancer will come back or relapse 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 Parent (13-18) Brain Tumor          Not to be reproduced without permission      
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
 All rights reserved 
 
 
  PedsQL ™  
Brain Tumor Module 
 
Version 1.0 
 
 
PARENT REPORT for TEENS (ages 13-18) 
 
 
 
 
 
 
DIRECTIONS 
 
       Teens with brain tumors sometimes have special problems. On the following   
      pages is a list of things that might be a problem for your teen. Please tell us 
      how  much of a problem each one has been for your teen during the past 7 
      days by circling: 
 
0 if it is never a problem  
1 if it is almost never a problem  
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
     There are no right or wrong answers.   
     If you do not understand a question, please ask for help. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 Parent (13-18) Brain Tumor        Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                 All rights reserved 
In the past 7 days, how much of a problem has your teen had with … 
 
COGNITIVE PROBLEMS (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty figuring out what to do when something 
bothers him/her 
0 
1 
2 
3 
4 
2. Trouble solving math problems 
0 
1 
2 
3 
4 
3. Trouble writing school papers or reports 
0 
1 
2 
3 
4 
4. Difficulty paying attention to things 
0 
1 
2 
3 
4 
5. Difficulty remembering what he/she reads 
0 
1 
2 
3 
4 
6. Difficulty learning new things 
0 
1 
2 
3 
4 
7. Getting mixed up easily 
0 
1 
2 
3 
4 
 
 
PAIN AND HURT (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Aches in joints and/or muscles 
0 
1 
2 
3 
4 
2. Having a lot of pain 
0 
1 
2 
3 
4 
3. Getting headaches 
0 
1 
2 
3 
4 
 
 
MOVEMENT AND BALANCE (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Difficulty keeping his/her balance 
0 
1 
2 
3 
4 
2. Difficulty using his/her legs 
0 
1 
2 
3 
4 
3. Difficulty using his/her hands 
0 
1 
2 
3 
4 
 
 
 
PROCEDURAL ANXIETY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Needle sticks (i.e. injections, blood tests, IV’s) 
causing him/her pain 
0 
1 
2 
3 
4 
2. Getting anxious about having blood drawn 
0 
1 
2 
3 
4 
3. Getting anxious about having needle sticks (i.e. 
injections, blood tests, IV’s) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 Parent (13-18) Brain Tumor        Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                 All rights reserved 
 
In the past 7 days, how much of a problem has your teen had with … 
 
 
NAUSEA (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Becoming nauseated during medical treatments 
0 
1 
2 
3 
4 
2. Food not tasting very good to him/her 
0 
1 
2 
3 
4 
3. Becoming nauseated while thinking about medical 
treatments 
0 
1 
2 
3 
4 
4. Feeling too nauseous to eat 
0 
1 
2 
3 
4 
5. Some foods and smells making him/her nauseous 
0 
1 
2 
3 
4 
 
 
WORRY (problems with…) 
Never 
Almost 
Never 
Some-
times 
Often 
Almost 
Always 
1. Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
2. Worrying about whether or not his/her medical 
treatments are working 
0 
1 
2 
3 
4 
3. Worrying that the cancer will reoccur or relapse 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (2-4) Brain Tumor           
Not to be reproduced without permission          
               Copyright © 1998 JW 
Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 1.0 
 
REPORTE DE LOS PADRES (edades 2- 4) 
 
 
 
 
 
 
INSTRUCCIONES 
 
Algunas veces, los niños(as) con tumores cerebrales tienen problemas especiales.  
A continuación hay una lista de situaciones que pueden ser un problema para su 
hijo(a).  Por favor díganos qué tanto problema ha sido cada una de éstas para 
su hijo(a) durante los últimos siete días.  Por favor circule su respuesta 
 
 
0 si nunca es un problema  
1 si casi nunca es un problema  
2 si algunas veces es un problema 
3 si a menudo es un problema  
4 si casi siempre es un problema  
 
 
     No hay respuestas correctas o incorrectas. 
     Si no entiendes una pregunta, por favor pide ayuda. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL1.0 (2-4) Brain Tumor          Not to be reproduced without permission           
            Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
 
DOLOR Y MOLESTIAS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dolores en las articulaciones y/o músculos 
0 
1 
2 
3 
4 
2. Teniendo mucho dolor 
0 
1 
2 
3 
4 
3. Teniendo dolores de cabeza 
0 
1 
2 
3 
4 
 
 
MOVIMIENTO Y EQUILIBRIO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultad manteniendo su equilibrio 
0 
1 
2 
3 
4 
2. Dificultad usando las piernas 
0 
1 
2 
3 
4 
3. Dificultad usando las manos 
0 
1 
2 
3 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Los piquetes de agujas (ej. inyecciones, pruebas de 
sangre, sueros) le causan dolor  
0 
1 
2 
3 
4 
2. Sintiendo ansiedad porque le van a sacar sangre 
0 
1 
2 
3 
4 
3. Sintiendo ansiedad porque le van a picar con 
agujas (ej. inyecciones, pruebas de sangre, sueros) 
0 
1 
2 
3 
4 
 
 
 
NÁUSEA (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Sintiendo náuseas durante los tratamientos 
médicos 
0 
1 
2 
3 
4 
2. La comida no le sabe muy bien 
0 
1 
2 
3 
4 
3.  Sintiendo náuseas cuando piensa en los 
tratamientos médicos 
0 
1 
2 
3 
4 
4. Sintiendose con mucha náusea para comer 
0 
1 
2 
3 
4 
5. Algunos alimentos y olores le provocan náusea 
0 
1 
2 
3 
4 
 
 
 
 
 

PedsQL 3 
PedsQL1.0 (2-4) Brain Tumor          Not to be reproduced without permission           
            Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Preocupándose por los efectos secundarios de los 
tratamientos médicos 
0 
1 
2 
3 
4 
2. Preocupándose acerca de si sus tratamientos 
médicos están funcionando o no 
0 
1 
2 
3 
4 
3.  Preocupándose de que el cáncer regrese o    
empeore   
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL1.0 (5-7) Brain Tumor           
Not to be reproduced without permission          
               Copyright © 1998 JW 
Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 1.0 
 
 
REPORTE de NIÑOS (edades 5 – 7) 
 
 
 
Instrucciones para el/ la entrevistador(a):  
 
Te voy a hacer algunas preguntas acerca de cosas que podrían ser un problema para 
algunos(as) niños(as).  Quisiera saber qué tanto problema serían estas cosas para tí. 
 
Muéstrele al/ la niño(a) el dibujo con las caritas y señale las respuestas a medida que las lee. 
 
Si ésto nunca es un problema para tí, señala la cara sonriente 
 
Si ésto algunas veces es un problema para tí, señala la cara de en medio 
Si ésto es muchas veces problema para tí, señala la cara enojada 
 
Te voy a leer cada pregunta.  Señala los dibujos para enseñarme qué tanto problema es ésto 
para tí.  Vamos a practicar con el primero. 
 
 
Nunca 
Algunas Veces 
Muchas Veces 
Es difícil para tí tronar tus dedos 
 
 
 
 
Pídale al niño que le muestre cómo truena sus dedos para determinar si la pregunta fue contestada 
correctamente o no.  Repita la pregunta si el/la  niño(a) parece responder de una manera diferente a 
como actúa. 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (5-7) Brain Tumor          
Not to be reproduced without permission           
           Copyright © 1998 JW Varni, 
Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
Piensa en cómo te ha ido en los últimos siete días.  Por favor escucha con 
cuidado    
 cada oración y dime qué tanto problema ha sido ésto para tí. 
 
 Después de leer cada oración, refiérase a los dibujos.  Si el niño duda o parece no entender cómo           
 contestar, lea las opciones de respuesta mientras señala las caras. 
 
 
PROBLEMAS COGNITIVOS (problemas con…) 
Nunca 
Algunas 
Veces 
Muchas 
Veces 
1. Es difícil para tí saber qué hacer cuando hay algo 
que te molesta 
0 
2 
4 
2. Se te hace difícil usar números o hacer matemáticas 
0 
2 
4 
3. Te es difícil poner atención 
0 
2 
4 
4. Te es difícil recordar lo que se te lee 
0 
2 
4 
5. Te es difícil aprender cosas nuevas 
0 
2 
4 
6. Te confundes fácilmente 
0 
2 
4 
 
 
DOLOR Y MOLESTIAS (problemas con…)  
Nunca 
Algunas 
Veces 
Muchas 
Veces 
1. Tienes dolores en tus huesos y/o músculos 
0 
2 
4 
2. Tienes mucho dolor 
3
0 
2 
4 
3.  Te dan dolores de cabeza  
0 
2 
4 
 
 
 MOVIMIENTO Y EQUILIBRIO (problemas con…)  
Nunca 
Algunas 
Veces 
Muchas 
Veces 
1.   Es difícil para tí mantener el equilibrio    
0 
2 
4 
2.   Es difícil para tí usar las piernas 
4
0 
2 
4 
3.   Es difícil para tí usar las manos 
0 
2 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTOS (problemas con…) 
Nunca 
Algunas 
Veces  
Muchas 
Veces 
1. Te duelen los piquetes de agujas (ej. piquetes,  
pruebas de sangre, sueros)  
0 
2 
4 
2. Te da miedo cuando te tienen que sacar sangre 
0 
2 
4 
3. Te da miedo cuando te tienen que picar con agujas 
(ej. piquetes, pruebas de sangre, sueros) 
0 
2 
4 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (5-7) Brain Tumor          
Not to be reproduced without permission           
           Copyright © 1998 JW Varni, 
Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
 
 
 
 
Piensa en cómo te ha ido en los últimos siete días .  Por favor escucha con 
cuidado    
 cada oración y dime qué tanto problema ha sido ésto para tí. 
 
 
 
NÁUSEA (problemas con…) 
Nunca 
Algunas 
Veces 
Muchas 
Veces 
1. Te hacen sentirte mal del estómago tus medicinas 
0 
2 
4 
2. Te sabe mal la comida 
0 
2 
4 
3. Te enfermas del estómago cuando piensas en tus 
medicinas 
0 
2 
4 
4. Te sientes tan mal del estómago que no puedes 
comer 
0 
2 
4 
5. Algunos alimentos y olores te hacen sentir mal del 
estómago 
0 
2 
4 
 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Algunas 
Veces 
Muchas 
Veces 
1. Te preocupas de como tus medicinas te hacen sentir 
0 
2 
4 
2. Te preocupa saber si tus medicinas están funcionando o 
no 
0 
2 
4 
3. Te preocupa que la enfermenda del cáncer regrese  
0 
2 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PedsQL 4 
PedsQL 1.0 (5-7) Brain Tumor          
Not to be reproduced without permission           
           Copyright © 1998 JW Varni, 
Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
 
 
 
 
 
 
 
¿Cuánto problema es ésto para tí? 
 
 
 
 
 
            Nunca  
 
         A Veces  
 
  Muchas Veces 
 
          

PedsQL 1.0 (5-7) Brain Tumor           
Not to be reproduced without permission          
              Copyright © 1998 JW 
Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 1.0 
 
REPORTE DE LOS PADRES (edades 5- 7) 
 
 
 
 
 
 
INSTRUCCIONES 
 
Algunas veces, los niños(as) con tumores cerebrales tienen problemas especiales.  
A continuación hay una lista de situaciones que pueden ser un problema para su 
hijo(a).  Por favor díganos qué tanto problema ha sido cada una de éstas para 
su hijo(a) durante los últimos siete días.  Por favor circule su respuesta 
 
 
0 si nunca es un problema  
1 si casi nunca es un problema  
2 si algunas veces es un problema 
3 si a menudo es un problema  
4 si casi siempre es un problema  
 
 
     No hay respuestas correctas o incorrectas. 
     Si no entiendes una pregunta, por favor pide ayuda. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL1.0 (5-7) Brain Tumor          Not to be reproduced without permission           
            Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
PROBLEMAS COGNITIVOS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultades sabiendo qué hacer cuando algo le 
molesta 
0 
1 
2 
3 
4 
2. Dificultades resolviendo problemas de 
matemáticas 
0 
1 
2 
3 
4 
3. Dificultades poniendo atención 
0 
1 
2 
3 
4 
4. Dificultades recordando lo que se le lee 
0 
1 
2 
3 
4 
5. Dificultades con aprender cosas nuevas 
0 
1 
2 
      3 
4 
6. Confundiéndose fácilmente 
0 
1 
2 
      3 
4 
 
 
DOLOR Y MOLESTIAS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dolores en las articulaciones y/o músculos 
0 
1 
2 
3 
4 
2. Teniendo mucho dolor 
0 
1 
2 
3 
4 
3. Teniendo dolores de cabeza 
0 
1 
2 
3 
4 
 
 
MOVIMIENTO Y EQUILIBRIO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultad manteniendo su equilibrio 
0 
1 
2 
3 
4 
2. Dificultad usando las piernas 
0 
1 
2 
3 
4 
3. Dificultad usando las manos 
0 
1 
2 
3 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Los piquetes de agujas (ej. inyecciones, pruebas de 
sangre, sueros) le causan dolor  
0 
1 
2 
3 
4 
2. Sintiendo ansiedad porque le van a sacar sangre 
0 
1 
2 
3 
4 
3. Sintiendo ansiedad porque le van a picar con 
agujas (ej. inyecciones, pruebas de sangre, sueros) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL1.0 (5-7) Brain Tumor          Not to be reproduced without permission           
            Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                           All rights reserved 
 
 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
NÁUSEA (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Sintiendo náuseas durante los tratamientos 
médicos 
0 
1 
2 
3 
4 
2. La comida no le sabe muy bien 
0 
1 
2 
3 
4 
3.  Sintiendo náuseas cuando piensa en los 
tratamientos médicos 
0 
1 
2 
3 
4 
4. Sintiendose con mucha náusea para comer 
0 
1 
2 
3 
4 
5. Algunos alimentos y olores le provocan náusea 
0 
1 
2 
3 
4 
 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Preocupándose por los efectos secundarios de los 
tratamientos médicos 
0 
1 
2 
3 
4 
2. Preocupándose acerca de si sus tratamientos 
médicos están funcionando o no 
0 
1 
2 
3 
4 
3.  Preocupándose de que el cáncer regrese o    
empeore   
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL .0 (8-12) Brain Tumor           
Not to be reproduced without permission          
              Copyright © 1998 JW 
Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 3.0 
 
 
REPORTE de NIÑOS (edades 8 – 12) 
 
 
 
 
 
 
INSTRUCCIONES 
 
       Niños con tumores cerebrales tienen a veces problemas especiales.   
      Por favor circula èstos y díganos cuán problemático ha sido para ti cada  
      uno de éstos durante los últimos siete días: 
 
0 si nunca es un problema  
1 si casi nunca es un problema 
2 si algunas veces es un problema 
3 si a menudo es un problema 
4 si casi siempre es un problema 
 
 
     No hay respuestas correctas o incorrectas. 
     Si no entiendes una pregunta, por favor pide ayuda. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (8-12) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                               All rights reserved 
En los últimos 7 días, cuán problemático ha sido para tí … 
 
 
PROBLEMAS COGNITIVOS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Me es difícil saber qué hacer cuando algo me 
molesta 
0 
1 
2 
3 
4 
2. Tengo dificultad resolviendo problemas de 
matemáticas 
0 
1 
2 
3 
4 
3. Tengo dificultad haciendo tareas y reportes de la 
escuela 
0 
1 
2 
3 
4 
4. Me es difícil poner atención 
0 
1 
2 
3 
4 
5. Me es difícil recordar lo que leo 
0 
1 
2 
3 
4 
6. Es difícil para mí aprender cosas nuevas 
0 
1 
2 
3 
4 
7. Me confundo fácilmente 
0 
1 
2 
3 
4 
 
 
DOLOR Y MOLESTIAS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Tengo dolores en las articulaciones y/o músculos   
0 
1 
2 
3 
4 
2. Tengo mucho dolor  
0 
1 
2 
3 
4 
3. Tengo dolores de cabeza  
0 
1 
2 
3 
4 
 
 
MOVIMIENTO Y EQUILIBRIO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Es difícil para mí mantener el equilibrio 
0 
1 
2 
3 
4 
2. Es difícil para mí el usar las piernas 
0 
1 
2 
3 
4 
3. Es difícil para mí usar las manos 
0 
1 
2 
3 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Los piquetes de agujas (ej. inyecciones, pruebas de 
sangre, sueros) me duelen 
0 
1 
2 
3 
4 
2. Me da miedo cuando me tienen que sacar sangre 
0 
1 
2 
3 
4 
3. Me da miedo cuando me tienen que picar con 
agujas (ej. inyecciones, pruebas de sangre, sueros) 
0 
1 
2 
3 
4 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (8-12) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                               All rights reserved 
 
 
 
 
 
 
En los últimos 7 días, cuán problemático ha sido para tí … 
 
 
 
NÁUSEA (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Me enfermo del estómago cuando tengo 
tratamientos médicos 
0 
1 
2 
3 
4 
2. La comida no me sabe muy bien 
0 
1 
2 
3 
4 
3.  Me enfermo del estómago cuando pienso en los  
tratamientos médicos 
0 
1 
2 
3 
4 
4. Me siento tan mal del estómago que no puedo 
comer 
0 
1 
2 
3 
4 
5. Algunos alimentos y olores hacen que me sienta 
mal del estómago 
0 
1 
2 
3 
4 
 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Me preocupan los efectos de los tratamientos 
médicos 
0 
1 
2 
3 
4 
2. Me preocupa saber si los tratamientos médicos 
están funcionando o no   
0 
1 
2 
3 
4 
3.  Me preocupa que el cáncer regrese o empeore 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (8-12) Brain Tumor           
Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 1.0 
 
REPORTE DE LOS PADRES (edades 8- 12) 
 
 
 
 
 
 
INSTRUCCIONES 
 
Algunas veces, los niños(as) con tumores cerebrales tienen problemas especiales.  
A continuación hay una lista de situaciones que pueden ser un problema para su 
hijo(a).  Por favor díganos qué tanto problema ha sido cada una de éstas para 
su hijo(a) durante los últimos siete días.  Por favor circule su respuesta       
 
 
0 si nunca es un problema  
1 si casi nunca es un problema  
2 si algunas veces es un problema 
3 si a menudo es un problema  
4 si casi siempre es un problema  
 
 
     No hay respuestas correctas o incorrectas. 
     Si no entiendes una pregunta, por favor pide ayuda. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (8-12) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
PROBLEMAS COGNITIVOS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultades sabiendo qué hacer cuando algo le 
molesta 
0 
1 
2 
3 
4 
2. Dificultades resolviendo problemas de 
matemáticas 
0 
1 
2 
3 
4 
3. Problemas haciendo tareas y reportes de la 
escuela 
0 
1 
2 
3 
4 
4. Dificultades poniendo atención 
0 
1 
2 
3 
4 
5. Dificultades recordando lo que lee 
0 
1 
2 
      3 
4 
6. Dificultades con aprender cosas nuevas 
0 
1 
2 
      3 
4 
7. Confundiéndose fácilmente 
0 
1 
2 
      3 
4 
 
 
DOLOR Y MOLESTIAS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dolores en las articulaciones y/o músculos 
0 
1 
2 
3 
4 
2. Teniendo mucho dolor 
0 
1 
2 
3 
4 
3. Teniendo dolores de cabeza 
0 
1 
2 
3 
4 
 
 
MOVIMIENTO Y EQUILIBRIO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultad manteniendo su equilibrio 
0 
1 
2 
3 
4 
2. Dificultad usando las piernas 
0 
1 
2 
3 
4 
3. Dificultad usando las manos 
0 
1 
2 
3 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Los piquetes de agujas (ej. inyecciones, pruebas de 
sangre, sueros) le causan dolor  
0 
1 
2 
3 
4 
2. Sintiendo ansiedad porque le van a sacar sangre 
0 
1 
2 
3 
4 
3. Sintiendo ansiedad porque le van a picar con 
agujas (ej. inyecciones, pruebas de sangre, sueros) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (8-12) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
 
 
 
 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
NÁUSEA (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Sintiendo náuseas durante los tratamientos 
médicos 
0 
1 
2 
3 
4 
2. La comida no le sabe muy bien 
0 
1 
2 
3 
4 
3.  Sintiendo náuseas cuando piensa en los 
tratamientos médicos 
0 
1 
2 
3 
4 
4. Sintiendose con mucha náusea para comer 
0 
1 
2 
3 
4 
5. Algunos alimentos y olores le provocan náusea 
0 
1 
2 
3 
4 
 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Preocupándose por los efectos secundarios de los 
tratamientos médicos 
0 
1 
2 
3 
4 
2. Preocupándose acerca de si sus tratamientos 
médicos están funcionando o no 
0 
1 
2 
3 
4 
3.  Preocupándose de que el cáncer regrese o    
empeore   
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (13-18) Brain Tumor           
Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 1.0 
 
 
REPORTE de ADOLESCENTES (edades 13 – 18) 
 
 
 
 
 
 
INSTRUCCIONES 
 
       Adolescentes con tumores cerebrales tienen a veces problemas especiales.   
      Por favor circula èstos y díganos cuán problemático ha sido para ti cada  
      uno de éstos durante los últimos siete días: 
 
0 si nunca es un problema  
1 si casi nunca es un problema 
2 si algunas veces es un problema 
3 si a menudo es un problema 
4 si casi siempre es un problema 
 
 
     No hay respuestas correctas o incorrectas. 
     Si no entiendes una pregunta, por favor pide ayuda. 
 
 
 
 
 
 
 
 
 
 
En los últimos 7 días, cuán problemático ha sido para tí … 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (13-18) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
 
PROBLEMAS COGNITIVOS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Me es difícil saber qué hacer cuando algo me 
molesta 
0 
1 
2 
3 
4 
2. Tengo dificultad resolviendo problemas de 
matemáticas 
0 
1 
2 
3 
4 
3. Tengo dificultad haciendo tareas y reportes de la 
escuela 
0 
1 
2 
3 
4 
4. Me es difícil poner atención 
0 
1 
2 
3 
4 
5. Me es difícil recordar lo que leo 
0 
1 
2 
3 
4 
6. Es difícil para mí aprender cosas nuevas 
0 
1 
2 
3 
4 
7. Me confundo fácilmente 
0 
1 
2 
3 
4 
 
 
DOLOR Y MOLESTIAS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Tengo dolores en las articulaciones y/o músculos   
0 
1 
2 
3 
4 
2. Tengo mucho dolor  
0 
1 
2 
3 
4 
3. Tengo dolores de cabeza  
0 
1 
2 
3 
4 
 
 
MOVIMIENTO Y EQUILIBRIO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Es difícil para mí mantener el equilibrio 
0 
1 
2 
3 
4 
2. Es difícil para mí el usar las piernas 
0 
1 
2 
3 
4 
3. Es difícil para mí usar las manos 
0 
1 
2 
3 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Los piquetes de agujas (ej. inyecciones, pruebas de 
sangre, sueros) me duelen 
0 
1 
2 
3 
4 
2. Me da miedo cuando me tienen que sacar sangre 
0 
1 
2 
3 
4 
3. Me da miedo cuando me tienen que picar con 
agujas (ej. inyecciones, pruebas de sangre, sueros) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (13-18) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
 
 
En los últimos 7 días, cuán problemático ha sido para tí … 
 
 
 
NÁUSEA (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Me enfermo del estómago cuando tengo 
tratamientos médicos 
0 
1 
2 
3 
4 
2. La comida no me sabe muy bien 
0 
1 
2 
3 
4 
3.  Me enfermo del estómago cuando pienso en los        
tratamientos médicos   
0 
1 
2 
3 
4 
4. Me siento tan mal del estómago que no puedo 
comer 
0 
1 
2 
3 
4 
5. Algunos alimentos y olores hacen que me sienta 
mal del estómago 
0 
1 
2 
3 
4 
 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Me preocupan los efectos de los tratamientos 
médicos 
0 
1 
2 
3 
4 
2. Me preocupa saber si los tratamientos médicos 
están funcionando o no   
0 
1 
2 
3 
4 
3.  Me preocupa que el cáncer regrese o empeore 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 1.0 (13-18) Brain Tumor           
Not to be reproduced without permission          
Copyright © 1998 JW Varni, Ph.D.  
2/06                                                   
 
 
 
 
 
All rights reserved 
 
 
  PedsQL ™  
Módulo de Tumores Cerebrales  
 
Versión 1.0 
 
REPORTE DE LOS PADRES (edades 13- 18) 
 
 
 
 
 
 
INSTRUCCIONES 
 
Algunas veces, los adolescentes con tumores cerebrales tienen problemas 
especiales.  A continuación hay una lista de situaciones que pueden ser un 
problema para su hijo(a).  Por favor díganos qué tanto problema ha sido cada 
una de éstas para su hijo(a) durante los últimos siete días.  Por favor circule su 
respuesta 
 
 
0 si nunca es un problema  
1 si casi nunca es un problema  
2 si algunas veces es un problema 
3 si a menudo es un problema  
4 si casi siempre es un problema  
 
 
     No hay respuestas correctas o incorrectas. 
     Si no entiendes una pregunta, por favor pide ayuda. 
 
 
 
 
 
 
 
 
 
 
ID# _________________________ 
 
Date:________________________ 

PedsQL 2 
PedsQL 1.0 (13-18) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
PROBLEMAS COGNITIVOS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultades sabiendo qué hacer cuando algo le 
molesta 
0 
1 
2 
3 
4 
2. Dificultades resolviendo problemas de 
matemáticas 
0 
1 
2 
3 
4 
3. Problemas haciendo tareas y reportes de la 
escuela 
0 
1 
2 
3 
4 
4. Dificultades poniendo atención 
0 
1 
2 
3 
4 
5. Dificultades recordando lo que lee 
0 
1 
2 
      3 
4 
6. Dificultades con aprender cosas nuevas 
0 
1 
2 
      3 
4 
7. Confundiéndose fácilmente 
0 
1 
2 
      3 
4 
 
 
DOLOR Y MOLESTIAS (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dolores en las articulaciones y/o músculos 
0 
1 
2 
3 
4 
2. Teniendo mucho dolor 
0 
1 
2 
3 
4 
3. Teniendo dolores de cabeza 
0 
1 
2 
3 
4 
 
 
MOVIMIENTO Y EQUILIBRIO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Dificultad manteniendo su equilibrio 
0 
1 
2 
3 
4 
2. Dificultad usando las piernas 
0 
1 
2 
3 
4 
3. Dificultad usando las manos 
0 
1 
2 
3 
4 
 
 
 
ANSIEDAD POR PROCEDIMIENTO (problemas con…) 
Nunca 
Casi 
Nunca 
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Los piquetes de agujas (ej. inyecciones, pruebas de 
sangre, sueros) le causan dolor  
0 
1 
2 
3 
4 
2. Sintiendo ansiedad porque le van a sacar sangre 
0 
1 
2 
3 
4 
3. Sintiendo ansiedad porque le van a picar con 
agujas (ej. inyecciones, pruebas de sangre, sueros) 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 

PedsQL 3 
PedsQL 1.0 (13-18) Brain Tumor          
Not to be reproduced without permission           
Copyright © 1998 JW Varni, Ph.D.  
2/06                                               
 
 
 
 
 
                              All rights reserved 
 
 
 
 
 
En los últimos 7 días, qué tanto problema tuvo su hijo(a) con… 
 
NÁUSEA (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Sintiendo náuseas durante los tratamientos 
médicos 
0 
1 
2 
3 
4 
2. La comida no le sabe muy bien 
0 
1 
2 
3 
4 
3.  Sintiendo náuseas cuando piensa en los 
tratamientos médicos 
0 
1 
2 
3 
4 
4. Sintiendose con mucha náusea para comer 
0 
1 
2 
3 
4 
5. Algunos alimentos y olores le provocan náusea 
0 
1 
2 
3 
4 
 
 
PREOCUPACIONES (problemas con…) 
Nunca 
Casi 
Nunca  
Algunas 
  Veces 
A 
Menudo 
Casi 
Siempre 
1. Preocupándose por los efectos secundarios de los 
tratamientos médicos 
0 
1 
2 
3 
4 
2. Preocupándose acerca de si sus tratamientos 
médicos están funcionando o no 
0 
1 
2 
3 
4 
3.  Preocupándose de que el cáncer regrese o    
empeore   
0 
1 
2 
3 
4