Clinical trial NCT02839720
Conditions: Cutaneous Neurofibroma Neurofibromatosis Type 1 Optic Nerve Glioma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-08-26; Completion date: 2023-08-31
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial studies how well selumetinib works in treating patients with neurofibromatosis type 1 and cutaneous neurofibromas. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. Determine if selumetinib sulfate (selumetinib) can result in shrinkage of cutaneous neurofibromas.

SECONDARY OBJECTIVE:

I. Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior treatment and on treatment with selumetinib for analysis of percent inhibition of phosphorylated ERK (pERK), and changes in phosphorylated AKT (pAKT).

EXPLORATORY OBJECTIVES:

I. Assess the effect of selumetinib on the development on new cutaneous neurofibromas while on treatment with selumetinib.

II. Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior treatment and on treatment with selumetinib for analysis of the tumor kinome.

III. Assess the effect of selumetinib skin related morbidity and pain using the Skindex, the Global Impression of Change Scale and Numeric Rating Scale, all of which are patient reported outcome measures.

IV. Quantify the development of new cutaneous neurofibromas on treatment with selumetinib.

V. Detailed pathologic analysis of cutaneous neurofibromas pretreatment and on treatment with selumetinib for changes in cell composition (including macrophage and mast cell infiltration).

VI. Investigate alterations that correlate with cutaneous neurofibroma (cNF) response to selumetinib treatment with pilot genomic, deoxyribonucleic acid (DNA) methylation, and transcriptomic studies.

OUTLINE:

Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a volume decrease in the target cutaneous neurofibromas may continue treatment for 12 additional cycles.

After completion of study treatment, patients are followed up every 4 months for 1 year.

Arms: arm 1: Patients receive selumetinib sulfate PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a volume decrease in the target cutaneous neurofibromas may continue treatment for 12 additional cycles.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Selumetinib Sulfate
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
i 
 
Title: Pilot Study of the MEK1/2 inhibitor selumetinib (AZD6244 hydrogen sulfate) for 
adults with neurofibromatosis type 1 (NF1) and Cutaneous neurofibromas (CN) 
Table of changes 
This protocol has been updated to reflect the selumetinib pharmaceutical information regarding the capsule 
appearance and the product in-use period from the Pharmaceutical Management Branch. The specific 
changes to the protocol are described in the table below (page numbers refer to the clean pdf version of the 
study; additions are noted in bold italics and deletions are noted with a strikethrough): 
Protocol: 
# 
Section 
Change 
Rationale 
1 
Title page and 
Header 
The version number and version date 
have been updated. 
Protocol Type / Version # / Version 
Date: Amendment / v98.0 / 106 
July December 2021 2019 
 
 
Administrative update 
2 
8.1 Selumetinib, 
Other Names 
 
 
 
 
8.1 Selumetinib, 
Solubility 
 
Correct current list of “Other Names” 
from Selumetinib hydrogen sulfate; 
ARRY-142886 to KOSELUGO, 
Selumetinib Hydr-sulfate; selumetinib 
sulfate; ARRY-142886.  
Other 
Names: 
KOSELUGO, 
Selumetinib 
Hydr-sulfate; 
sSelumetinib 
hydrogen 
sulfate; 
ARRY-142886 
 
Correct “Solubility” from 2.5 to 2.4. 
Solubility: Very low aqueous 
solubility (2.45 mcg/mL at pH 7.4). 
 
 
Updates to sub-section consistent with 
the PMB Pharmaceutical Data Sheet. 


ii 
 
3 
8.1 Selumetinib,  
Section 8.1.1, 
Mode of Action 
 
Addition of (AZD6244 Hydrogen 
Sulfate) x2 to subsection paragraph. 
8.1.1 Mode of Action: Selumetinib 
(AZD6244 hydrogen sulfate) is a 
selective mitogen-activated protein 
kinase (MEK) inhibitor.  By 
inhibiting 
MEK, 
selumetinib 
(AZD6244 
hydrogen 
sulfate) 
inhibits 
ERK 
phosphorylation, 
which 
may 
inhibit 
oncogenic 
growth signaling in tumor cells by 
targeting the RAS/RAF/MEK/ERK 
pathway. 
The 
RAS/RAF/MEK/ERK pathway is 
an important mediator of many 
cellular 
processes 
including 
proliferation, 
survival, 
differentiation, apoptosis, motility, 
and metabolism.   
 
 
Updates to sub-section consistent with 
the PMB Pharmaceutical Data Sheet. 


iii 
 
4 
8.1 Selumetinib, 
Section 8.1.2, 
How Supplied 
The How Supplied sub-section 
updates the supply of 10 mg and 25 
mg capsules as banded and marked 
with “SEL 10” or “SEL 25” 
respectively. There is no change in 
formulation. Formatted as 
appropriate. 
8.1.2 How Supplied: Astra Zeneca 
supplies and PMB, CTEP, NCI, 
DCTD 
distributes 
selumetinib 
(AZD6244 hydrogen sulfate).  The 
agent is 
supplied 
as 
size 4 
hydroxypropylmethylcellulose 
(HPMC) capsules available in 10 mg 
(plain white) and 25 mg (blue) 
strengths, expressed as free base. 
Capsules are packaged in white, 
high density polyethylene (HDPE) 
containers with induction-seals and 
child-resistant closures.  Each bottle 
contains 60 capsules with desiccant. 
• 
10 mg: white, opaque, size 4 
hard capsule, banded and marked 
with "SEL 10" in black ink.  The 
capsule 
shell 
contains 
hypromellose, 
carrageenan, 
potassium 
chloride, 
titanium 
dioxide, 
carnauba 
wax, 
and 
purified water.  The capsule is 
imprinted with black ink that 
contains shellac, iron oxide black, 
propylene glycol and ammonium 
hydroxide. 
• 
25 mg: blue, opaque, size 4 
hard capsule, banded and marked 
with "SEL 25" in black ink. The 
capsule 
shell 
contains 
hypromellose, 
carrageenan, 
potassium 
chloride, 
titanium 
dioxide, FD&C blue 2, ferric oxide 
yellow, purified water, carnauba 
wax, and/or corn starch.  The 
capsule is imprinted with black ink 
that contains ferric oxide red, ferric 
oxide yellow, FD&C Blue 2 
The PMB has updated selumetinib 
pharmaceutical information for NCI 
protocols using PMB-supplied 
Selumetinib (AZD6244 hydrogen 
sulfate), regarding the capsule 
appearance and the product in-use 
period. Thus, updates to sub-section 
consistent with PMB Pharmaceutical 
Data Sheet. 


iv 
 
aluminum lake, carnauba wax, 
shellac, and glyceryl monooleate. 
Selumetinib (AZD6244 hydrogen 
sulfate) capsules contain vitamin E 
as the excipient a dispersion of drug 
in 
D-alphaα-tocopheryl 
polyethylene glycol 1000 succinate 
(TPGS; a water soluble form of 
vitamin E)).  Each 10 mg capsule 
contains 32.4 mg vitamin E as  
TPGS and each 25 mg capsule 
contains 365.9 mg vitamin E as 
TPGS.  
 
5 
8.1 Selumetinib, 
Section 8.1.3, 
Storage 
Addition of (AZD6244 hydrogen 
sulfate) and addition of “controlled.” 
Addition of paragraph regarding 
storage temperature excursion. 
Formatted as appropriate. 
8.1.3 Storage: Store the selumetinib 
(AZD6244 
hydrogen 
sulfate) 
capsules 
at 
controlled 
room 
temperature 
(20°C-25°C). 
Brief 
excursions are permitted between 
15°C and 30°C.    
 
If a storage temperature excursion 
is 
identified, 
promptly 
return 
selumetinib (AZD6244 hydrogen 
sulfate) 
to 
controlled 
room 
temperature and quarantine the 
supplies.  Provide a detailed report 
of 
the 
excursion 
(including 
documentation 
of 
temperature 
monitoring and duration of the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for 
determination of suitability.    
 
 
Updates to sub-section consistent with 
the PMB Pharmaceutical Data Sheet. 


v 
 
6 
8.1 Selumetinib, 
Section 8.1.4, 
Stability 
The Stability sub-section updates the 
product in-use period to provide 
moisture protection over the storage 
period. Deletion of current paragraph 
with exception of first sentence and 
replaced with updates consistent with 
PMB Data Sheet. Addition of 
paragraph about repackaging. 
Formatted as appropriate. 
8.1.4 Stability: Shelf-life sStability 
studies 
are 
ongoing. 
Dispense 
selumetinib (AZD6244 hydrogen 
sulfate) 
capsules 
in 
the 
manufacturer’s HDPE container.  
Do not remove desiccant.  Protect 
from moisture.  Once the container 
induction seal is broken the water 
vapor transmission rate is higher 
than the intact induction sealed 
bottle. Significant increase in the 
moisture content can affect the 
drug product. The current stability 
data for selumetinib (AZD6244 
hydrogen 
sulfate) 
capsules 
supports an in-use period of up to 
60 days. 
If repackaging into a pharmacy-
supplied HDPE bottle is necessary 
for patient dispensing, provide a 
detailed description of the bottle to 
PMBAfterHours@mail.nih.gov for 
determination of suitability.  The 
container must be repackaged with 
desiccant.  A 60 day in-use period 
from the point at which the patient 
reopens the bottle is permitted. 
 If a storage temperature excursion is 
identified, 
promptly 
return 
selumetinib (AZD6244 hydrogen 
sulfate) 
to 
controlled 
room 
temperature and quarantine the 
supplies. Provide a detailed report of 
the 
excursion 
(including 
documentation 
of 
temperature 
monitoring and duration of the 
The PMB has updated selumetinib 
pharmaceutical information for NCI 
protocols using PMB-supplied 
Selumetinib (AZD6244 hydrogen 
sulfate), regarding the capsule 
appearance and the product in-use 
period. Thus, updates to sub-section 
consistent with PMB Pharmaceutical 
Data Sheet. 


vi 
 
excursion) 
to 
PMBAfterHours@mail.nih.gov for 
determination of stability. 
 
7 
8.1 Selumetinib, 
Section 8.1.5, 
Route of 
Administration 
Formatted as appropriate. 
Oral. Do not eat or drink (except 
water only) for 2 hours prior to 
dosing and 1 hour after dosing 
selumetinib (AZD6244 hydrogen 
sulfate) capsules. 
 
 
Updated format of sub-section. 


vii 
 
8 
8.1 Selumetinib, 
Section 8.1.6, 
Potential Drug 
Interactions 
Multiple additions and deletions as 
needed to match PMB Pharmaceutical 
Data Sheet. Formatted as appropriate. 
 
8.1.6 Potential Drug Interactions: 
Avoid 
concomitant 
intake 
of 
supplemental vitamin E. High 
vitamin E doses may potentiate 
warfarin’s anticoagulant activity.  
Monitor PT/INR more frequently in 
patients receiving both warfarin and 
selumetinib capsules.   
Avoid 
concomitant 
intake 
of 
supplemental Vitamin E.  
Selumetinib (AZD6244 hydrogen 
sulfate) is primarily metabolized 
by CYP 31A42 and to a lesser 
extent by CYP2C19, CYP1A2, 
CYP2C9, CYP2E1, and CYP3A5. 
Selumetinib (AZD6244 hydrogen 
sulfate) 
also 
undergoes 
glucuronidation by UGT1A1 and 
UGT1A3.  The active human 
Phase I metabolite, N-desmethyl 
selumetinib, is approximately 3- to 
5-times 
more 
potent 
than 
selumetinib (AZD6244 hydrogen 
sulfate) and metabolized through 
the same routes as selumetinib 
(AZD6244 hydrogen sulfate).  Co-
administration 
of 
selumetinib 
(AZD6244 hydrogen sulfate) with 
the 
potent 
CYP3A4 
inducer 
rifampicin decreased selumetinib 
(AZD6244 hydrogen sulfate) AUC 
by ~50%.  The potent CYP3A4 and 
2C19 inhibitors, itraconazole and 
fluconazole, increased the AUC of 
selumetinib (AZD6244 hydrogen 
sulfate) by ~49% and 53%, 
respectively. 
It 
is 
therefore 
recommended that patients should 
avoid taking strong CYP3A4 
inhibitors/inducers or fluconazole 
(strong CYP2C19 inhibitor and 
Updates to sub-section consistent with 
the PMB Pharmaceutical Data Sheet. 


viii 
 
moderate 
CYP3A4 
inhibitor). 
Moderate inducers and inhibitors 
of CYP3A4 should be avoided as 
well, unless considered clinically 
indicated. to form the active N-
desmethyl metabolite; in addition, 
UGT1A1 
and 
1A3 
form 
glucuronide conjugates. CYP 2C8, 
2C19, 3A4/5 can also metabolize 
the parent agent to form N-
desmethyl selumetinib; however, 
as observed during in vitro studies 
using a pan-CYP inhibitor, other 
available pathways contribute to 
selumetinib 
and 
N-desmethyl 
selumetinib 
metabolism. 
Use 
caution in patients who are taking 
strong inducers or inihibitors of 
these CYP or UGT enzymes. 
Selumetinib (AZD6244 hydrogen 
sulfate) is a substrate of BCRP 
(breast cancer resistance protein) 
and is a low affinity substrate for 
P-gp transporters. Selumetinib 
(AZD6244 hydrogen sulfate) does 
not 
inhibit 
BCRP, 
P-gp, 
OATP1B1, 
OATP1B3, 
OCT2, 
OAT1, 
OAT3, 
MATE1, 
or 
MATE2K 
transporters. 
Selumetinib is also a substrate of 
BCRP (breast cancer resistance 
protein) and P-gp transporters.  Use 
caution in patients who are taking 
strong inducers or inhibitors of 
either transport protein. 
Selumetinib does not inhibit CYP 
1A2, 2C8, 2C19 and 3A4 or UGT 
isoforms 1A1 and 2B7. It is a weak 
inducer of CYP enzymes 3A, 1A 
and 2C9 and a weak inhibitor of 
CYP 2C9, 2B6 and 2D6. In vitro 
studies demonstrate selumetinib is 
an inhibitor of BCRP, OATP1B1, 
OATP1B3, OCT2, OAT1 and 
OAT3 transporters. It does not 


ix 
 
inhibit OCT1, MATE1, MATE2K 
or P-glycoprotein (MDR1). The N-
desmethyl metabolite is a weak 
inhibitor of CYP3A4 and 1A2. In 
vitro data suggest that selumetinib 
is unlikely to cause clinically 
relevant drug-drug interactions by 
these mechanisms. 
Patient Care Implications: Study 
participants should be counseled to 
avoid excessive sun exposure and 
use 
adequate 
sun 
protection 
measures if sun exposure is 
anticipated during the study. 
 


x 
 
9 
13 Statistical 
Considerations  
 
 
 
 
 
Added additional information  
 
In all patients, when possible, ≥3 
areas will be chosen, but only one 
area for a patient is required 
minimally because of the difficulty in 
obtaining patients with multiple 
areas.  
The effect of selumetinib will be 
separately evaluated in up to 3-5 
smaller 
(longest 
neurofibroma 
diameter 4-7 mm) and 3-5 larger 
(longest neurofibroma diameter ≥8 
mm) neurofibromas in each of the 3 
regions.  
 Any patient with at least two lesions 
classified 
as 
smaller 
and/or 
2 
classified as larger in a single area 
will be considered evaluable and 
included in the appropriate analyses. 
The analyses will be supplemented by 
a description of the numbers of 
tumors of each type and number of 
areas evaluated per patient, which 
will be used to further interpret the 
findings. Sub-analyses, which may 
largely be descriptive, and based on 
the numbers of areas included may 
also be done to further interpret the 
results. 
 
With 16 evaluable patients with 
measurements available at pre cycle 
13 who have continued to receive 
selumetinib for the same duration, this 
would provide 90% power to detect a 
1.0 effect size (1 SD of the difference 
in volume from pre to post treatment), 
using a 0.025 two-sided paired t-test in 
order to allow for a Bonferroni 
adjustment for two tests to hold the 
overall significance level to 0.05. In 
practice, the two comparisons (one for 
smaller and one for larger tumors) 
may be reported using a less overly 
conservative Hochberg adjustment.  
Updates to sub-section consistent with the 
GrossCutaneousNeurofibromasRevision
072720.doc 
 
 
 
 
 


xi 
 
10 
Multiple sections 
and sub-sections 
within table of 
contents 
 
 
 
 
 
Table of contents. Multiple field code 
changes and deletions/additions to 
update page numbers post amendment 
changes. Would not let me hyperlink 
changes to table of contents on the left 
column but they are tracked for 
reference. Thus, only changes were 
several page numbers across multiple 
sections and sub-sections. 
 
Table of contents, page numbers 
updated. 
 
 


 
1 
 
Abbreviated Title: Pilot Selumetinib Cutaneous NF 
UAB Protocol #:   NCI Protocol #:  9990 
Protocol Type / Version # / Version Date: Amendment/ v9.0 / 16 July 2021 
ClinicalTrials.gov Identifier: NCT02839720 
TITLE: PILOT STUDY OF THE MEK1/2 INHIBITOR SELUMETINIB (AZD6244 
HYDROGEN SULFATE) FOR ADULTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) 
AND CUTANEOUS NEUROFIBROMAS (CNF) 
Principal Investigator:   
+Bruce R. Korf, M.D., Ph.D., University of Alabama at 
Birmingham, AL (UAB) 
 
Coordinating Center: 
 
University of Alabama at Birmingham 
 
 
 
 
 
720 20th Street South 
 
 
 
 
 
Birmingham, AL 35294-0024 
Co-Principal Investigator: 
 
+Brigitte Widemann, M.D., POB, NCI * 
Associate Investigators:    
 
**Shaila Handattu, Ph.D., P.M.P., UAB 
 
 
 
 
 
Ashley Cannon, Ph.D., M.S., CGC, UAB 
 
 
 
 
 
Tammi Skelton, M.S.N., CRNP, NP-C, UAB 
** Seth M. Steinberg, Ph.D. (Biostatistics, OD, CCR, NCI) 
Trish Whitcomb, RN, OD, CCR, NCI 
Eva Dombi, M.D, POB, NCI 
Joanne Derdak, NP, POB, NCI 
Pam Wolters, Ph.D., POB, NCI 
Staci Peron, Ph.D., POB, NCI 
Alessandra Brofferio, M.D., NHLBI 
Edward W. Cowen, M.D. DB, NIAMS 
Dominique Pichard, M.D., DB, NIAMS 
Non-NIH Associate Investigators: 
**, &Wade Clapp, M.D., Riley Hospital for Children, Indianapolis, IN  
 **, & Gary L. Johnson, Ph.D., University of North Carolina School of 
Medicine, Chapel Hill, NC  
 Jennifer DeSanto, R.N., Leidos Biomedical Research, Inc.  
** Not responsible for direct patient care 
+ Responsible for selumetinib prescription   
*Pharmacology & Experimental Therapeutics Section 
& Receiving samples for analysis; non-enrolling sites 
Referral Contact: 
Shaila Handattu, Ph.D., P.M.P., UAB, Trish Whitcomb, RN, OD, CCR, NCI 
Investigational Agents:     
Drug Name: 
Selumetinib (AZD6244 hyd sulfate) 
NSC# 
748727 
Sponsor: 
CTEP 
Manufacturer: 
Astra-Zeneca 
KEY WORDS:  Neurofibromatosis type 1, cutaneous neurofibromas, tumor response 
PROPRIETARY and CONFIDENTIAL 


2 
 
PARTICIPATING SITES 
Name of Institutional PI: Bruce R. Korf, M.D., Ph.D. 
Institution: University of Alabama at Birmingham 
Institution FWA# FWA00005960  
Address: 720 20th Street South, Birmingham, Alabama 35294-0024 
Phone Number: 205-934-9411 
Email: bkorf@uabmc.edu 
 
Name of IRB Contact: Leslie Cooper, CIP, Interim Director 
IRB of Record Name: University of Alabama at Birmingham Institutional Review Board 
IRB IORG #: IRB00000196 U of Alabama at Birmingham IRB #1; IRB00000726 U of Alabama at 
Birmingham IRB #2 
Address: 701 20th Street South, Administration Building Room 470, Birmingham, AL 35294-0104 
Phone Number: 205-934-3789 
Email: irb@uab.edu 
 
Name of Pharmacy Contact: Chris Chapleau, PharmD, PhD, MBA 
Address: 1802 6th Avenue South, UAB North Pavilion Room 3470, Birmingham, AL 35249 
Phone Number: 205-934-7191 
Email: cchapleau@uabmc.edu 
 
Name of Institutional Study Coordinator: Ashley Cannon, PhD, MS, CGC  
Address: 720 20th Street South, Birmingham, AL 35294-0024 
Phone Number: 205-996-2916 
Email: ashleycannon@uabmc.edu 
 
Name of Institutional PI: Brigitte Widemann, MD 
Institution: Pediatric Oncology Branch, NCI 
Institution FWA#:  FWA#00005897 / IRB#00000001 
Address:  10 Center Drive, MSC 1104, Building 10-CRC, Room 1-3750, Bethesda, MD 20892-1104 
Phone Number:  240-760-6203 
Email: widemanb@mail.nih.gov 
 
Name of IRB Contact:  Philip Arlen, MD, Chair 
IRB of Record Name:  NCI IRB 
Address: 11400 Rockville Pike, Suite 700, MSC 9171, Bethesda, MD 20892-9171 
Phone Number:  240-276-7991 
Email:  philip.arlen@nih.gov 
 
Name of Pharmacy Contact:  Nicole Barnes, PharmD, Pharmacy, CC, NIH 
Address:  10 Center Drive, Building 10, 1C240, Bethesda, MD 20892-1196 
Phone Number:  301-496-4363 
Email:  nicole.barnes@nih.gov  
 
Name of Institutional Study Coordinator: Trish Whitcomb, RN 


3 
 
Address:  10 Center Drive, Building 10-CRC, Rm 1-5750, Bethesda, MD 20892-1104 
Phone Number:  240-760-6104 
Email: whitcombt@mail.nih.gov 
 
 
 


4 
 
PRÉCIS:  
Background: 
• Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3500 in the 
US.  One of the hallmark features of NF1 is the development of histologically benign peripheral 
nerve sheath tumors called cutaneous neurofibromas in most individuals with NF1. Some patients 
develop hundreds to thousands of cutaneous neurofibromas. While cutaneous neurofibromas have 
not been described to undergo malignant transformation, they can be debilitating, affecting 
emotional and social quality of life, especially when they occur in large numbers in visible body 
areas. 
• Selumetinib (AZD6244) is a novel orally bioavailable mitogen activated protein kinase inhibitor, is 
a specific inhibitor of MEK 1, which may mediate anti-tumor effects in NF1 related tumors by 
inhibition of downstream signaling of Ras. Selumetinib is currently undergoing evaluation in adult 
cancers and children with brain tumors and in children and adults with NF1-related plexiform 
neurofibromas (PN). 
• In an NCI phase I trial of selumetinib for children and young adults with NF1 and inoperable PN we 
have observed preliminary activity with PN volume decrease in 71% of patients enrolled. This 
degree of activity has not been observed in prior trials directed at PN. We observed shrinkage in 
progressive and non-progressive PN, and a subset of patients also experienced an improvement in 
function and decrease in pain.  Selumetinib has been tolerated well over multiple treatment cycles, 
and all dose-limiting toxicities were reversible. 
• We hypothesize that selumetinib will result in shrinkage of existing cutaneous neurofibromas in 
individuals with NF1 and may prevent or delay the development of new cutaneous neurofibromas.   
Objectives: 
• 
The primary objective will be to determine if selumetinib can result in shrinkage of cutaneous 
neurofibromas.  
• 
Secondary objectives will include the assessment of the effect of selumetinib on:  
o Target inhibition in cutaneous neurofibroma(s) excised prior treatment and on treatment with 
selumetinib for analysis of percent inhibition of pERK and changes in pAKT; 
• 
Exploratory objectives will include the assessment of the effect of selumetinib on: 
o The development on new cutaneous neurofibromas while on treatment with selumetinib; 
o Target inhibition in cutaneous neurofibroma(s) excised prior treatment and on treatment with 
selumetinib for analysis of the tumor kinome. 
o Skin related morbidity and pain using the Skindex, the Global Impression of Change Scale and 
Numeric Rating Scale, all of which are patient reported outcome measures. 
o Quantify the development of new cutaneous neurofibromas on treatment with selumetinib; and 
o Detailed pathologic analysis of cutaneous neurofibromas pre-treatment and on treatment with 
selumetinib for changes in cell composition (including macrophage and mast cell infiltration). 
o Alterations that correlate with cNF response to selumetinib treatment with pilot genomic, DNA 
methylation, and transcriptomic studies. 
Eligibility: 
• Patients must be at least 18 years of age with a diagnosis of NF1, must have measurable cutaneous 
neurofibromas, and substantial neurofibroma burden causing distress, disfigurement, or itching.    


5 
 
• Patients must have adequate organ function, and have recovered from acute toxicity of all prior NF1 
tumor directed treatment. 
Design: 
• This is a limited institution open label pilot study in which all subjects will receive selumetinib orally 
at the recommended phase II dose for NF1 PN (50 mg/dose) approximately every 12 hours (one 
cycle = 28 days). If tolerated, the dose may be escalated after cycle 1 to 75 mg every 12 hours.  
• Patients will undergo regular evaluation for selumetinib related toxicities. In absence of treatment 
limiting toxicity, or progression of disease, patients may remain on treatment for a maximum of 24 
cycles unless they experience a volume decrease in the target cutaneous neurofibromas, in which 
case treatment may continue for additional 12 cycles. Patients who discontinue treatment with 
selumetinib will be monitored after every 4 months for 12 months off treatment for changes in 
cutaneous neurofibroma volume and number. Volume decrease will be defined as a ≥ 20% decrease 
in the sum of the volumes of the smaller and/or larger target cutaneous neurofibromas. 
• For response evaluation, the average volume of 3-5 small (longest neurofibroma diameter 3-7 mm) 
and 3-5 larger (longest neurofibroma diameter ≥8 mm) target cutaneous neurofibromas in 3 different 
body regions will be calculated at each response evaluation (baseline, and then after every 4 cycles). 
Cutaneous neurofibromas will be measured with calipers, and volumes will be calculated by 
multiplying length, width, and height of each target neurofibroma. At each response evaluation the 
sum of the on-treatment volumes for the smaller tumors will be subtracted from the pre-treatment 
volumes of the same tumors to arrive at an overall percentage change in tumor size for each patient. 
This will be repeated for the larger tumors. Then, the average percentage change for each size 
category will be reported along with its 95% confidence interval, and other associated statistics. A 
maximum of 24 patients will be enrolled, and 16 evaluable patients will be required to have 90% 
power to detect a 1.0 effect size. Enrollment will proceed over approximately 12 months. 
• In order to assess changes in skin related morbidity and pain, patients will complete both the Skindex 
and the Global Impression of Change Scale along with the Numeric Rating Scale, all of which are 
patient reported outcome measures. 
• In order to evaluate the pharmacodynamic effects of selumetinib, patients will undergo mandatory 
excisions of ≥ 1 cutaneous neurofibroma prior to treatment and once on treatment with selumetinib 
to assess percent inhibition of pERK and changes in pAKT and other molecular markers such as 
tumor kinome.  
 
 


6 
 
SCHEMA 
 
 
 
 


7 
 
Table of Contents  
TITLE: PILOT STUDY OF THE MEK1/2 INHIBITOR SELUMETINIB (AZD6244 
HYDROGEN SULFATE) FOR ADULTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) 
AND CUTANEOUS NEUROFIBROMAS (CNF) .............................................................................. 1 
PARTICIPATING SITES ..................................................................................................................... 2 
PRÉCIS:.................................................................................................................................................. 4 
SCHEMA ................................................................................................................................................ 6 
TABLE OF CONTENTS ...................................................................................................................... 7 
1 
STUDY OBJECTIVES ................................................................................................................ 11 
1.1 
Primary Objective: ................................................................................................................. 11 
1.1.1 
Determine if selumetinib can result in shrinkage of cutaneous neurofibromas. ............................. 11 
1.2 
Secondary Objective: ............................................................................................................. 11 
1.2.1 
Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior 
treatment and on treatment with selumetinib for analysis of percent inhibition of pERK, and changes in 
pAKT. 11 
1.3 
Exploratory Objective(s): ....................................................................................................... 11 
1.3.1 
Assess the effect of selumetinib on the development on new cutaneous neurofibromas while on 
treatment with selumetinib. .......................................................................................................................... 11 
1.3.2 
Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior 
treatment and on treatment with selumetinib for analysis of the tumor kinome. ......................................... 11 
1.3.3 
Assess the effect of selumetinib skin related morbidity and pain using the Skindex, the Global 
Impression of Change Scale and Numeric Rating scale, all of which are patient reported outcome 
measures. ...................................................................................................................................................... 11 
1.3.4 
Quantify the development of new cutaneous neurofibromas on treatment with selumetinib ......... 11 
1.3.5 
Detailed pathologic analysis of cutaneous neurofibromas pretreatment and on treatment with 
selumetinib for changes in cell composition (including macrophage and mast cell infiltration). ................ 11 
1.3.6 
Investigate alterations that correlate with cNF response to selumetinib treatment with pilot 
genomic, DNA methylation, and transcriptomic studies.............................................................................. 11 
2 
BACKGROUND AND RATIONALE ....................................................................................... 11 
2.1 
Pathogenesis and clinical presentation of cutaneous and plexiform neurofibromas in 
neurofibromatosis type 1: .................................................................................................................. 11 
2.1.1 
Cutaneous neurofibromas:............................................................................................................... 12 
2.1.2 
Plexiform neurofibromas: ............................................................................................................... 12 
2.1.3 
Pathogenesis of cutaneous and plexiform neurofibromas: .............................................................. 12 
2.1.4 
Imaging and measurement of cutaneous neurofibromas: ................................................................ 13 
2.1.5 
Clinical trials directed at cutaneous neurofibromas: ....................................................................... 14 
2.1.6 
Clinical trials directed at PN ........................................................................................................... 14 
2.2 
Selumetinib [AZD6244 (ARRY-142886; selumetinib)] ....................................................... 15 
2.2.1 
Nonclinical Studies ......................................................................................................................... 16 
2.2.2 
Clinical Experience ......................................................................................................................... 18 
2.2.3 
Clinical trials of selumetinib in adults with refractory cancers and children with NF1 and PN: .... 20 
2.3 
Rationale for the proposed Pilot Study: ................................................................................. 22 
2.4 
Correlative Studies Background ............................................................................................ 23 
2.4.1 
Effect of selumetinib on target inhibition in cutaneous neurofibroma(s) ........................................ 23 
2.4.2 
Investigate genomic alterations that correlate with cNF size response to selumetinib treatment: .. 24 


8 
 
3 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................... 25 
3.1 
Eligibility Criteria .................................................................................................................. 25 
3.1.1 
Inclusion Criteria ............................................................................................................................. 25 
3.1.2 
Exclusion Criteria ............................................................................................................................ 27 
3.2 
Inclusion of Women and Minorities ...................................................................................... 29 
4 
REGISTRATION PROCEDURES ............................................................................................ 29 
4.1 
Registration with the Coordinating Center ............................................................................ 29 
4.2 
Screening Evaluation ............................................................................................................. 30 
5 
TREATMENT PLAN .................................................................................................................. 31 
5.1 
Study Design Overview ......................................................................................................... 31 
5.2 
Agent Administration ............................................................................................................. 32 
5.3 
Duration of Treatment............................................................................................................ 33 
5.4 
Supportive Therapies ............................................................................................................. 33 
5.4.1 
Follow up for certain AEs should be performed to better characterize the effects of selumetinib 
therapy: ......................................................................................................................................................... 33 
5.4.2 
Dermatologic adverse events: ......................................................................................................... 33 
5.4.3 
Visual adverse events: ..................................................................................................................... 34 
5.4.4 
Gastrointestinal adverse events: Diarrhea ....................................................................................... 34 
5.4.5 
Gastrointestinal adverse events: Oral mucositis .............................................................................. 35 
5.4.6 
Pulmonary adverse events: Dyspnea ............................................................................................... 35 
5.4.7 
Surgical procedures ......................................................................................................................... 35 
5.5 
Concurrent Therapies ............................................................................................................. 35 
5.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria .................................... 36 
5.6.1 
Criteria for removal from protocol therapy ..................................................................................... 36 
5.6.2 
Off-Study Criteria ........................................................................................................................... 37 
6 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................ 37 
6.1 
Treatment Limiting Toxicities ............................................................................................... 37 
6.2 
Dose Modifications ................................................................................................................ 38 
6.3 
Cardiac Toxicity ..................................................................................................................... 41 
6.4 
Toxicity Criteria ..................................................................................................................... 43 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
43 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ..................................... 43 
7.2 
Definitions.............................................................................................................................. 46 
7.2.1 
Adverse Event ................................................................................................................................. 46 
7.2.2 
Any untoward medical occurrence in a human subject, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in research, whether or not considered related to the subject’s participation in the 
research. ....................................................................................................................................................... 46 
7.2.3 
Suspected adverse reaction .............................................................................................................. 46 
7.2.4 
Unexpected adverse reaction ........................................................................................................... 47 
7.2.5 
Serious ............................................................................................................................................. 47 
7.2.6 
Serious Adverse Event .................................................................................................................... 47 
7.2.7 
Disability ......................................................................................................................................... 47 
7.2.8 
Life-threatening adverse drug experience ....................................................................................... 47 
7.2.9 
Protocol Deviation: ......................................................................................................................... 47 
7.2.10 
Non-compliance .......................................................................................................................... 48 


9 
 
7.2.11 
Unanticipated Problem ............................................................................................................... 48 
7.3 
Coordinating Center and IRB Reporting ............................................................................... 48 
7.3.1 
IRB Expedited Reporting of Unanticipated Problems and Deaths ................................................. 48 
7.3.2 
IRB Requirements for PI Reporting at Continuing Review ............................................................ 48 
7.3.3 
IRB Reporting of IND Safety Reports ............................................................................................ 49 
7.4 
Adverse Events: List and Reporting Requirements to CTEP A ............................................ 49 
7.4.1 
Adverse Event Characteristics ........................................................................................................ 49 
7.4.2 
Expedited Adverse Event Reporting to CTEP ................................................................................ 50 
7.4.3 
Distribution of Adverse Event Reports ........................................................................................... 50 
7.4.4 
Expedited Reporting Guidelines ..................................................................................................... 50 
7.4.5 
Routine Adverse Event Reporting ................................................................................................... 52 
7.4.6 
Secondary Malignancy .................................................................................................................... 52 
7.4.7 
Second Malignancy ......................................................................................................................... 52 
7.5 
Data Safety Monitoring Plan ................................................................................................. 52 
7.5.1 
Principal Investigator/Research Team ............................................................................................ 52 
7.5.2 
Sponsor Monitoring Plan ................................................................................................................ 53 
8 
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION ................ 53 
8.1 
Selumetinib ............................................................................................................................ 53 
8.1.1 
Mode of Action: .............................................................................................................................. 54 
8.1.2 
How Supplied: ................................................................................................................................. 54 
8.1.3 
Storage: ........................................................................................................................................... 54 
8.1.4 
Stability: .......................................................................................................................................... 54 
8.1.5 
Route of Administration: ................................................................................................................. 55 
8.1.6 
Potential Drug Interactions: ............................................................................................................ 55 
8.1.7 
Agent Ordering and Agent Accountability: .................................................................................... 55 
8.1.8 
Useful links and Contacts ................................................................................................................ 56 
8.1.9 
Selumetinib Administration ............................................................................................................ 56 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................... 57 
9.1 
Correlative Studies for Research ........................................................................................... 57 
9.1.1 
Biopsies (See Appendix VI) ............................................................................................................ 58 
9.2 
Sample Storage, Tracking and Disposition ............................................................................ 58 
9.2.1 
Tumor Collection ............................................................................................................................ 58 
9.2.2 
Sample Storage and Destruction ..................................................................................................... 58 
10 STUDY CALENDAR .................................................................................................................. 59 
10.1 
On-Study Evaluations (See Appendix III) ............................................................................. 59 
10.2 
Off Therapy Evaluations ........................................................................................................ 61 
10.3 
Study Calendar ....................................................................................................................... 61 
11 MEASUREMENT OF EFFECT ................................................................................................ 61 
12 DATA REPORTING / REGULATORY REQUIREMENTS ................................................. 62 
12.1 
Data Collection ...................................................................................................................... 62 
12.2 
Data Sharing Plans ................................................................................................................. 62 
12.2.1 
Genomic Data Sharing Plan ........................................................................................................ 62 
12.3 
CTEP Multicenter Guidelines ................................................................................................ 62 
12.4 
Collaborative Agreements Language ..................................................................................... 62 
13 STATISTICAL CONSIDERATIONS ....................................................................................... 64 
13.1 
Sample Size Accrual .............................................................................................................. 65 


10 
 
14 HUMAN SUBJECTS PROTECTIONS ..................................................................................... 66 
14.1 
Rationale For Subject Selection ............................................................................................. 66 
14.2 
Participation of Children ........................................................................................................ 66 
14.3 
Evaluation of Benefits and Risks/Discomforts ...................................................................... 66 
14.3.1 
Risks of Selumetinib ................................................................................................................... 66 
14.3.2 
Risk of cutaneous neurofibroma biopsy ..................................................................................... 67 
14.4 
Consent and Assent Process and Documentation .................................................................. 67 
15 MULTI-INSTITUTIONAL GUIDELINES .............................................................................. 67 
15.1 
IRB Approvals ....................................................................................................................... 67 
15.2 
Amendments and Consents .................................................................................................... 67 
15.3 
IND Action Letters or Safety Reports ................................................................................... 67 
15.4 
Drug Ordering ........................................................................................................................ 68 
16 REFERENCES ............................................................................................................................. 69 
17 APPENDICES .............................................................................................................................. 74 
17.1 
Appendix I:  Medications to Avoid ....................................................................................... 75 
17.1.1 
PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ............................... 75 
17.2 
Appendix II: New York Heart Association Classifications ................................................... 77 
17.3 
Appendix III: Required Study Evaluations ............................................................................ 78 
17.4 
Appendix IV: Skindex ........................................................................................................... 79 
17.5 
Appendix V: Safety Management Algorithm for Dyspnea ................................................... 84 
17.6 
Appendix VI:  Biopsy Collection and Transport for Analysis .............................................. 84 
17.6.1 
Biopsies for pAKT/pERK analysis, pathologic analysis, and kinome analysis. ......................... 85 
Samples for pERK/pAKT (Priority #1).................................................................................................... 85 
Pathology, Formalin Fixed Specimens (Priority #2) ............................................................................... 86 
Kinome Analyses (Priority #3) .................................................................................................................. 86 
17.6.2 
Optional biopsies for whole genome sequencing, transcriptome analysis, and DNA methylation 
studies (To be performed by Ashley Cannon at UAB and HudsonAlpha). ................................................. 87 
17.7 
Appendix VII: Patient Daily Medication Diary for Selumetinib ........................................... 88 
17.8 
Appendix VIIA:  Adherence .................................................................................................. 90 
17.9 
Appendix VIII:  Measurement and counting of cutaneous neurofibromas ............................ 91 
A) Measurement of cutaneous neurofibromas ........................................................................................ 91 
B) Counting of cutaneous neurofibromas ................................................................................................ 92 
17.10 
Appendix IX: CTEP Multicenter Guidelines ..................................................................... 94 
17.11 
Appendix X: Global Impression of Change Scale..............................................................95 
17.12 
Appendix XI: Numeric Rating Scale..................................................................................97 


11 
 
1 
STUDY OBJECTIVES 
1.1 
PRIMARY OBJECTIVE: 
1.1.1 Determine if selumetinib can result in shrinkage of cutaneous neurofibromas. 
1.2 
SECONDARY OBJECTIVE: 
1.2.1 Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior 
treatment and on treatment with selumetinib for analysis of percent inhibition of pERK, and 
changes in pAKT. 
1.3 
EXPLORATORY OBJECTIVE(S): 
1.3.1 Assess the effect of selumetinib on the development on new cutaneous neurofibromas while on 
treatment with selumetinib. 
1.3.2 Assess the effect of selumetinib on target inhibition in cutaneous neurofibroma(s) excised prior 
treatment and on treatment with selumetinib for analysis of the tumor kinome. 
1.3.3 Assess the effect of selumetinib skin related morbidity and pain using the Skindex, the Global 
Impression of Change Scale and Numeric Rating Scale, all of which are patient reported outcome 
measures.  
1.3.4 Quantify the development of new cutaneous neurofibromas on treatment with selumetinib 
1.3.5 Detailed pathologic analysis of cutaneous neurofibromas pretreatment and on treatment with 
selumetinib for changes in cell composition (including macrophage and mast cell infiltration). 
1.3.6 Investigate alterations that correlate with cNF response to selumetinib treatment with pilot 
genomic, DNA methylation, and transcriptomic studies. 
2 
BACKGROUND AND RATIONALE 
2.1 
PATHOGENESIS 
AND 
CLINICAL 
PRESENTATION 
OF 
CUTANEOUS 
AND 
PLEXIFORM 
NEUROFIBROMAS IN NEUROFIBROMATOSIS TYPE 1:  
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 tumor 
suppressor with an incidence of 1:3500 in the US(1). NF1 is characterized by diverse, progressive 
cutaneous, neurological, skeletal, and neoplastic manifestations with no standard drug treatment options 
available. The neurofibroma is the defining clinical feature of NF1 and is responsible for much of the 
medical burden of the disorder.  Although the fundamental pathology is similar, neurofibromas come in 
a variety of forms and in various locations.  Ratner and Carroll(2) distinguished five distinct forms of 
neurofibromas: localized cutaneous, diffuse cutaneous, localized intraneural, plexiform, and massive 
soft tissue.   


12 
 
2.1.1 Cutaneous neurofibromas: 
Localized cutaneous neurofibromas occur either on the surface of the skin or within the dermis and are 
easily visible in adults with NF1. In her 1988 population-based survey in Wales, Huson(3) found 
cutaneous neurofibromas in >99% of adults with NF1, making this the most common medically 
significant manifestation of the condition in adults.  This study described an increase in the number of 
cutaneous neurofibromas with increasing age in individuals with NF1(3). This study also reported that 
10/30 (33%) parous women described an increase in size and number of cutaneous neurofibromas during 
pregnancy. Most reports in the literature quantified cutaneous neurofibromas by counting them at a 
single time point, and longitudinal measurements in individual patients have not been reported. 
Spontaneous shrinkage of cutaneous neurofibromas has not been described to date. The growth and 
increasing number of these lesions can cause substantial cosmetic burden and may cause symptoms of 
bleeding and itching. Treatment of cutaneous neurofibromas has been limited to surgical excision or 
extirpation using a laser(4-9) or by electrodessication.  Some individuals have hundreds of skin tumors 
removed in a single session, but it is usually impossible to remove all of the tumors.  Also, all of these 
approaches leave a scar and additional tumors will reappear over time.  There have been very few efforts 
to test non-surgical treatment. 
2.1.2 Plexiform neurofibromas: 
Another cardinal feature of NF1 the development of histologically benign peripheral nerve sheath 
tumors called plexiform neurofibromas (PN) in 25-40% of individuals with NF1. Unlike discrete 
neurofibromas, PN grow along the length of nerves and involve multiple branches of a nerve (10). They 
are a major source of morbidity(11-13), causing disfigurement, impairment of nerve function, pain, and 
in some cases development of malignant peripheral nerve sheath tumors (14, 15).  Many PN are thought 
to be congenital or occur at early age, have a complex shape, and can become very large. Currently, 
there are no standard treatment options other than surgery for these tumors.  Complete resection is often 
not feasible due to the extensive growth of the tumor, rich vascular supply, and invasion of the 
surrounding tissues, and regrowth after surgery is common (16, 17).  
2.1.3 Pathogenesis of cutaneous and plexiform neurofibromas: 
Histologically, cutaneous neurofibromas and PN are composed of neoplastic Schwann cells, which lack 
NF1 gene expression, accompanied by a varying number of cellular and non-cellular components 
including fibroblasts, perineurial cells, mast cells, and collagen (18). The gene responsible for NF1 
encodes a protein called neurofibromin. Although the function of neurofibromin is not completely 
understood, it is known to include a GTPase activating protein (GAP) domain that regulates hydrolysis 
of Ras-GTP to Ras-GDP. Therefore, loss of neurofibromin is associated with Ras activation (18).  
Activated Ras results in the initiation of a cascade of signaling events such as activation of Raf and 
MAPK that lead to increased cell proliferation (19, 20). In addition, activation of the mTOR pathway 
has been identified in benign and malignant NF1 tumors (21-23), and the tumor microenvironment 
contributes to the pathogenesis of PN. Schwann cells have been shown to secrete kit ligand, which 
recruits mast cells, and results in abnormal growth properties (24-26). Blocking Ras activity or Ras 
signaling provides thus a rational approach towards the treatment of PN. 
These insights into the pathogenesis of neurofibromas have opened the door towards development of 
therapies that that target the pathogenetic mechanisms. Various inhibitors of Ras or its downstream 
effectors have been tested in preclinical models or clinical trials, reviewed by Gutmann et al.(27) and 
described in more detail below.  Extracellular signaling proteins, especially those involving mast cells 


13 
 
that are abundant in neurofibromas, have also been targeted.  Several agents have been shown to be 
effective in reducing the rate of growth or even shrinking neurofibromas in mouse models, and have 
subsequently been advanced to clinical trials in humans with NF1.  All of these recent clinical trials 
have targeted plexiform neurofibromas, rather than cutaneous neurofibromas.  This is due to the 
significant morbidity of these tumors, including their propensity to cause major disfigurement, pain, or 
compression of critical structures.  These complications often occur in children and are typically beyond 
the reach of surgical treatment, lending urgency to the development of non-surgical therapies. 
Although the rationale for focusing on plexiform neurofibromas in clinical trials is understandable, the 
morbidity of cutaneous neurofibromas should not be underestimated.  These tumors are not life-
threatening, but they can be highly disfiguring, prone to bleeding and infection, itch, and can be painful 
by rubbing against clothing.  As such, they are responsible for major negative effects on quality of life 
for patients with NF1, typically adults.  Wolkenstein et al.(28) surveyed 128 adults in France with NF1 
for quality of life measures and found that visibility of lesions was associated with negative effects on 
emotions, physical symptoms, and functioning.  Similar findings were reported by Kodra et al.(29) in 
an Italian cohort and Page et al.(30) in U.S. cohort.  Although the number and size of cutaneous 
neurofibromas varies widely from one person to the next, some individuals have thousands of visible 
neurofibromas, including on areas of the body that cannot be covered up, such as the hands and face.   
2.1.4 Imaging and measurement of cutaneous neurofibromas:   
The development of clinical trials directed at cutaneous neurofibromas has been hampered by the 
difficulty in measuring and counting cutaneous neurofibromas. We recently developed and validated an 
approach to quantification of number and size of cutaneous neurofibromas that will provide a reliable 
outcome measure. This is through the combined use of a method to document the number of tumors and 
a caliper-based measurement to determine surface volume. We have developed paper frames with a 100 
cm2 cut-out area that is used to guide the assessment (Figure 1).  The frames are made from paper that 
is sticky on the back and are adhered to areas of skin, typically on the back, the abdomen, and the thigh.  
Visible landmarks are used to align the frames consistently when measurements are done at different 
times, using photographs to insure similar positioning from one time to the next (the neurofibromas 
themselves provide clear landmarks).  Counts can be done manually in “real time,” marking 
neurofibromas with a washable marker to avoid counting a tumor more than once; counts can also be 
done on a photograph.  We have shown that different observers obtain similar counts(31), provided there 
is prior agreement on the threshold size of tumors to be counted; we typically set a lower size threshold 
of 4 mm in longest diameter for counting.   
We have also developed an approach to measure the size of cutaneous neurofibromas.  In our first test, 
we compared measurements done with a calipers to measurements done with a 3-D laser scanner using 
a set of 16 plaster model “tumors” of known volume that were placed on the skin.  The models ranged 
from 1.18-452.39 cubic mm in volume and from 2 to 12 mm in longest diameter, and 1 to 6 mm in 
height.  Three different observers measured the models with a caliper, measuring two perpendicular 
diameters and height above the skin, and results were compared with the results of the laser scanner 
calculated volumes.  Table 1 only shows data indicating Pearson correlation coefficients of the volumes 
calculated from measurements made by the three observers (H1, H2, and H3) as compared with the true 
volumes of the models.  Data on the use of the laser scanner are not shown, as we concluded that the 
manual measurements were more accurate than those obtained with the scanner and therefore manual 
measurements with a caliper will be used in this clinical trial.  We have used this approach to monitor 
tumor size in a cohort of 24 patients with NF1 followed over a two-year period, with measurements 


14 
 
done every 4 months, for a total of seven visits.  A minimum of six and maximum of 18 tumors were 
monitored for each patient, for a total of 1980 tumors measured cumulatively across all patients and all 
seven time points.  Aggregate data for all tumors is shown in Figure 2.  Tumor growth was significant 
(p = 0.0185) over the period of observation, although the trend of increased volume was very slight. 
 
We believe that these studies provide the basis for meaningful evaluation of targeted agents in trials for 
cutaneous neurofibromas. 
2.1.5 Clinical trials directed at cutaneous neurofibromas:  
Riccardi conducted a trial with the antihistamine ketotifen in the 1980s(32) and reported improvement 
in neurofibroma-related itching and pain, but not in tumor size or number.  A search of clinicaltrials.gov 
(July 20, 2015) reveals several entries of clinical trials for cutaneous neurofibromas, including 
ranibizumab, imiquimod 5% cream, erbium-YAG laser vaporization, topical rapamycin, and 
photodynamic therapy.  No current information is posted about the ranibizumab, imiquimod, or topical 
rapamycin studies and there is no published information on these trials in PubMed.  There is substantial 
literature on the effectiveness of laser therapy. The photodynamic therapy trial involves use of delta 
aminolevulinic acid as a photosensitizer with subsequent illumination with 630 nm light; this trial is 
indicated as ongoing in clinicaltrials.gov. 
2.1.6 Clinical trials directed at PN  
In contrast to cutaneous neurofibromas, multiple clinical trials targeting plexiform neurofibromas have 
been conducted to date (27) including  the farnesyltransferase inhibitor tipifarnib(33), the antifibrotic 
agent pirfenidone(34-36), the mTOR inhibitor sirolimus(37, 38), the antiangiogenic and immune 
modulatory agent peginterferon alfa-2b (39, 40), and the c-kit inhibitor imatinib. The tipifarnib trial was 
double-blinded and included a placebo control group (29 patients), and the median time to progression 
(TTP) of progressive PN treated with placebo was 10. 6 months. Tipifarnib did not result in a doubling 
of the TTP compared to the placebo arm. Three subsequent open label phase II trials used the tipifarnib 
trial placebo group to evaluate if the agent of interest would result in an increase in the TTP compared 
to the placebo control group. Of all phase II trials performed to date, the following agents have 
demonstrated activity: Compared to the tipifarnib placebo control group, peginterferon alfa-2b achieved 
a doubling in the TTP (39) and sirolimus achieved a statistically significant increase in the median TTP 


15 
 
by 3.5 months(37). PN volume decreases by ≥20% have been infrequently observed in clinical trials 
utilizing volumetric MRI analysis at the NCI for response evaluation: In 60 patients enrolled on the 
tipifarnib phase II trial (29 placebo, 31 tipifarnib) the maximum volume decrease observed was 11.3% 
in one patient(33). On the pirfenidone phase II trial (36 patients) the maximum volume decrease 
observed was 12% (36). On the peginterferon alfa-2b phase II trial 3 of 80 patients had a volume 
decrease of >20% (21, 22, and 27%) (unpublished, confidential information, Regina Jakacki). On the 
sirolimus phase II trial of 58 patients, no PN volume decrease ≥20% was observed, and 3 patients had a 
maximum decrease of >15%, <20%(37). In a phase II trial of the c-kit and PDGFR inhibitor imatinib 
conducted by Kent Robertson, PN volume decrease ranging from 20 to 40% was observed in 6 of 23 
response evaluable patients(41). This trial used a different method of volumetric analysis and responses 
were only observed in very small PN (≤20 mL). In contrast, most target PN enrolled on NCI clinical 
trials have much larger volumes: Tipifarnib median PN volume 364 mL (range 20.5-5573 mL); 
pirfenidone: median PN volume 349 mL (range 12-5629 mL). 
Recently, in a CTEP sponsored phase I clinical trial of selumetinib for children with NF1 and inoperable 
plexiform neurofibromas (NCT01362803), preliminary activity has been observed (See section 2.2.3). 
Decreases in plexiform neurofibroma volumes Have been observed in >71% of patients enrolled. This 
degree of activity has not been observed in prior trials directed at PN. We observed shrinkage in 
progressive and non-progressive PN, and a subset of patients also experienced an improvement in 
function and decrease in pain.  Selumetinib has been tolerated well over multiple treatment cycles, and 
all dose-limiting toxicities were reversible. 
Based on a strong unmet need for the development of effective medical therapies for cutaneous 
neurofibromas in NF1, the preliminary activity of selumetinib in NF1 related plexiform neurofibromas, 
the tolerability of selumetinib over multiple treatment cycles, and the availability to measure the number 
and size changes of cutaneous neurofibromas, we are proposing a pilot study of selumetinib for patients 
with NF1 and substantial cutaneous neurofibroma burden that is causing distress to the patient.  
2.2 
SELUMETINIB [AZD6244 (ARRY-142886; SELUMETINIB)] 
All preclinical information provided in this protocol is from the Investigator’s Brochure. 
AZD6244 (ARRY-142886; selumetinib) is a potent, selective, orally (PO) available, and non-ATP 
competitive small molecule inhibitor of the mitogen-activated protein (MAP) kinase kinase, MEK1/2 
(Investigator's Brochure, 2015)(42).  AZD6244 inhibits the activity of purified MEK by 50% at 10-
14 nmol/L (IC50), and is inactive or only minimally active at 10 mcmol/L against epicutaneous growth 
factor receptor (EGFR), ERB2, p38, ERK2, and MAPKK 6 kinases.  AZD6244 is metabolized to 
biologically active N-desmethyl AZD6244, which is approximately 3- to 5-fold more active than the 
parent compound.   
The RAS/RAF/MEK/ERK signaling pathway plays a central role in the regulation of many cellular 
processes including proliferation, survival, differentiation, apoptosis, motility, and metabolism (43, 44).  
This pathway is one of the most important and best understood MAP kinase signal transduction 
pathways, activated by a diverse group of extracellular signals including integrins, growth factor 
receptors (i.e., EGFR, platelet-derived growth factor receptor [PDGFR], and insulin-like growth factor-
1 receptor), and cytokines (45).  Activated RAS triggers the phosphorylation and activation of RAF 
kinase, which then phosphorylates MEK1 and MEK2 on two serine residues (46). Activated MEK 
phosphorylates its only known substrates, ERK1 and ERK2.  Phosphorylated ERK (pERK) dimerizes 


16 
 
and translocates to the nucleus (47) where it is involved in several important cellular functions, including 
cell proliferation.   
Overexpression of growth factors or growth factor receptors involved in the RAS/RAF/MEK/ERK 
pathway and activating genetic mutations of the signaling proteins may lead to uncontrolled proliferation 
and tumor formation.  For example, RAS genes are the most frequently mutated oncogenes detected in 
human tumors(45).  RAS proteins are guanine nucleotide binding proteins that activate RAF proteins 
when bound to GTP.  Cancer-associated mutations in RAS proteins stabilize the GTP-bound form of 
RAS, thereby providing a constitutive signal downstream in the cascade.  In addition to being found in 
almost all pancreatic adenocarcinomas, RAS mutations are found in ~40% of colorectal carcinomas 
(CRC), 20-25% of lung adenocarcinomas, and also in some breast or ovarian cancers.  BRAF mutations 
have also been observed in many human cancers, particularly melanoma (30-60%), thyroid cancer (30-
50%), CRC (5-20%), and ovarian cancer (~30%) (42, 44).  These mutations in BRAF usually involve 
gain-of-function substitutions that render the kinases constitutively active.  Also, studies of primary 
tumor samples and cell lines have shown constitutive activation or overactivation of the kinase pathways 
in cancers of the pancreas, colon, lung, ovary, biliary tract, and kidney (48).  Therefore, agents targeting 
the RAS/RAF/MEK/ERK pathway may inhibit oncogenic signaling in tumor cells.  
2.2.1 Nonclinical Studies 
2.2.1.1 Efficacy 
In vitro studies have shown that AZD6244 is a potent and selective inhibitor of MEK with IC50 of 10-
14 nM (Investigator's Brochure, 2015).  Significant biochemical activity has not been detected when 
tested at 10 mcmol/L against a diverse panel of >300 other molecules, including enzymes, receptors, 
kinases, transporters, and ion channels.  The effects of AZD6244 on ERK phosphorylation and cell 
viability were determined in a panel of cell lines with known RAF and RAS mutant status.  AZD6244 
inhibited ERK1 and ERK2 phosphorylation with IC50 0.0018-0.0408 mcmol/L.  In cell viability assays, 
IC50 values ranged from <10 nM to >10 μM and most of the cell lines that were sensitive to selumetinib 
contained either a BRAF or RAS gene mutation.  Two metabolites of AZD6244 (N-desmethyl AZD6244 
and an amide AZD6244) have been identified.  The N-desmethyl metabolite was found to be 3-to 5-fold 
more potent inhibitor than the parent compound in cellular ERK phosphorylation and cell viability 
inhibition assays.  In contrast, the AZD6244 amide metabolite was up to 50-fold less active than 
AZD6244 and therefore is unlikely to significantly contribute to biological activity of AZD6244.  In 
tumor cell viability inhibition assays, N-desmethyl metabolite was ≥5-fold more potent than AZD6244 
in inhibiting cell viability.   
Significant suppression of tumor growth in response to AZD6244 treatment was observed in several 
xenograft mouse models derived from a range of tumor types including melanoma, breast, pancreatic, 
lung, colon, and hepatocellular carcinomas (49-52).  In papillary thyroid cancer models, AZD6244 
effectively inhibited tumor growth, both in vitro and in vivo, particularly in tumor cells carrying 
activating BRAF gene mutations (53).  In the Calu-6 lung cancer xenograft model, AZD6244 suppressed 
tumor growth at doses of 10, 25, or 100 mg/kg given twice daily (BID), and the minimal effective dose 
was identified as 0.75 mg/kg administered BID (50).  In this model, MEK activity was inhibited as 
assessed by determination of pERK levels in tumor.  Studies using human CRC xenograft models 
demonstrated that AZD6244 inhibited tumor growth by inhibition of cell proliferation in SW620 model 
and by induction of apoptosis in Colo205 model.  In vivo studies with mutant KRAS positive (KRAS+) 
human cancer xenografts have demonstrated the potential for using AZD6244  in combination with a 


17 
 
number of cytotoxic and targeted agents, including docetaxel, irinotecan, gemcitabine, pemetrexed, 
gefitinib, cediranib, rapamycin, cisplatin, and temozolomide (Investigator’s Brochure, 2015). 
2.2.1.2 Pharmacokinetic/Pharmacodynamic Studies 
Two oral formulations of AZD6244 have been tested in preclinical pharmacology studies:  the original 
mix-and-drink formulation (AZD6244 free-base), and the AZD6244 hydrogen sulfate salt (capsule) 
formulation (AZD6244 Hyd-Sulfate) (Investigator’s Brochure, 2015).  The former requires 
reconstitution of the AZD6244 free-base crystalline powder in the 25% (w/v) Aqueous 
Captisol®(sulfobutyl ether β-cyclodextrin) (SBE-CD) solution.  While systemic exposure was 
demonstrated in the rat and monkey studies with AZD6244 free-base, the exposure was not dose-
proportional; bioavailability was decreasing with increasing dose.  This is likely a reflection of dose-
limited absorption due to limited solubility of AZD6244 free-base.  However, AZD6244 hydrogen 
sulfate produced approximately proportional exposures with dose in the mouse and monkey, and 
allowed higher exposures than AZD6244 free-base.  There was no/minimal accumulation of AZD6244, 
whether dosed with AZD6244 free-base or AZD6244 hydrogen sulfate on multiple dosing in the mouse, 
rat, or monkey.  N-desmethyl metabolite was not detectable in rat and at only trace levels in the monkey, 
but was produced in mouse at circulating levels around 2-12% of parent compound.  Studies in rats and 
mice indicate that AZD6244 is widely distributed, although concentrations were generally lower in 
tissue than blood.  High levels of protein binding (93.7%-99.7%) were observed in all preclinical species 
tested and in humans (98.4%).  There was no evidence of AZD6244-related material binding to melanin 
and minimal penetration into the central nervous system (CNS).   
AZD6244 is metabolized in human hepatocytes by cytochrome P450 (CYP enzymes) 1A2, 2C19 and 
3A4, with CYP1A2 being the enzyme primarily responsible for the formation of the N-desmethyl 
metabolite.  Glucuronidation appears to be a significant clearance mechanism for AZD6244 and the N-
desmethyl metabolite.  It is a weak inducer of CYP 3A, 1A, and 2C9.  AZD6244 does not inhibit CYP 
1A2, 2C8, 2C19, 2D6, and 3A4.  It was a weak inhibitor of CYP2C9 (IC50 44.7 mcM).  N-desmethyl 
AZD6244 does not inhibit CYP 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, but is a weak inhibitor of 1A2 
(IC50 of 18.9 mcM).  In the rat, mouse, and monkey, fecal excretion was the predominant route after 
oral and intravenous dosing. 
2.2.1.3 Toxicologic Studies 
Toxicity of AZD6244 was evaluated in the acute dosing (one or two doses on a single day) and 
continuous daily dosing studies (for a 1month and 6 months) in Sprague-Dawley rats and cynomolgus 
monkeys (Investigator's Brochure, 2015).  The repeat-dose study in rats indicated that the agent was 
well tolerated but produced soft stools and gastrointestinal mucosal mineralization associated with 
increased serum phosphorus and decreased albumin.  Tissue mineralisation was not apparent in 
cynomolgus monkeys when dosed for up to 1 month with AZD6244 free-base or for up to 6 months 
with AZD6244 hydrogen sulfate.  However, mineralization was seen in multiple tissues (cornea, kidney, 
liver, myocardium, skeletal muscle, and glandular stomach) in mice dosed with AZD6244 hydrogen 
sulfate for up to 1 month, and in the liver of a small number of mice dosed up to 6 months. Physeal 
dysplasia was observed at a dose level of selumetinib 10 mg/kg/day (arithmetic mean AUC 546 uM.h) 
in 4 of 10 male rats receiving 13 weeks treatment at substantially greater drug exposure than that 
achieved in children or adults receiving selumetinib at the recommended doses: For total selumetinib 
AUC, there is a  43.3-fold exposure margin in comparison to adult patients with advanced cancer 
receiving selumetinib 75 mg BID (arithmetic mean AUC0-12 12.62 uM.h) and a 64.2-fold exposure 
margin in comparison to pediatric patients with low grade glioma receiving selumetinib 25 mg/m2 BID 


18 
 
(arithmetic mean AUC0-12 8.5 uM.h). Focal decreased cellularity of the femoral bone marrow adjacent 
to the physis was observed at a dose level of selumetinib 25 mg/kg/day (arithmetic mean AUC 806 
uM.h) in 4 of 10 female rats receiving 30 days treatment (all terminated before planned 13 weeks due 
to skin lesions).  For total selumetinib AUC, there is a  63.9-fold exposure margin in comparison to adult 
patients with advanced cancer receiving selumetinib 75 mg BID (arithmetic mean AUC0-12 12.62 uM.h) 
and a 94.8-fold exposure margin in comparison to paediatric patients with low grade glioma receiving 
selumetinib 25 mg/m2 BID (arithmetic mean AUC0-12 8.5 uM.h).Physeal dysplasia and decreased bone 
marrow cellularity were not observed at lower dose levels of selumetinib (5 mg/kg/day in male rats; 
12.5 mg/kg/day in female rats). 
 
Twice daily (BID) oral dosing with AZD6244 free-base for 1 month in monkeys produced diarrhea, 
dehydration, and electrolyte imbalance, in some animals associated with renal toxicity.  Dosing with 
AZD6244 hydrogen sulfate (0.5, 1.5, and 4 mg/kg BID) for up to 6 months in monkeys was also 
associated with fluid and/or red-colored feces, but with no notable gastrointestinal (GI) tract or renal 
pathology. 
AZD6244 and its N-desmethyl metabolite showed no evidence of mutagenic potential, but AZD6244 
produced an increase in micronucleated immature erythrocytes in mice, predominantly via an aneugenic 
mode of action.  AZD6244 showed enhanced cytotoxicity in the presence of ultraviolet (UV) light.  
Reproductive toxicology data in mice indicate that AZD6244 can have adverse effects on embryofetal 
development and survival at dose levels that were not toxic to mothers. 
In summary, preclinical studies demonstrated that AZD6244 exposures can be significantly enhanced 
by using AZD6244 hydrogen sulfate, compared to AZD6244 free-base.  In 6-month toxicology studies, 
AZD6244 exposures, expressed as area under the concentration-time curve from time 0 h to 12 h (AUC0-
12), achieved with AZD6244 hydrogen sulfate at high dose levels (4 mg/kg BID in monkeys and 
20 mg/kg BID in mice) were approximately 3-fold and 15-fold higher in primates and mice, 
respectively, when compared with those achieved in man at 75 mg BID AZD6244 hydrogen sulfate.  At 
the NOAEL of 1.5 mg/kg BID from 1-month and 6-month studies in primates, exposures were generally 
similar to those seen in man after dosing at 75 mg BID AZD6244 hydrogen sulfate.  Exposure achieved 
in the 6-month mouse study at the low dose level of 1 mg/kg BID was slightly below that seen to date 
in man after dosing with AZD6244 hydrogen sulfate (75 mg BID).  Preclinical pharmacology studies 
suggest an acceptable safety profile for administering AZD6244 free-base or AZD6244 hydrogen sulfate 
to cancer patients.  
2.2.2 Clinical Experience 
2.2.2.1 Pharmacokinetics 
AZD6244 plasma PK parameters of AZD6244 hydrogen sulfate were similar after single and multiple 
dosing, suggesting a minimal accumulation over time after BID dosing (Investigator’s Brochure, 2015).  
The AZD6244 exposure parameters, i.e., the maximum plasma concentration (Cmax) and the AUC were 
approximately dose-proportional across the 25- to 100-mg BID dose range after single (day 1) or 
multiple dosing studied on days 1, 8, 15, and 22.  The geometric mean values of exposure parameters 
were:  Cmax=369-1483 ng/mL and AUC0-12=1361-7055 ng∙h/mL on day 1, and Cmax=458-1365 ng/mL 
and AUC0-12=1515-4758 ng∙h/mL on day 8.  AZD6244 was absorbed relatively quickly across all dose 
levels, with a median time-to-reach Cmax (tmax) of 1.5 hours.  Following the peak, AZD6244 
concentration declined multi-exponentially with a mean terminal elimination half-life (t1/2) ranging from 
5 to 7 hours, which was consistent across dose levels.  The apparent volume of distribution at steady 


19 
 
state (Vss/F) and apparent clearance (CL/F) also remained largely consistent across the dose range, with 
mean values ranging from 87 to 126 L and 12 to 19 L/h, respectively.  The plasma PK profile of the 
AZD6244 active metabolite, N-desmethyl AZD6244, was similar to that of AZD6244, although 
exposure was much lower, achieving Cmax and AUC values generally <15% of the parent compound, in 
each patient.  The median tmax was approximately 1.5 hours and t1/2 ranged from 9-13 hours.  The 
AZD6244 amide metabolite showed increased exposure on multiple dosing indicating some 
accumulation.  Given the 3-to 5-fold greater potency of the N-desmethyl metabolite compared to 
AZD6244 shown by the in vitro cell-based ERK phosphorylation assay, the N-desmethyl AZD6244 is 
likely to contribute to pharmacodynamic effects.  In contrast, AZD6244 amide, which was 
approximately 40- to 50-fold less active than AZD6244 in this assay, is unlikely to contribute 
significantly to AZD6244 biological activity.   
The capsule formulation significantly improved oral bioavailability compared the free-base formulation, 
although large inter-patient variability was noted.  The estimated oral bioavailability of capsule relative 
to the free-base suspension based on a dose-normalized AUC0-24 was 263% (90% confidence interval 
[CI]=214%-322%).  The geometric mean values of exposures obtained for AZD6244 hydrogen sulfate 
at the maximum tolerated dose (MTD) of 75 mg BID (AUC0-24=6335 and 5448 ng∙h/mL on day 1 and 
8, respectively, and Cmax=1207 and 1439 ng/mL on day 1 and 8, respectively) were statistically 
significantly higher than those obtained at the MTD of AZD6244 free-base (100 mg BID); the relative 
estimated exposures by hydrogen sulfate vs.  free-base were 197% (90% CI=161 to 242%) for AUC0–24 
and 252% (90% CI=182 to 348%) for Cmax. 
A food effect study involving administration of AZD6244 hydrogen sulfate to patients with advanced 
solid malignancies under fasting conditions and with a high-fat meal indicated a statistically significant 
effect of food on the exposure of AZD6244.  Geometric mean Cmax and AUC values were reduced by 
approximately 62% and 19%, respectively, under fed conditions.  Therefore for further clinical studies, 
it is recommended that AZD6244 be taken on an empty stomach (i.e., no food other than water can be 
taken) at least 2 hours after a meal and 1 hour before the next meal.   AZD6244 capsule should be taken 
with water.    
At a population level, plasma exposure of AZD6244 (Cmax and AUC) appeared to be increased in healthy 
volunteers of Asian descent by approximately 1.5- to 2-fold, in non-Japanese Asians and Japanese 
Asians, respectively, compared with Western healthy volunteers.  However, the AZD6244 PK was 
highly variable and there was overlap in the range of exposure experienced by Asian and Western 
subjects. 
There is no evidence of PK interactions between docetaxel, dacarbazine, temsirolimus, or erlotinib and 
AZD6244.  
2.2.2.2 Efficacy  
Four randomized phase 2 monotherapy studies comparing efficacy of AZD6244 free-base formulation 
(100mg BID) to standard chemotherapy regimens in patients with solid tumors (melanoma, pancreatic 
cancer, CRC, and NSCLC) did not demonstrate superior efficacy of AZD6244 over standard 
chemotherapy agents (Investigator’s Brochure, 2015).  Several objective responses were observed in 
melanoma patients with mutant BRAF tumors and in patients with mutant KRAS NSCLC.  
Although statistical significance in overall survival (OS) was not achieved, a statistically significant 
improvement was seen in progression-free survival (PFS) for AZD6244 in combination with docetaxel 
in patients with mutant KRAS NSCLC (P=0.014)(54) and for AZD6244 in combination with 


20 
 
dacarbazine in patients with mutant BRAF cutaneous melanoma (P=0.021) (55), when compared to the 
respective chemotherapy/placebo groups.  Clinical activity of AZD6244 hydrogen sulfate monotherapy 
was demonstrated in uveal melanoma (56). 
2.2.2.3 Safety 
The tolerability profile of AZD6244 free-base at 100 mg BID was similar to that of AZD6244 hydrogen 
sulfate at 75 mg BID (Investigator’s Brochure, 2015).  The most common AEs associated with 
AZD6244 are acneiform rash, diarrhea, nausea, vomiting, peripheral edema, and fatigue.  Stomatitis, 
dry skin, and pyrexia have also been commonly reported in the AZD6244 studies. Dose escalation of 
selumetinib was limited mainly by the occurrence of rash and diarrhea. 
Events consistent with central serous retinopathy/retinal pigment epithelial detachment have been 
reported in a small number of patients receiving treatment with AZD6244, generally in combination 
with other novel targeted anticancer agents. 
Mild (generally grade 1) elevations in serum liver transaminases have been recorded within the first 
week of starting treatment with AZD6244 and levels tend not to increase further beyond the first month 
of continued dosing.  Mild increases in serum phosphate and in calcium phosphate product have been 
reported.   
Dyspnea and exertional dyspnea have been reported in patients receiving AZD6244.  The majority of 
these events have occurred in patients with lung or pleural disease due to their underlying malignancy. 
There have been reports of pneumonitis-type events, including symptoms of shortness of breath, fatigue, 
cough and/or fever, in a small number of patients receiving AZD6244, but pneumonitis-AZD6244 
association has not been established.  Studies of AZD6244 should include guidance for the management 
and investigation of new or worsening dyspnea or symptoms of pneumonitis-type events that are not 
attributed to the patient’s underlying cancer. 
Increases in systolic or diastolic blood pressure, sometimes exceeding the threshold for therapeutic 
intervention, have been observed in studies with AZD6244.  Asymptomatic reductions in left ventricular 
ejection fraction (LVEF) to below 55% have been observed in a small number of patients during 
AZD6244 treatment and evidence of reversibility while on continuous dosing was demonstrated in some 
patients.  Studies of AZD6244 should include baseline and symptom-triggered echocardiography 
assessments and guidance for the management and investigation of decreases of LVEF.  Review of 
electrocardiogram (ECG) parameters has shown no evidence of QT interval corrected according to 
Fridericia’s formula (QTcF) prolongation during treatment with AZD6244.   
Increased creatine phosphokinase (CPK) levels have been reported in a small number of patients with 
advanced cancer receiving AZD6244.  A relationship between selumetinib and increased CK levels has 
not been established. 
2.2.3 Clinical trials of selumetinib in adults with refractory cancers and children with NF1 and PN:  
Selumetinib is an oral specific MEK1/2 inhibitor with activity in adult cancers characterized by 
activation of the Ras pathway at the adult recommended dose of 75 mg BID (capsules) (54, 55, 57). In 
an adult phase I trial using a powder for reconstitution formulation paired tumor biopsies were obtained 
prior to treatment with selumetinib and 2-4 hours after the day 15 dose during cycle 1. Tumor samples 
were analyzed for inhibition of pERK using immunohistochemistry (58). Of 24 paired biopsies 19 had 
pretreatment pERK expression. Strong inhibition of pERK with a gmean of 79% (90% CI 50%-91%) 


21 
 
was seen with most patients having received 100 mg selumetinib per dose. At the 100 mg dose level the 
gmean for the day 1 Cmax was 807 ng/mL, and the AUC was 3124 ngh/mL.  
In adults, selumetinib is being evaluated in multiple malignancies, including uveal melanoma, non-small 
cell lung cancer, and radioiodine refractory differentiated thyroid cancer. In patients with advanced 
uveal melanoma, patients treated with selumetinib demonstrated modestly improved progression-free 
survival and response rate; however, no improvement in overall survival was observed. In addition a 
high rate of adverse events was noted. A randomized phase II trial of docetaxel with and without 
selumetinib in NSCLC demonstrated improved overall survival and a statistically significant 
improvement in progression-free survival and objective response rate with combination therapy. 
Selumetinib produced increases in iodine uptake and retention in a subgroup of patients with thyroid 
cancer that is refractory to radioiodine. Of 8 patients treated with radioiodine and selumetinib, 5 had 
confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin 
levels (mean reduction, 89%). As 5 of these patients had NRAS mutations, the authors postulate that the 
effectiveness may be greater in patients with RAS-mutant disease.  
The Pediatric Brain Tumor Consortium is conducting a phase I/II trial with selumetinib in recurrent or 
refractory low grade gliomas based on the finding of activation of the Ras-MAP kinase signaling 
pathway in these tumors. The maximum tolerated dose in this trial was 25 mg/m2/dose BID on a 
continuous dosing schedule. Thus far there have been 8/38 sustained responses (1 complete and 7 
partial). Of 5 with available biologic data, 3 demonstrated BRAF fusion, 1 had BRAFV600E mutation 
and 1 displayed neither (59).  
In our CTEP sponsored phase I clinical trial of selumetinib for children with NF1 and inoperable PNs 
(NCT01362803), preliminary activity has been observed. The primary objectives of this trial are to 
determine the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK) of selumetinib in 
patients 3-18 years old with NF1 and inoperable PNs. Selumetinib is administered twice daily as 
capsules (10 mg and 25 mg) on a continuous dosing schedule (1 cycle = 28 days). The MTD is 
determined based on cycle 1-3 toxicities. Three dose levels have been evaluated: dose level 1 (20 mg/ 
m2/dose, 50% of the adult recommended dose), dose level 2: (30 mg/ m2/dose, 75% of the adult 
recommended dose), and dose level 1.5 (25 mg/m2/dose, 60% of the adult recommended dose). 
Response evaluation with volumetric MRI analysis occurs after cycles 5, 10, and then after every 6 
cycle. A partial response is defined as a ≥20% decrease in the PN volume compared to baseline at 
enrollment.  
As of January 2016: This trial has completed the primary objectives. Twenty-four patients (13 M:11 F, 
median age 10.9 years, range 3-18) with a median target PN volume of 1,205mL (range 29-7,210mL) 
have enrolled. Dose level 2 (30 mg/m2/dose) exceeded the MTD with dose-limiting toxicity (DLT) in 
2/6 patients: grade (gr) 3 creatine kinase (CK) elevation (n=1), and gr 3 decrease in left ventricular 
ejection fraction (n=1). DL1 (20 mg/m2/dose) was tolerated with DLT in 2/12 patients: gr 3 cellulitis 
(n=1), and grade 3 urticaria (n=1). All DLTs were reversible. No other patients developed a decrease in 
LVEF requiring holding selumetinib. The DL1 dose of 20 mg/m2/dose is similar to the MTD of 25 
mg/m2/dose determined in the Pediatric Brain Tumor Consortium (PBTC) study of selumetinib for low 
grade gliomas.  For consistency in treating pediatric patients, we therefore evaluated the PBTC MTD of 
25 mg/m2/dose in the NF1 PN trial as dose level 1.5. Of six patients enrolled at this dose level, one 
patient experienced a gr 3 rash as DLT during cycle 2. No other DLTs were observed during cycles 1-


22 
 
3, and the 25 mg/m2 dose level is thus the MTD and the recommended phase II dose for children with 
NF1 and PN.  
The most frequent selumetinib toxicities (all grades) are acneiform rash, asymptomatic CK elevation, 
nausea, vomiting, abdominal pain, diarrhea, and fatigue. Preliminary median (range) selumetinib C1 
day 1 PK parameters were: AUC0-24h DL1 (n=8) 2118 (1872-3240) ngh/mL, DL2 (n=5) 2702 (2088-
6008) ngh/mL; half-life DL1 6.8 h (5.6-14.3), DL2 7.6 h (5.4-9.8).  Five patients developed paronychia 
that was deemed possibly related to selumetinib; 2 had grade 1 and 3 experienced grade 2, paronychia.  
One patient enrolled on the phase I selumetinib trial developed asymptomatic grade 1 cataract in both 
eyes, not interfering with vision, which were not appreciated at prior exams.  The patient had previously 
been treated with imatinib and retinoid acid, both of which are associated with cataracts.  This patient 
also experienced clinical benefit with reduction in PN related pain; celebrex, which was administered at 
trial entry for PN related pain, could be discontinued on treatment. As the patient derived clinical benefit, 
selumetinib was continued. A review by Astra Zeneca of development of cataract in studies with 
selumetinib identified 4 cases, all of which had confounding factors (>60 years old, hypertensive, 
previous exposure to steroids).  Based on the information in the most relevant clinical studies, cataract 
was reported for very few patients on selumetinib therapy, and due to the presence of alternative risk 
factors like hypertension, older age and steroid therapy, a causal link with selumetinib could not been 
established.  Decreased LVEF was seen in only one patient, who did not experience recurrent decreased 
in LVEF after dose reduction. Reversible, asymptomatic reductions in LVEF have been recorded in a 
small number of patients receiving selumetinib in studies with scheduled echocardiography assessments. 
Evidence of reversibility of LVEF changes on continuing selumetinib, often without therapeutic 
treatment, has been demonstrated in patients with follow-up assessments available. 
Decrease in PN volumes (median -31%, range -5.8 to -47.7%) was observed in all patients and occurred 
slowly over time. The maximum response was reached after a median of 20 (range 5-42) cycles. 
Seventeen of 24 patients (71%) met criteria for confirmed partial response. These responses have been 
maintained for a median of 23 cycles (range 6 to 42). No patients have experienced disease progression 
to date, but slow regrowth has been observed in some cases, most notably following dose reductions, 
and in the case of one patient, who required prolonged interruption of selumetinib dosing for toxicity.  
Anecdotal evidence of clinical improvement included: decrease in PN related pain in 8 of 13 patients, 
improvement in motor function in 5 of 8 patients, and decreased disfigurement based on photography 
in 5 of 18 patients. 
Selumetinib thus has preliminary activity in children and adolescents with NF1 PN at doses as low as 
50% of the adult recommended dose (75 mg BID) and a phase II trial was developed and is now ongoing 
to assess objective response rate by 3D MRI, pain, QOL, and functional changes prospectively.  
2.3 
RATIONALE FOR THE PROPOSED PILOT STUDY:  
As described in this protocol, cutaneous neurofibromas cause substantial morbidity in individuals with 
NF1, and there is a strong unmet need for the development of effective medical therapies.  
Preclinical studies in an NF1 mouse model have shown significant reduction in the size of plexiform 
neurofibromas in animals treated with a MEK inhibitor or in human neurofibroma cell cultures(60).  
Selumetinib has been evaluated in clinical trials for adult(54, 55, 57, 58) and pediatric tumors(59, 61). In a phase 
I trial of selumetinib for children with NF1 and inoperable plexiform neurofibromas, selumetinib has 
been well tolerated over multiple treatment cycles and has resulted in shrinkage of progressive and non-


23 
 
progressive plexiform neurofibromas (> 20% reduction in tumor volume) in 67% of subjects. A subset 
of patients also experienced an improvement in function and decrease in pain.  This is the most 
impressive response that has been seen to date in medical treatment of plexiform neurofibromas.   
We are proposing herein a pilot study for treatment of cutaneous neurofibromas with the oral MEK1/2 
inhibitor selumetinib for the following reasons:   
First, as noted above, cutaneous neurofibromas impose a significant emotional burden on adults with 
NF1 and there are no existing medical treatments or current clinical trials.   
Second, although inhibition of MEK has not been tested in a preclinical model for cutaneous 
neurofibromas (because there is only one such model which does not mirror the human tumors precisely 
and it is not used in the preclinical consortium), cutaneous tumors are similar to plexiform neurofibromas 
histologically, and both are derived from Schwann cells in which biallelic NF1 mutation has been seen.   
The third factor that has led us to propose this trial is that we have developed an approach to 
quantification of number and size of cutaneous neurofibromas that will provide a reliable outcome 
measure as described above.  This method will not only allow to monitor the size of cutaneous 
neurofibromas over time, but also to assess changes in the number of cutaneous neurofibromas. 
We hypothesize that selumetinib will result in shrinkage of existing cutaneous neurofibromas and may 
prevent or delay the development of new cutaneous neurofibromas. In the absence of validated response 
measured for cutaneous neurofibromas we are proposing a small pilot study of selumetinib to evaluate 
the potential utility of selumetinib in individuals ≥ 18 years old with NF1 and cutaneous neurofibromas.  
The primary objective will be to determine if selumetinib can result in shrinkage of cutaneous 
neurofibromas. Secondary objectives will include the assessment of the effect of selumetinib on target 
inhibition, on the tumor microenvironment, and on skin related morbidity. We will also quantify the 
development of new cutaneous neurofibromas. 
As cutaneous neurofibromas are predominantly a problem in adults, we plan to limit enrollment for this 
pilot study to patients ≥ 18 years old. In addition, as no validated response criteria are available for 
cutaneous neurofibroma trials we will focus on assessing changes in the size (percent change in volume) 
of target cutaneous neurofibromas. We hope that findings from our trial will allow for the development 
of response criteria in future trials directed at cutaneous neurofibromas. In order to allow for consistent 
in the measurements we will have only three sites participating in the study, which will be trained in the 
measurement of cutaneous neurofibromas at UAB so that consistent measurements will be obtained. 
2.4 
CORRELATIVE STUDIES BACKGROUND 
2.4.1 Effect of selumetinib on target inhibition in cutaneous neurofibroma(s)  
Proposed studies from cutaneous neurofibroma biopsies/ excision: We hypothesize that inhibition of 
pERK is required for cutaneous neurofibroma shrinkage and that lack of response is a result of 
insufficient inhibition of pERK (integrated biomarker), or of upregulation of another pathway, such as 
AKT (exploratory biomarker). Our goal in this study will be to analyze this relationship by determining 
the percent decrease in pERK in paired biopsies/excisions of cutaneous neurofibromas obtained prior to 
treatment and on treatment with selumetinib. pAKT and changes in the tumor kinome will also be 
analyzed.  
Evaluation of skin related morbidity using the skindex: 
Cutaneous neurofibromas can severely affect the quality of life of individuals with NF1. As a 


24 
 
exploratory endpoint this study therefore aims to evaluate changes in patient reported outcomes 
(Skindex) during treatment with selumetinib. Skindex was chosen because the scale is validated for 
dermatologic skin diseases and has very good psychometric properties.  The primary diagnoses in the 
validation paper were eczematous dermatitis, psoriasis, non-melanoma skin cancer, benign growths, 
warts, alopecia, acne rosacea, etc.(62), and the author says it can be used by patients with any skin 
condition.  It also has been used in clinical trials, even as a primary endpoint (in a study evaluating 
treatments for basal cell carcinoma and squamous cell carcinoma), and it has been found to be sensitive 
to change(63).  The Skindex has been used in individuals with NF1 in several studies and was found to 
"measure most of the dermatologic effects of NF1(28, 29, 64)." It assesses the domains of symptoms 
(e.g., itching, pain, burning, irritation, bleeding), functioning (e.g., relationships, daily living activities, 
work, and sleep), and emotions (e.g., worried, embarrassed, ashamed, frustrated, depressed), so it covers 
the areas that would seem to be affected by cutaneous neurofibromas and that may improve with 
effective treatment.  Since this is a specific trial evaluating a treatment for cutaneous neurofibromas, 
which is a skin condition, it seems like the content of Skindex items is appropriate.  
The Skindex will also be utilized to establish efficacious cutaneous neurofibroma volume reduction. A 
20% reduction in average cutaneous neurofibroma volume has been established as the minimum 
response criterion; however, we are unable to know a priori the size reduction a patient considers to be 
significant. Therefore, surveys will be completed by study participants before selumetinib treatment 
(Day 0) after the first cycle and then after every 4 cycles of the clinical trial. Skindex measurements will 
be related to the cutaneous neurofibroma volume measurements collected at the same study visit to 
qualitatively determine an efficacious cutaneous neurofibroma volume reduction. 
Evaluation of skin related morbidity using the Global Impression of Change Scale: 
The patient Global Impression of Change (GIC) Scale is a single item scale that evaluates the clinical 
significance of changes in pain intensity or other morbidities. We will administer an adapted version of 
the GIC Scale at the follow-up PRO evaluations only (it should not be given pre-study because it 
assesses change from baseline). On the adapted GIC, patients will give their overall impression of 
change in cutaneous neurofibroma size. Patients will also be given the opportunity to describe any 
noticeable changes in a follow-up free text response. 
 
Evaluation of pain using the Numeric Rating Scale: 
The NRS-11 Pain Scale is a simple and commonly used numeric scale in which patients rate pain from 
0 (no pain) to 10 (worst pain).This information will help evaluate the effects of the study drug on pain 
as well as provide data on clinically meaningful changes in pain. 
 
2.4.2 Investigate genomic alterations that correlate with cNF size response to selumetinib treatment: 
Clinical observation of patients with cutaneous neurofibromas reveal tumors of various sizes and our 
experience in measuring tumors suggests that different tumors in the same patient may grow at different 
rates.  The cause of this heterogeneity is not known, but we hypothesize that tumors with faster growth 
or larger growth have a different genomic composition, such as more deleterious NF1 somatic mutation, 
other driver mutation(s), or epigenetic changes may underlie these differences. In addition, it is possible 
that different tumors will respond differently to selumetinib, and we will also be in a position to explore 
genetic or epigenetic factors that contribute to such differences, if they occur. 


25 
 
Biallelic inactivation of the NF1 gene is known to be required for tumorigenesis but several genes 
associated with mismatch repair (MMR) and regulatory cell cycle (e.g. TP53, CDKN2A, and RB1) have 
been implicated as modifiers of NF1-related tumors, especially malignant peripheral nerve sheath 
tumors [19, 20]. Thomas and colleagues (2010) analyzed 89 cNF from 3 unrelated patients and found 
that 64% had a detectable NF1 somatic mutation; 24% of these were due to NF1 loss of heterozygosity 
(LOH), and 24% had microsatellite instability (MSI)[21]. This group also analyzed TP53, CDKN2A, 
and RB1 and found no pathogenic mutations; however, 1 cNF had RB1 LOH and 4 DNs had TP53 LOH. 
These results suggest other genes may influence cNF development. 
For this exploratory objective, genomic analyses of cNFs will be performed under the direction of Dr. 
Ashley Cannon to identify somatic mutations that are driving tumorigenesis as well as mutations that 
may be influencing tumor response to selumetinib. These are pilot genomic studies that may not have 
sufficient statistical power and will likely warrant more comprehensive analyses and larger sample sizes 
in future studies. Prior to selumetinib treatment, ≥1 cNF will be biopsied from each patient. If a decrease 
in cNF size is observed by cycle 12 of selumetinib treatment, two types of tissue will be collected from 
patients: at least 1 cNF with no change in size and at least 1 cNF with a substantial size decrease. 
These exploratory investigations will be performed solely for research purposes, the results of which 
may not be directly interpretable to the clinical setting.  There is no plan for looking for incidental 
findings that are relevant to other diseases. Therefore results will not be shared with patients or referring 
physicians. 
3 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
3.1 
ELIGIBILITY CRITERIA 
3.1.1 Inclusion Criteria 
3.1.1.1 Patients must be ≥ 18 years old at the time of enrollment and have a documented germline NF1 
mutation in a CLIA certified laboratory or a diagnosis of NF1 based on clinical NIH consensus 
criteria(65). In addition to substantial cutaneous neurofibroma burden as defined below, at least 
one of the criteria below have to be present:  
• Six or more café-au-lait macules (≥0.5cm in prepubertal subjects or ≥1.5 cm in post 
pubertal subjects) 
• Freckling in axilla or groin 
• Optic glioma 
• Two or more Lisch nodules 
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of 
long bone cortex) 
• A first-degree relative with NF1 
Histologic confirmation of tumor is not necessary in the presence of consistent clinical 
findings. 
3.1.1.2 Measurable disease:  Patients must have substantial cutaneous neurofibroma burden causing 
distress to the patient by disfigurement or itching. Patients must have ≥ 9 measurable cutaneous 
neurofibromas. For the purpose of this study measurability will be defined for each of the 


26 
 
lesions selected as target lesions as a neurofibroma with a longest diameter ≥ 4 mm in the 
longest diameter.  
3.1.1.3 ECOG performance status <2  
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 
e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% 
of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity and Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. 
3.1.1.4 Patients must have normal organ and marrow function as defined below:  
− hemoglobin  
 
 
>10 g/dL (not requiring RBC transfusions) 
− absolute neutrophil count >1,500/mcL 
− platelets  
 
 
 
>100,000/mcL (not requiring platelet transfusions) 
− total bilirubin 
 
 
< 1.5 X upper limit of normal (ULN), with the exception 
of patients with Gilbert Syndrome who are required to have < 3 X ULN 
− ALT(SGPT)  
 
 
<3.0 X ULN 
− creatinine 
 
 
 
within normal institutional limits 
 
OR 
− creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal. 
 
3.1.1.5 Ability of subject or Legally Authorized Representative (LAR)) to understand and the 
willingness to sign a written informed consent document. 
3.1.1.6 Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun 
exposure is anticipated. 
3.1.1.7  Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products 
containing these fruits, e.g. grapefruit juice or marmalade) during the study.  
3.1.1.8 Prior therapy:   
• Since there is no standard effective chemotherapy for patients with NF1 and cutaneous 
neurofibromas, patients may be treated on this trial without having received prior medical 
therapy directed at their PN.  


27 
 
• Since selumetinib is not expected to cause substantial myelosuppression, there will be no 
limit to number of prior myelosuppressive regimens previously received for NF1 related 
or other tumor manifestations.   
• Patients who have received previous investigational agents or biologic therapy, such as 
tipifarnib, pirfenidone, Peg-Intron, sorafenib, or other VEGFR inhibitors are eligible for 
enrollment.  
• Growth factors that support platelet or white cell number or function must not have been 
administered within the past 7 days and are not permitted while on the study. 
• At least 6 weeks must have elapsed prior to enrollment since the patient received any 
prior radiation therapy, and the target cutaneous neurofibromas have to be in areas 
outside of a prior radiation field.  
• At least 4 weeks must have elapsed since receiving medical therapy directed at NF1 
related tumor manifestations. 
• At least 4 weeks must have elapsed since any surgeries, with evidence of completed 
wound healing. 
• Patients who received prior medical therapy for a NF1 related tumor must have recovered 
from the acute toxic effects of all prior therapy to ≤ grade 1 CTCAE version 5.0 before 
entering this study.   
3.1.1.9 The effects of selumetinib on the developing human fetus at the recommended therapeutic dose 
are unknown.  For this reason women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for 4 weeks after dosing with selumetinib 
ceases.  Women of child-bearing potential must have a negative pregnancy test prior to entry.  
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, the patient should inform her treating physician immediately.  Please 
note that the selumetinib manufacturer recommends that adequate contraception for male 
patients should be used for 12 weeks post-last dose due to sperm life cycle. 
3.1.1.10 Informed Consent: Diagnostic or laboratory studies performed exclusively to determine 
eligibility for this trial must only be done after obtaining written informed consent from all 
patients, which can be accomplished using the study specific informed consent or another 
consent, such as the NCI, POB screening protocol. Studies or procedures that were performed 
for clinical indications (not exclusively to determine eligibility) may be used for screening or 
baseline values even if the studies were done before informed consent was obtained, if the 
patient agrees.  
3.1.2 Exclusion Criteria 
3.1.2.1 Patients who are receiving any other investigational agents, or have received an investigational 
agent within the past 30 days. 
3.1.2.2 May not have a NF1 related tumor such as optic pathway glioma or malignant peripheral nerve 
sheath tumor, which requires treatment with chemotherapy, radiation, or surgery. 
3.1.2.3 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active 


28 
 
bleeding diatheses or renal transplant, including any patient known to have hepatitis B, 
hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations 
that would limit compliance with study requirements.  Patients with HIV who have adequate 
CD4 counts and who have no requirement for antiviral therapy will be eligible. 
3.1.2.4 Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic 
adverse events of an investigational agent. Males or females of reproductive potential may not 
participate unless they have agreed to use an effective contraceptive method.  Abstinence is an 
acceptable method of birth control.  
3.1.2.5 Prior treatment with selumetinib or another specific MEK 1/2 inhibitor.  
3.1.2.6 No supplementation with vitamin E is permitted. 
3.1.2.7 Inability to swallow capsules, since capsules cannot be crushed or broken. 
3.1.2.8 Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel 
disease), or significant bowel resection that would preclude adequate absorption. 
3.1.2.9 Strong inhibitors or inducers of hepatic microsomal isoenzymes 
3.1.2.10 While not an exclusion criterion, unless clinically indicated, patients should avoid taking other 
additional non-study medications that may interfere with the study medications. In particular, 
patients should avoid medications that are known to be strong inhibitors or inducers of hepatic 
microsomal isoenzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5, UGT1A1, 
UGT1A3 and transporters BCRP and P-gp. Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated medical reference.  As part 
of the enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or if 
the patient is considering a new over-the-counter medicine or herbal product.  Section 17.1.1 
is the Patient Drug Information Handout and Wallet Card that should be provided to patients. 
Known Cardiac Disorder, including:  
• Uncontrolled hypertension (blood pressure [BP] of ≥150/95 despite medical 
support/management) 
• Acute coronary syndrome within 6 months prior to starting treatment 
• Uncontrolled angina – Canadian Cardiovascular Society grade II-IV despite medical 
support/management 
• Heart failure NYHA Class II or above (for the NYHA Classification refer to Appendix 
II) 
• Prior or current cardiomyopathy including but not limited to the following: 
o Known hypertrophic cardiomyopathy 
• Known arrhythmogenic right ventricular cardiomyopathy 
• Baseline left ventricular ejection fraction (LVEF) ≤ 53%  
• Previous moderate or severe impairment of left ventricular systolic function (LVEF 
<40% on echocardiography or equivalent on Multi-Gated Acquisition Scan [MUGA]) 
even if full recovery has occurred. 
• Severe valvular heart disease 
• Atrial fibrillation with a ventricular  rate >100 bpm on ECG at rest 
• QTcF interval >450 msec or other factors that increase the risk of QT prolongation or 
arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval 
syndrome) are excluded.  The use of medication(s) that can prolong QTc interval is 


29 
 
prohibited while treated on this study.  For a comprehensive list of agents that prolong 
QTc refer to a frequently-updated medical reference, such as 
https://www.crediblemeds.org/everyone/composite-list-all-qtdrugs. 
 
3.1.2.11 Known Ophthalmologic conditions, such as: 
a. Current or past history of retinal pigment epithelial detachment (RPED)/central serous 
retinopathy (CSR)  
b. Current or past history of retinal vein occlusion 
c. Known intraocular pressure (IOP) > 21 mmHg (or ULN adjusted by age) or uncontrolled 
glaucoma (irrespective of IOP); patients with controlled glaucoma and increased IOP who 
do not have meaningful vision (light perception only or no light perception) may be eligible 
after discussion with the study chair. 
d. Subjects with any other significant abnormality on ophthalmic examination (performed by 
an ophthalmologist) should be discussed with the Study Chair for potential eligibility 
e. Ophthalmological findings secondary to long-standing optic pathway glioma (such as 
visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as 
visual loss, strabismus) will NOT be considered a significant abnormality for the purposes 
of the study 
3.1.2.12 Known severe hypersensitivity to selumetinib or any excipient of selumetinib or history of 
allergic reactions attributed to compounds of similar chemical or biologic composition to 
selumetinib  
3.1.2.13 Have had recent major surgery within a minimum of 4 weeks prior to starting study treatment, 
with the exception of surgical placement for vascular access.  
3.1.2.14 Have any unresolved chronic toxicity with CTC AE grade ≥ 2, from previous anti-NF1 therapy, 
except for alopecia.   
3.1.2.15 Clinical judgment by the investigator that the patient should not participate in the study 
3.2 
INCLUSION OF WOMEN AND MINORITIES 
NIH policy requires that women and members of minority groups and their subpopulations be included 
in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical 
research unless a clear and compelling rationale and justification establishes to the satisfaction of the 
funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research.  Exclusion under other circumstances must be designated by the 
Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and 
justification.  Cost is not an acceptable reason for exclusion except when the study would duplicate data 
from other sources.  Women of childbearing potential should not be routinely excluded from 
participation in clinical research.  Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
4 
REGISTRATION PROCEDURES 
4.1 
REGISTRATION WITH THE COORDINATING CENTER 
Authorized staff will register eligible candidates through a web-based data entry system called 
OnCore. OnCore is the UAB Comprehensive Cancer Center’s Clinical Trial Management System. 
Registration must occur prior to the initiation of therapy. Any participant not registered to the protocol 


30 
 
before treatment begins will be considered ineligible and registration will be denied. A physician on 
the study team will confirm eligibility criteria and complete the protocol-specific eligibility checklist. 
Following registration, participants may begin protocol treatment. Issues that would cause treatment 
delays should be discussed with the protocol Principal Investigator (PI).  
The registration procedures are as follows:  
1. Obtain written informed consent from the participant prior to the performance of any study 
related procedures or assessments.  
2. Complete the protocol-specific eligibility checklist using the eligibility assessment documented 
in the participant’s medical/research record. To be eligible for registration to the study, the 
participant must meet each inclusion and exclusion criteria listed on the eligibility checklist.  
3. Enrollment and exclusion criteria will be entered through OnCore after receiving email 
confirmation from the Protocol PI (or his designee) that consented subject is eligible for study 
entry.  
4. OnCore will send enrollment confirmation via automated email alerts to study protocol team, 
coordinating center, site PI, and site study coordinator. 
5. Following registration, participants should begin protocol treatment within 14 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If a participant 
does not receive protocol therapy following registration, the participant’s protocol status must 
be changed. The coordinating center should be notified of participant status changes as soon as 
possible by email.  
4.2 
SCREENING EVALUATION 
Eligibility will be determined during a pre-study evaluation period after subjects have signed a screening 
consent or the protocol specific consent.  Subject information must be entered onto a screening log and 
for subjects not enrolled; a brief reason will be entered onto the screening log.   
Eligibility blood tests should be performed within 2 weeks (14 days) prior to enrollment on the trial 
unless otherwise stated (Appendix III).  If greater than 7 days elapses between eligibility blood tests and 
starting therapy, blood tests should be repeated.  If test results are outside the window of eligibility, they 
must be corrected prior to started therapy. 
1. History and physical examination:  Complete history, including prior and concurrent therapy; 
physical examination including performance status, blood pressure, height, weight, signs and 
symptoms.  Documentation of substantial cutaneous neurofibroma burden, the presence of ≥ 9 
measurable cutaneous neurofibromas, and the presence of distress to the patient should be 
documented prior to enrollment.  
2. Hematology:  Complete blood count with differential and platelets.  
3. Chemistries:  Electrolytes (including sodium, potassium, chloride, CO2), calcium, phosphorus, 
magnesium, creatinine, BUN, glucose, ALT, bilirubin, urinalysis, total protein, albumin, 
amylase, lipase and CPK. 
4. EKG/Echo: Electrocardiogram and echocardiogram to be performed within 8 weeks prior to 
enrollment on the trial. 
5. Urine or serum pregnancy test for all females of childbearing potential.  This test is to be 
performed within 72 hours prior to enrollment. 


31 
 
6. Ophthalmology evaluation: A complete ophthalmology evaluation will be performed 
pretreatment. Particular emphasis will be given to the evaluation of corneal opacification and 
retinal changes. 
5 
TREATMENT PLAN 
5.1 
STUDY DESIGN OVERVIEW 
This is a limited institution open label pilot study in which all subjects will commence treatment with 
selumetinib orally at 50 mg /dose approximately every 12 hours (one cycle = 28 days). This dose 
corresponds approximately the pediatric phase II dose of selumetinib for children with NF1 and 
plexiform neurofibromas or for children with low-grade gliomas, which is 25 mg/m2 BSA per dose. The 
recommended phase II dose of selumetinib for adults with refractory solid tumors is 75 mg per dose 
twice daily. This dose was evaluated in a phase II trial of selumetinib for adult with inoperable PN. The 
first 2 patients enrolled on this trial experienced toxicities requiring dose modification including skin 
rash and scalp pain. This adult trial was thus amended to initiate treatment at a dose of 50 mg per dose 
with an option to increase the dose to 75 mg per dose, provided the 50 mg dose is well tolerated. We 
will use the same strategy in this trial directed at cutaneous neurofibromas. Patients will be able to 
escalate to 75mg every 12 hours [BID], if the medication is tolerated well for the first cycle, with no 
toxicities of grade 2 or greater. 
Patients will undergo regular evaluation for selumetinib related toxicities. In absence of treatment 
limiting toxicity, or progression of disease, patients may remain on treatment for a maximum of 24 
cycles unless they experience a volume decrease in the target cutaneous neurofibromas, in which case 
treatment may continue for additional 12 cycles.  
For response evaluation, the average volume of 3-5 small (longest neurofibroma diameter 4-7 mm) and 
3-5 larger (longest neurofibroma diameter ≥8 mm) target cutaneous neurofibromas in 3 different body 
regions will be calculated at each response evaluation (baseline, and then after every 4 cycles). 
Cutaneous neurofibromas will be measured with calipers as developed by Dr. Korf, and volumes will 
be calculated by multiplying length, width, and height of each target neurofibroma. At each response 
evaluation the sum of the on-treatment volumes for the smaller tumors will be subtracted from the pre-
treatment volumes of the same tumors to arrive at an overall percentage change in tumor size for each 
patient. This will be repeated for the larger tumors. Then, the average percentage change for each size 
category will be reported. 
In absence of validated response criteria for cutaneous neurofibromas for the purpose of determining 
the duration of treatment with selumetinib, responsive disease will be defined as a ≥20% decrease in the 
average volume of the smaller or larger cutaneous neurofibromas compared to the baseline volume. 
Progressive disease will be defined as a ≥ 20% increase in the average volume of smaller or larger 
cutaneous neurofibromas compared to the baseline volume. Stable disease will be defined as 
measurements not meeting criteria for responsive or progressive disease.  
In order to assess changes in skin related morbidity and pain, patients will complete both the Skindex 
(Appendix IV) and the Global Impression of Change Scale (Appendix X) along with the Numeric Rating 
Scale (Appendix XI), which are all patient reported outcome measures.. 
In order to evaluate the pharmacodynamic effects of selumetinib, patients will undergo mandatory 
excisions of ≥ 1 cutaneous neurofibroma prior to treatment and once on treatment with selumetinib to 


32 
 
assess percent inhibition of pERK and changes in pAKT and other molecular markers such as tumor 
kinome (Appendix VI).  
The study schema is as follows: 
 
5.2 
AGENT ADMINISTRATION 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks are 
described in Section 7.  Appropriate dose modifications are described in Section 6.  No investigational 
or commercial agents or therapies other than those described below may be administered with the intent 
to treat the patient's malignancy. 
Selumetinib will be supplied in in 10 mg (plain white) and 25 mg blue capsules. Selumetinib will be 
administered orally twice daily (approximately every 12 hours) at a dose of 50 mg per dose on a 
continuous dosing schedule (1 cycle =28 days) with no rest periods between cycles. Patients will be able 
to escalate to 75 mg BID if the medication is tolerated well for the first cycle, with no toxicities of grade 
2 or greater.  
Patients should be instructed to take the dose of selumetinib on an empty stomach (no food or drink other 
than water for 2 hours before and 1 hour after dosing) with water only. The capsules cannot be crushed 
and have to be swallowed whole.   


33 
 
Patients will be instructed to keep a diary of medication taken (Section 17.7 Appendix VI) to document 
intake of each dose of selumetinib and potential side effects.  The patient diary will be reviewed at the 
time of study visits.  
Patients should avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is 
anticipated. 
5.3 
DURATION OF TREATMENT 
In absence of treatment limiting toxicity, or progressive disease, patients may remain on treatment for a 
maximum of 24 cycles unless they experience a volume decrease in the target cutaneous neurofibromas, 
in which case treatment may continue for additional 12 cycles.  
Patients who discontinue treatment with selumetinib will be monitored after every 4 months for 12 
months off treatment for changes in cutaneous neurofibroma volume and number. Patients who are 
permanently removed from treatment with selumetinib will also continue to be followed for 30 days 
after the last dose of selumetinib until toxicities have resolved to baseline or stabilized, OR they no 
longer meet criteria for reporting (whichever is later).   
5.4 
SUPPORTIVE THERAPIES 
Appropriate antibiotics, blood product support, anti-emetics, and general supportive care will be used 
as indicated.  
5.4.1 Follow up for certain AEs should be performed to better characterize the effects of selumetinib 
therapy:  
• Patients experiencing edema should have cardiac ejection fraction (EF) measurements, 
serum chemistry (including electrolytes and albumin), and routine urinalysis. 
• Patients with symptoms consistent with cardiac impairment (e.g., congestive cardiac failure, 
edema, or dyspnea) should have EF measurements (MUGA scan or echocardiography) at the 
time of the event as well as other routine investigations.  Decreases in left ventricular ejection 
fraction (LVEF) from baseline (if known) may be investigated according to the algorithm 
described in Section 6.3. 
• Respiratory events (pulmonary edema) should be followed up with an electrocardiogram, 
EF measurement, and chest X-ray.  All new dyspnea AEs or worsening of pre-existing 
dyspnea AEs should be followed according to the dyspnea management algorithm (Appendix 
V).  
• Oxygen saturation will be measured at baseline and again following any respiratory event. 
• Patients experiencing visual disturbances should undergo a complete ophthalmologic 
examination, including a slit lamp examination. 
5.4.2 Dermatologic adverse events:  
The use of medications for the supportive care of rash is permitted, provided that compliance with 
Appendix I regarding concomitant medications is observed(66).  Early initiation of treatment for rashes 
is strongly recommended to minimize the duration and severity of the adverse event.  For pediatric 
subjects, the following guidelines have been found to be useful: 


34 
 
Acneiform rash: 
Experience with acneiform rash suggests that topical clindamycin gel or lotion applied BID, rather than 
steroids, is the most helpful for pustular rash. In severe cases, semisynthetic oral tetracyclines such as 
doxycycline or minocyline may also be useful. 
Eczematous rash/xerosis: 
Eczematous/dry skin rash and other macular (non-acneiform) rash should be treated with a moisturizer 
such as Cerave or Eucerin. A low potency topical steroid may also be used if symptomatic.   
Ketoconazole shampoo should be used for any rash involving the scalp. 
Paronychia: 
For patients who do not undergo drainage, silver nitrate may be used, as well as topical bactroban, 
steroids, and/or antifungals.  Silver nitrate is only of value when there is open inflamed skin or 
granulation tissue (e.g. pyogenic-granuloma-like lesions). If the periungual skin is swollen but intact 
(whether infectious or non-infectious), silver nitrate is not recommended. Patients should be cautioned 
to avoid trauma to the area.  Podiatry consult may be considered for partial nail removal.   
Patients who undergo incision and drainage and are found to have no infectious organisms on culture, 
should be treated as above.  If infection is identified, patients may be treated with systemic antibiotics 
(oral tetracyclines).   
If paronychia recurs or develops in other fingers or toes, flurandrenolide (e.g. Cordran) tape or topical 
steroid cream such as triamcinolone can be used in the morning and Bactroban and Nizoral topical 
ointments in the evening. 
For any questions regarding management of skin toxicity, please contact: Dominique Pichard (Email: 
picharddc@nih.gov, phone 301-594-3457). 
5.4.3 Visual adverse events: 
All patients will have a detailed ophthalmologic evaluation at baseline.  In patients who develop visual 
symptoms, a repeat ophthalmologic evaluation will be performed to include: best corrected visual acuity, 
intraocular pressure, slit lamp fundoscopy (photograph if abnormal); consider optical coherence 
tomography.  
If a diagnosis of retinal pigment epithelial detachment (PRED) or central serous retinopathy (CSR) is 
made, treatment with selumetinib will be held and repeat ophthalmologic evaluations will be performed 
until resolution.  Treatment may be restarted after a dose reduction using the criteria described in Section 
6.  
If a diagnosis of retinal vein occlusion (RVO) is made, selumetinib will be discontinued permanently. 
For the development of cornea or lens opacification see Section 6.1. 
5.4.4 Gastrointestinal adverse events: Diarrhea 
Patients should be made aware that they may experience diarrhea, and should be encouraged to record 
the number of stools and possible associated symptoms in the patient diary (Section 17.7, Appendix 
VII). Patients should be given loperamide to take home and should start taking loperamide immediately 
after the first episode of unformed, loose stool (in accordance with local regulations and practice). 
Additional agents may be used concurrently if loperamide is not adequate to control diarrhea as a single 
agent. 


35 
 
In addition, the following dietary advice should be considered: BRAT diet (bananas, rice, apple sauce, 
toast, plain pasta), readily digestible food, avoidance of lactose-containing products and fried, fatty or 
spicy foods, increased fluid intake (8-10 glasses of clear fluids/day (including water, clear broth, fluids 
containing salt and sugar).  Patients should be encouraged to seek advice early from their physician or 
study nurse if they have persistent diarrhea, diarrhea complicated by vomiting, or inability to take oral 
liquids. 
5.4.5 Gastrointestinal adverse events: Oral mucositis 
Patients should be encouraged to follow a daily oral health care regime, both before and during treatment 
with selumetinib. 
Patients with a healthy mouth may use nonalcoholic mouthwash 4 to 6 times daily (e.g. after each meal), 
or according to the instructions, during the study.  
Saline mouthwashes (Sodium chloride 0.9%) are preferred in cases of stomatitis, and should be used at 
a different time than toothbrushing (e.g. after tea).  
Use of a mouthwash immediately after selumetinib intake is recommended. 
The tongue can be gently brushed (if not sore) with a soft toothbrush. 
Patients with, or at risk of, stomatitis should not use commercial/over-the-counter mouthwashes because 
of the alcohol content and astringency.  Chlorhexidine mouthwashes are not recommended for the 
treatment of established stomatitis.  
The mouth should be regularly inspected by the patient and healthcare professionals. 
Teeth should be brushed twice daily with a fluoride toothpaste and soft toothbrush, in the morning before 
breakfast and last thing in the evening before bed, about 30 minutes after eating. The toothbrush should 
be replaced regularly (at least every 3 months).  Patients with stomatitis should change their toothbrush 
every 4 - 6 weeks. 
Consider treating stomatitis at an early stage (CTCAE grade 1) or as soon as the patient complains of a 
sore mouth.  Consider using an oral topical analgesic, with or without topical steroids, depending on the 
patient’s clinical condition and the local standard medical practice.  
Consider culture to rule out herpes simplex. 
5.4.6 Pulmonary adverse events: Dyspnea 
Patients who develop dyspnea while receiving selumetinib should undergo standard clinical evaluations 
to rule out infectious etiology and pneumonitis.  Selumetinib will be held for grade ≥2 pneumonitis, and 
may be restarted at a reduced dose following criteria for dose reduction in Section 6. 
5.4.7 Surgical procedures 
Major surgery will require holding selumetinib 1 week prior to surgery and until wound has healed 
completely. 
5.5 
CONCURRENT THERAPIES 
1) Other cancer chemotherapy, radiation, immunotherapy, biologic therapy, hematopoietic growth 
factors, or investigational agents cannot be administered to patient while receiving selumetinib. 


36 
 
2) Doses of vitamin E greater than the 100% daily recommended doses are contraindicated. 
Selumetinib capsules contain vitamin E in the form of D-α-tocopheryl polyethylene glycol 
1000 succinate (TPGS), a water-soluble form of vitamin E which acts as a formulation 
excipient.  
 
 
Capsule Ingredient Maximum amount of Vitamin E per capsule 
10 mg 
Active 
32.4 mg 
25 mg 
Active 
35.9 mg 
The maximum daily dose of vitamin E that a study subject may receive from selumetinib is 
approximately 143.6 mg/day (patients who receive 50 mg BID) or 215.4 mg (patients who receive 75 
mg BID) or 136.6 mg/day (patients who receive 35 mg BID) or 71.8 mg/day (patients who receive 25 
mg BID). Therefore: 
a. Patients should not take any supplemental vitamin E. High doses of vitamin E have 
been reported to cause bleeding and interfere with blood coagulation processes.  
b. Selumetinib should be administered with caution in patients who are also receiving 
concomitant coumarin anticoagulant medications, e.g. warfarin. These patients 
should have their INR monitored / anticoagulant assessments conducted more 
frequently and the dose of the anticoagulant should be adjusted accordingly. 
3) The use of corticosteroids for control of symptoms related to the underlying NF1 or for other 
reasons will be allowed. 
4) Patients should avoid medications that are known to be strong inhibitors or inducers of hepatic 
microsomal isoenzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5, UGT1A1. 
UGT1A3 and transporters BCRP and P-gp. Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated medical reference. Refer to 
the patient drug interaction handout and wallet card in Appendix 1. 
 
5.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
5.6.1 Criteria for removal from protocol therapy 
1. A patient may be removed from the protocol treatment for the following non-medical or 
administrative reasons: 
a. Patient refusal of further treatments (reasons must be noted on the patient’s CRF). 
b. It is deemed in the best interest of the patient.  In this instance the PI should be 
notified and the reasons of withdrawal should be noted in the CRF. 
c. Serious protocol deviation or serious non-compliance as determined by the PI. 
2. 
Any patient who develops treatment-limiting toxicity, which does not resolve to meet study 
parameters within 21 days of drug discontinuation or within the time frame defined in 
Section 6.1. 


37 
 
3. 
If treatment-limiting toxicity recurs in a patient who has resumed treatment after two dose 
reductions. 
4. 
Any patient with clinical evidence of progressive disease on treatment following any 
treatment cycle will be removed from study treatment.  
5. 
A patient who develops a concurrent serious medical condition that might preclude or 
contraindicate the further administration of selumetinib will be removed from the study.  A 
patient who becomes pregnant will be immediately taken off therapy.  
6. 
Patients who initiate another cutaneous neurofibroma directed therapy will be removed from 
therapy. 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below).  Follow-up data will be required unless consent is withdrawn.   
Toxicities must be followed until stabilization or resolution prior to a subject being taken ‘off study’.  
5.6.2 Off-Study Criteria 
• Completed study follow-up period.  Patients will be followed for 30 days after the last dose of 
selumetinib, when treatment related toxicities have returned to baseline or stabilized, OR they 
no longer meet criteria for restarting treatment as outlined in Section 6.2(whichever is later). 
• Withdrawal of consent for any further data submission 
• Noncompliance with study requirements 
• Death 
Authorized staff must notify OnCore when a subject is taken off-study.  
6 
DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
TREATMENT LIMITING TOXICITIES 
Selumetinib will be held for selumetinib related toxicities requiring dose modifications: Any ≥ grade 3 
hematologic or non-hematologic toxicities with the specific exclusion of: 
• Skin rash, which can be managed successfully with supportive intervention including initiation 
of oral doxycycline or minocycline. 
• Asymptomatic grade 3 creatine kinase elevation, which remains <10 x ULN. 
• Gastrointestinal toxicity, such as grade 3 diarrhea, nausea, or vomiting, which can be managed 
successfully with supportive intervention within 72 hours. 
• Grade 3 elevation of ALT or AST that return to levels to meet initial eligibility criteria within 
14 days of selumetinib interruption and that do not recur upon re-challenge of selumetinib. 
• Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to 
supplementation. 
• Grade 3 cataracts will be considered on a case by case basis with consultation with the PI and 
ophthalmology.   


38 
 
In addition, selumetinib may be held for any ≥ grade 2 related toxicities of ≥7 days if they are intolerable 
to the patient and cannot be controlled with standard supportive measures.  
6.2 
DOSE MODIFICATIONS 
If the toxicity resolves to meet study parameters or  grade 1 within 21 days of drug discontinuation or 
the toxicity resolves to meet study parameters or  grade 1 within 3 months and the patient was receiving 
clinical benefit as defined below, the patient may resume treatment at a dose reduced by 30%, which is 
a dose of 35 mg/dose (See Figure 3).    
 
Subjects with AEs that are manageable with supportive therapy may not require dose reductions (e.g., 
nausea/vomiting may be treated with antiemetics, diarrhea may be treated with loperamide, electrolyte 
abnormalities may be corrected with supplements rather than by dose reduction).   
Dose reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity with the reduced 
dose.  Selumetinib doses held while the patient is recovering from toxicity should not be made up and 
the cycle remains 28 days.     
If disease progresses after dose reduction to > 20% increase in tumor volume, the patient will be removed 
from study treatment, but if volume increases ≤ 20%, the patient may resume dosing at 50 mg BID for 
5 days each week (2 day rest/week).  If the treatment limiting toxicity recurs on this schedule, the same 
rules will apply (if the toxicity resolves to meet study parameters or  grade 1 within 21 days of drug 
discontinuation or the toxicity resolves to meet study parameters or  grade 1 within 3 months and the 
patient was receiving clinical benefit), the patient may resume treatment at a dose of 35 mg/dose BID X 
5 days per week. 
Subjects will be withdrawn from the study if they fail to recover to CTCAE Grade 0-1 or tolerable grade 
2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) from a treatment-related 
AE within 21 days OR they experience agent-related AEs requiring dose modification despite two 
previous dose reductions (i.e., would require a third dose reduction) unless the investigator and CTEP 
monitor agree that the subject should remain in the study because of evidence that the patient is/may 
continue deriving benefit from continuing study treatment (i.e., patient has partial response [PR], 
complete response [CR], or stable disease [SD] for ≥3 months). The appropriate reduced dose will be 
determined after discussion between the principal investigator and CTEP monitor.  Benefit will be 
defined as either responsive disease (≥20% decrease in the average volume of smaller or larger 
cutaneous neurofibromas), or stable disease (<20% increase or < 20% decrease in the average volume 
of smaller or larger cutaneous neurofibromas) in a patient who enrolled on the trial with progressive 
disease, or improvement of symptoms or function.  For example, patients who experience dose limiting 
cardiotoxicity (decreased LVEF) and whose LVEF recovers to meet study parameters within >21 days 
but ≤3 months, may upon recovery continue protocol therapy at the reduced dose provided they have 
previously experienced clinical benefit while receiving selumetinib.  
If treatment-limiting toxicity recurs in a patient who has resumed treatment at the reduced dose, the dose 
may be reduced a second time from 35 mg per dose to 25 mg per dose if administered on a twice daily 
continuous dosing schedule using the same criteria, i.e., toxicity resolves to meet study parameters or  
grade 1 within 21 days of drug discontinuation, dose may not be re-escalated, doses held will not be 
made up.  If treatment-limiting toxicity recurs after two dose reductions, the patient must be removed 


39 
 
from protocol therapy.  Patients removed from study therapy for toxicity will be followed until resolution 
of toxicity and off study criteria are met. 
 


40 
 
 
Figure 3:  Selumetinib Dose Modification Schema 
 
 
 


 
41 
 
 
6.3 
CARDIAC TOXICITY 
Cardiac toxicity will be managed as described below in the figure below: 
 
 
1) Decline in LVEF from baseline of ≥ 10 percentage points but with a normal EF of ≥ 53% 
• Patients who have an asymptomatic decline in LVEF from baseline of ≥ 10 percentage points 
but continue to have a normal EF of ≥ 53% (if a range is given then the upper limit of the range 
will be used) will continue on treatment with selumetinib and have a repeat ECHO 3-6 weeks 
later.    
• Patients who have a symptomatic decline in LVEF from baseline of ≥ 10 percentage points but 
continue to have a normal EF of ≥ 53% (if a range is given then the upper limit of the range will 
be used) selumetinib will be held. A cardiology consult will be initiated to determine the etiology 
of the symptoms and direct management. At the same time the primary team will investigate 
other possible etiologies of the symptoms. The ECHO will be repeated in these patients after 3-
6 weeks and as recommended by cardiology.  If the patient is receiving benefit from selumetinib 
(see Section 6.2), and if symptoms were found to be related to heart failure selumetinib will be 


42 
 
restarted at reduced dose.  If symptoms were unrelated to heart failure, selumetinib may be 
resumed at full dose.  
2)  Decline in LVEF from baseline of ≥ 10 percentage points with an EF < 53% 
• For patients who have a symptomatic or asymptomatic decline in LVEF from baseline of ≥ 10 
percentage points to < 53% (if a range is given then the upper limit of the range will be used), 
selumetinib will be held.  Treatment with an ACE inhibitor should be initiated as soon as 
possible, and these patients will be referred to cardiology for additional evaluation and treatment.  
The ECHO will be repeated on these patients after 3-6 weeks, and as recommended by 
cardiology until recovery from toxicity (LVEF ≥ 53%). ECHOs will then be performed as 
described in Figure 3.   If the LVEF returns to ≥ 53% within 3 months of discontinuation of 
selumetinib, and the patient is receiving benefit from selumetinib (see Section 6.2), and 
symptoms have resolved, selumetinib may be restarted at a reduced dose.  
3)  Decline in LVEF from baseline of < 10 percentage points with an EF < 53% 
• For patients who have an asymptomatic decline in LVEF from baseline of < 10 percentage points 
to < 53% (if a range is given then the upper limit of the range will be used), selumetinib will be 
continued. Treatment with an ACE inhibitor should be initiated as soon as possible, and these 
patients will be referred to cardiology for additional evaluation and treatment.  An ECHO will 
be performed after 3-6 weeks and as directed by cardiology.  Treatment with selumetinib can be 
continued for as long as the decrease in LVEF remains less than 10 percentage points from 
baseline in these patients and patients remain asymptomatic.   
• Patients who have a symptomatic decline in LVEF from baseline of < 10 percentage points to < 
53% (if a range is given then the upper limit of the range will be used), selumetinib will be held. 
Treatment with an ACE inhibitor should be initiated as soon as possible, and these patients will 
be referred to cardiology for additional evaluation and treatment.  The ECHO will be repeated 
in these patients after 3-6 weeks and as recommended by cardiology until recovery of LVEF to 
≥ 53%. ECHOs will then be performed as described in Figure 3. If the LVEF returns to ≥ 53% 
within 3 months of discontinuation of selumetinib, and the patient is receiving benefit from 
selumetinib (see Section 6.2) and symptoms resolve, selumetinib may be restarted based on 
cardiology recommendation. If symptoms were related to heart failure selumetinib will be 
restarted at reduced dose. If symptoms were unrelated to heart failure, selumetinib may be 
resumed at full dose. 
Recommendations for treatment with ACE inhibitors: 
For patients meeting criteria to start an ACE inhibitor the following suggestions for choice and dosing 
of ACE inhibitors before cardiology consultation are made.  These can be modified by institutional 
guidelines or cardiology. 
1) Enalapril: start at 2.5 mg PO once daily. 
2) Lisinopril: start at 2.5 mg PO once daily.  
3) Captopril: start 6.25-12.5 PO mg TID. 
4) The above doses are starting doses. ACE inhibitor doses should be titrated upwards if tolerated by 
blood pressure and renal function; doses should be reduced by 50% in patients with hypovolemia, 
hyponatremia, or decreased renal function, or if receiving diuretics.  
5) After initiation, treatment with an ACE inhibitor should be continued for the duration of the study 
unless otherwise directed by cardiology.  


43 
 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each patient 
while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 986 patients. Below is the CAEPR for Selumetinib 
(AZD6244). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE 
in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and 
has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
Version 2.8, June 13, 20191 
 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244 hydrogen sulfate), AZD6244 
 (CTCAE 5.0 Term) 
[n= 986] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Febrile neutropenia2 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic 
dysfunction (Gr 2) 
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Eye disorders - Other (central 
serous retinopathy) 
  
 
 
Eye disorders - Other (retinal 
pigment epithelial detachment) 
  
 
 
Eye disorders - Other (retinal vein 
occlusion) 
  
 
Periorbital edema 
 
  


44 
 
 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244 hydrogen sulfate), AZD6244 
 (CTCAE 5.0 Term) 
[n= 986] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea3 
 
 
 Diarrhea3 (Gr 3)  
 
Dry mouth 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face 
 
 Edema face (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Pain 
 
  
INFECTIONS AND INFESTATIONS 
  
 
 
 Folliculitis  
  
 
 
 Nail infection  
  
 
 
 Papulopustular rash  
  
 
Paronychia 
 
  
 
 
 Skin infection 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
 CPK increased (Gr 3) 
 
 
Ejection fraction decreased 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
 
Hyperphosphatemia 
  
 
 
Hypoalbuminemia 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
 
Growth suppression 
 
 
 
 
Musculoskeletal and connective 
tissue disorder - Other (neck 
extensor muscle weakness) 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2)  
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  


45 
 
 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244 hydrogen sulfate), AZD6244 
 (CTCAE 5.0 Term) 
[n= 986] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
  
Rash acneiform 
 
 
 Rash acneiform (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your 
name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Febrile neutropenia/neutropenic infection has been observed primarily in trials combining Selumetinib (AZD6244) and 
docetaxel. 
 
3SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or diarrhea in rats and 
dogs; however, it is possible that some of these findings might be related to exacerbation of the vehicle effect by 
Selumetinib (AZD6244). 
 
 
Adverse events reported on Selumetinib (AZD6244) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Selumetinib (AZD6244) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (hemorrhagic 
anemia) 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Atrioventricular block first degree; Cardiac 
disorders - Other (Takotsubo cardiomyopathy syndrome); Cardiac disorders - Other (valvular heart disease); Chest pain - 
cardiac; Heart failure; Myocardial infarction; Palpitations; Pericardial effusion; Right ventricular dysfunction; Sinus 
bradycardia; Sinus tachycardia 
EYE DISORDERS - Dry eye; Eye disorders - Other (bilateral macular edema); Eye disorders - Other (black haze in line of 
vision); Eye disorders - Other (chalazion); Eye disorders - Other (diplopia); Eye disorders - Other (retinal bleeding); Eye 
disorders - Other (spotty vision; itchy vision); Flashing lights; Floaters; Glaucoma; Optic nerve disorder; Papilledema; 
Photophobia; Retinal detachment; Retinopathy; Uveitis; Vision decreased 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Cheilitis; Colitis; Duodenal ulcer; 
Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastric hemorrhage; Gastritis; Gastroesophageal reflux 
disease; Gastrointestinal disorders - Other (pneumatosis coli); Gingival pain; Ileal stenosis; Oral hemorrhage; Rectal 
hemorrhage; Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Disease progression; 
Facial pain; Flu like symptoms; Generalized edema; Localized edema; Malaise; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (liver dysfunction/ failure [clinical]) 
INFECTIONS AND INFESTATIONS – Infection4 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac troponin I increased; Creatinine 
increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; Electrocardiogram T wave 
abnormal; Hemoglobin increased; INR increased; Investigations - Other (ECG signs of myocardial ischemia); Lipase 
increased; Lymphocyte count decreased; Lymphocyte count increased; Serum amylase increased; Weight gain; Weight loss 


46 
 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (electrolyte abnormalities); Metabolism and 
nutrition disorders - Other (elevated calcium phosphorus product); Metabolism and nutrition disorders - Other (sensation of 
warmth) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; Bone pain; 
Chest wall pain; Generalized muscle weakness; Joint effusion; Joint range of motion decreased; Muscle weakness lower 
limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other (bilateral stiffness hands and feet 
[intermittent]); Musculoskeletal and connective tissue disorder - Other (muscle weakness neck); Musculoskeletal and 
connective tissue disorder - Other (neck myopathy); Myalgia; Myositis; Neck pain; Pain in extremity; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment related 
secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Cognitive disturbance; Concentration impairment; Depressed level of 
consciousness; Dysarthria; Dysgeusia; Dysphasia; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; 
Leukoencephalopathy; Memory impairment; Oculomotor nerve disorder; Paresthesia; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; Spinal cord compression; 
Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delusions; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Nephrotic syndrome 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Bronchopulmonary hemorrhage; Epistaxis; Hoarseness; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural 
effusion; Pulmonary edema; Sore throat; Voice alteration; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Erythroderma; Nail loss; Pain of skin; 
Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Scalp pain; Skin and subcutaneous tissue disorders - Other 
(skin fissures); Skin ulceration; Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Flushing; Hypotension; Lymphedema; Thromboembolic event 
Note: Selumetinib (AZD6244) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
7.2 
DEFINITIONS 
7.2.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in research, whether or not considered related to the subject’s participation in the 
research. 
7.2.2  Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means 
there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 


47 
 
7.2.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application. "Unexpected” also refers to 
adverse events or suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under investigation. 
7.2.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse 
Event or if it compromises the safety, welfare or rights of subjects or others. 
7.2.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the investigator 
or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.2.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.2.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the 
investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that had it occurred in a more severe form, might have caused death. 
7.2.8 Protocol Deviation:  
Any change, divergence, or departure from the IRB-approved research protocol.    
To accommodate changes in patients’ schedules, holidays, and provide flexibility for long term follow 
up, any change or divergence in the scheduling or conduct of examinations, tests and scans described in 
this protocol will NOT be considered a protocol deviation and will not require reporting to the IRB 
unless it meets the definition of unanticipated problem or non-compliance.  Similarly, 1) isolated missed 


48 
 
lab values or missed selumetinib doses will be documented, but not be reported as a protocol deviation, 
and 2) isolated missing lab values will be noted, but not reported as protocol deviation. 
7.2.9 Non-compliance  
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB 
requirements, or regulatory requirements for the protection of human research subjects. 
7.2.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
7.3 
COORDINATING CENTER AND IRB REPORTING 
In addition to the requirements below, the responsibilities of the protocol chair and the coordinating 
center are listed in Section 17.10, Appendix IX.  The PI of each site will report AE, SAEs and IND 
safety reports to their respective IRB(s) according to the institutional policies and procedures. 
7.3.1 IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Coordinating Center PI will be responsible for reporting all SAEs to the IRB of the Coordinating 
Center.  The PI of the Coordinating Center will report to the IRB: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance  
Reports must be received by the IRB within 7 working days of PI awareness according to the 
institution’s procedures. 
7.3.2 IRB Requirements for PI Reporting at Continuing Review 
The Coordinating Center PI is responsible for reporting all AEs occurring on this study to the IRB of 
the Coordinating Center at the time of the continuing review. The PI of the Coordinating Center will 
report to the IRB:   
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 


49 
 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.3.3 IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported 
to the UAB IRB. 
7.4 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS TO CTEP A  
All observed or volunteered adverse events, regardless of treatment group or suspected causal 
relationship to study drug, will be recorded on the Adverse Event page(s) of the case report form. 
Adverse events will be identified and graded using the NCI Common Toxicity Criteria version 5.0 
(CTCAE version 5.0).  Next it will be determined if the adverse event is related to the medical treatment 
(attribution). If so, it will be determined whether the adverse event is expected or unexpected. Using the 
guidelines outlined in this section, adverse events will then be reported to the NCI using a routine report 
(CDUS), and if required, the CTEP Adverse Event Reporting System (CTEP-AERS), an electronic 
system for expedited submission of adverse event reports.  Information regarding CTEP-AERS and 
instructions 
for 
training 
is 
available 
on 
the 
CTEP 
website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm 
The adverse event page will contain information if the reported event was expected or unexpected, and 
if the reported toxicity is included in the informed consent. A justification will be provided on the 
adverse event page if the observed toxicity in not included in the informed consent. For all adverse 
events, the investigator must pursue and obtain information adequate both to determine the outcome of 
the adverse event and to assess whether it meets the criteria for classification as a serious adverse event 
requiring immediate notification to the sponsor. Follow-up of the adverse event, even after the date of 
therapy discontinuation, is required if the adverse event or its sequelae persist. Follow-up is required 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator and sponsor. 
7.4.1 Adverse Event Characteristics  
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm ). 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the SPEER 
column) should be reported through CTEP-AERS only if the grade is above the grade 
provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in section 


50 
 
10.1.2. 
• Attribution of the AE: 
- 
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. 
7.4.2 Expedited Adverse Event Reporting to CTEP 
Expedited AE reporting for this study must use CTEP Adverse Event Reporting System (CTEP-
AERS), accessed Information regarding CTEP-AERS and instructions for training is available 
on 
the 
CTEP 
website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm.  The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  These requirements 
are briefly outlined in the tables below. 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
7.4.3 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
7.4.4 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 


51 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
(FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission  within the timeframes detailed in the table below. 
Hospitalization 
Grade 
1 
Timeframes 
Grade 
2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 
hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization ≥ 24 
hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via electronic submission within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
1. 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
• Expedited AE reporting timelines defined:  
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
within 24 hours of learning of the event followed by a complete CTEP-AERS report within 5 
calendar days of the initial 24-hour report. 


52 
 
➢ “10 calendar days” – A complete CTEP-AERS report on the AE must be submitted within 10 
calendar days of the investigator learning of the event. 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and designation 
as expected or unexpected with the exception of any events identified as protocol-specific expedited 
adverse event reporting exclusions.  
• Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with an 
agent under a CTEP IND. 
• Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration 
on all reports. 
Hospitalization for management of NF1 related complications unrelated to study drug will not require 
expedited reporting. 
7.4.5 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported through CTEP-
AERS must also be reported in routine study data submissions. 
7.4.6 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia (27))  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported 
via the routine reporting mechanisms outlined in each protocol.  
7.4.7 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy).  Second malignancies require ONLY routine reporting via CDUS unless 
otherwise specified.  
7.5 
DATA SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated on the 
trial to discuss each patient. The UAB and NCI study teams will have bi-weekly conference calls to 
discuss the study progress, adverse events, and any potential problems. 


53 
 
The OnCore trial management system electronically integrates patient demographics, study-specified 
visits, and procedures/activities. This data is easily accessible to study investigators by electronic case 
report forms. Severe adverse events and adverse events are also captured within the system. OnCore 
utilizes several reporting tools for the generation of numerous customized reports utilized by 
management and leadership staff.  The system and all clinical patient data is secure behind the UAB 
firewall and secure server with access only granted to staff with an approved ID and Password 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, new 
information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the IRB and to the Sponsor.  
The principal investigator will review adverse event and response data on each patient to ensure safety 
and data accuracy. The principal investigator will personally conduct or supervise the investigation and 
provide appropriate delegation of responsibilities to other members of the research staff.  
7.5.2 Sponsor Monitoring Plan 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly basis 
by FTP burst of data. Reports are due January 31, April 30, July 31, and October 31. Instructions for 
submitting 
data 
using 
the 
CDUS 
can 
be 
found 
on 
the 
CTEP 
Web 
site 
(http://ctep.cancer.gov/reporting/cdus.html).  
8 
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION   
8.1 
 SELUMETINIB  
Chemical 
name 
(IUPAC): 
 
5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-[(2-
hydroxyethoxy)carbamoyl]-1-methyl-1H-benzimidazol-3-ium hydrogen sulfate 
Other Names: KOSELUGO, Selumetinib Hydr-sulfate; selumetinib sulfate; ARRY-142886   
Chemical Structure:  
 
 
Classification:  Mitogen-activated protein kinase (MEK) inhibitor 
CAS Registry Number:  606143-52-6 
Molecular Formula:  C17H15BrClFN4O3.H2SO4  
 
 
 
M.W.:  555.76 


54 
 
Solubility:   Very low aqueous solubility (2.4 mcg/mL at pH 7.4).  
8.1.1 Mode of Action:   
Selumetinib (AZD6244 hydrogen sulfate) is a selective mitogen-activated protein kinase (MEK) 
inhibitor.  By inhibiting MEK, selumetinib (AZD6244 hydrogen sulfate) inhibits ERK phosphorylation, 
which may inhibit oncogenic growth signaling in tumor cells by targeting the RAS/RAF/MEK/ERK 
pathway. The RAS/RAF/MEK/ERK pathway is an important mediator of many cellular processes 
including proliferation, survival, differentiation, apoptosis, motility, and metabolism.   
8.1.2 How Supplied:   
AstraZeneca supplies and PMB, CTEP, DCTD distributes selumetinib (AZD6244 hydrogen sulfate).  The 
agent is supplied as hydroxypropylmethylcellulose (HPMC) capsules available in 10 mg and 25 mg 
strengths, expressed as free base. Capsules are packaged in high density polyethylene (HDPE) containers 
with induction-seals and child-resistant closures.  Each bottle contains 60 capsules with desiccant. 
• 10 mg: white, opaque, size 4 hard capsule, banded and marked with "SEL 10" in black ink.  
The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, 
carnauba wax, and purified water.  The capsule is imprinted with black ink that contains 
shellac, iron oxide black, propylene glycol and ammonium hydroxide. 
• 25 mg: blue, opaque, size 4 hard capsule, banded and marked with "SEL 25" in black ink. 
The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, 
FD&C blue 2, ferric oxide yellow, purified water, carnauba wax, and/or corn starch.  The 
capsule is imprinted with black ink that contains ferric oxide red, ferric oxide yellow, FD&C 
Blue 2 aluminum lake, carnauba wax, shellac, and glyceryl monooleate. 
Selumetinib (AZD6244 hydrogen sulfate) capsules contain vitamin E as the excipient D-alpha-tocopheryl 
polyethylene glycol 1000 succinate (TPGS). Each 10 mg capsule contains 32 mg vitamin E as TPGS and 
each 25 mg capsule contains 36 mg vitamin E as TPGS.  
8.1.3 Storage:   
Store the selumetinib (AZD6244 hydrogen sulfate) capsules at controlled room temperature (20°C-25°C). 
Brief excursions are permitted between 15°C and 30°C. 
If a storage temperature excursion is identified, promptly return selumetinib (AZD6244 
hydrogen sulfate) to controlled room temperature and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.    
8.1.4 Stability:   
Shelf-life stability studies are ongoing. Dispense selumetinib (AZD6244 hydrogen sulfate) capsules in the 
manufacturer’s HDPE container.  Do not remove desiccant.  Protect from moisture.  Once the container 
induction seal is broken the water vapor transmission rate is higher than the intact induction sealed bottle. 
Significant increase in the moisture content can affect the drug product. The current stability data for 
selumetinib (AZD6244 hydrogen sulfate) capsules supports an in-use period of up to 60 days. 
If repackaging into a pharmacy-supplied HDPE bottle is necessary for patient dispensing, provide 
a detailed description of the bottle to PMBAfterHours@mail.nih.gov for determination of 


55 
 
suitability.  The container must be repackaged with desiccant.  A 60 day in-use period from the 
point at which the patient reopens the bottle is permitted. 
8.1.5 Route of Administration:  
Oral. Do not eat or drink (except water only) for 2 hours prior to dosing and 1 hour after dosing selumetinib 
(AZD6244 hydrogen sulfate) capsules.   
8.1.6 Potential Drug Interactions:   
Avoid concomitant intake of supplemental vitamin E. High vitamin E doses may potentiate warfarin’s 
anticoagulant activity. Monitor PT/INR more frequently in patients receiving both warfarin and 
selumetinib (AZD6244 hydrogen sulfate) capsules.   
Selumetinib (AZD6244 hydrogen sulfate) is primarily metabolized by CYP3A4 and to a lesser extent 
by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib (AZD6244 hydrogen sulfate) 
also undergoes glucuronidation by UGT1A1 and UGT1A3.  The active human Phase I metabolite, N-
desmethyl selumetinib, is approximately 3- to 5-times more potent than selumetinib (AZD6244 
hydrogen sulfate) and metabolized through the same routes as selumetinib (AZD6244 hydrogen sulfate).  
Co-administration of selumetinib (AZD6244 hydrogen sulfate) with the potent CYP3A4 inducer 
rifampicin decreased selumetinib (AZD6244 hydrogen sulfate) AUC by ~50%.  The potent CYP3A4 
and 2C19 inhibitors, itraconazole and fluconazole, increased the AUC of selumetinib (AZD6244 
hydrogen sulfate) by ~49% and 53%, respectively. It is therefore recommended that patients should 
avoid taking strong CYP3A4 inhibitors/inducers or fluconazole (strong CYP2C19 inhibitor and 
moderate CYP3A4 inhibitor). Moderate inducers and inhibitors of CYP3A4 should be avoided as well, 
unless considered clinically indicated.  
Selumetinib (AZD6244 hydrogen sulfate) is a substrate of BCRP (breast cancer resistance protein) and 
is a low affinity substrate for P-gp transporters. Selumetinib (AZD6244 hydrogen sulfate) does not 
inhibit BCRP, P-gp, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters. 
Patient Care Implications: Study participants should be counseled to avoid excessive sun exposure and 
use adequate sun protection measures if sun exposure is anticipated during the study. 
8.1.7 Agent Ordering and Agent Accountability:   
NCI-supplied agents may be requested by the Principal Investigator (or their authorized designee) at 
each participating institution.  Pharmaceutical Management Branch (PMB) policy requires that agent be 
shipped directly to the institution where the patient is to be treated.  PMB does not permit the transfer 
of agents between institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
In general, sites may order initial agent supplies when a subject is being screened for enrollment onto 
the study. 


56 
 
Active CTEP-registered investigators and investigator-designated shipping designees and ordering 
designees can submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status and a “current” password.  For 
questions about drug orders, transfers, returns, or accountability, call or email anytime. 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all agents received from the 
PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record Form (DARF) 
available on the CTEP forms page.  Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.  
8.1.8 Useful links and Contacts 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm  
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application: 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/index.jsp 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov  
PMB IB Coordinator: IBcoordinator@mail.nih.gov 
PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) 
Investigator Brochure Availability: 
The current version of the IB for this agent will be accessible to site investigators and research staff 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an 
“active” account status and a “current” password. Questions about IB access may be directed to the 
PMB IB coordinator via email. 
8.1.9 Selumetinib Administration 
 
Patient Precautions: 
• Patients should avoid donating blood whilst participating in studies of selumetinib and for at 
least 1 weeks after receiving the last dose of the study medications or for longer if required in 
accordance with the prescribing information for the comparator / concomitant / compulsory 
administered medications.   
• Reproductive toxicology data indicate that selumetinib has the potential for adverse effects on 
embryofoetal development and survival.  Therefore:   


57 
 
o Females of child-bearing potential must use acceptable, effective and reliable methods 
of contraception from the time of screening until at least 4 weeks after discontinuing 
study treatment or longer if required, depending on the prescribing information of the 
combination or concomitantly administered medications. Selumetinib must not be 
administered to pregnant or breast-feeding women.  Conception while on treatment 
must be avoided.       
o Male patients with sexual partners who are pregnant or who could become pregnant 
(i.e. women of child-bearing potential) must use acceptable, effective and reliable 
methods of contraception during the study and for at least 12 weeks after the last dose 
of selumetinib or for longer if required, depending on the prescribing information of the 
combination or concomitantly administered medications. 
o Male and females of childbearing potential: reliable methods of contraception should 
be used consistently and correctly. 
− Acceptable effective methods of contraception for women include implants, 
injectables, combined oral contraceptives, some intrauterine devices/systems 
and sterilization including vasectomy of the partner, all being used in 
combination with barrier methods of contraception (e.g. condoms).   
− Acceptable methods of contraception for men include the use of condoms 
with spermicidal foams/gels or prior vasectomy. 
− True sexual abstinence is also an acceptable method of contraception (for both 
men and women). 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
9.1 
CORRELATIVE STUDIES FOR RESEARCH  
 
Biomarker name (Lead PI 
and Site) 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
pERK and pAKT, total ERK 
and AKT: Robert Kinders, 
NCI Frederick 
Quantitative ELISA 
Cutaneous neurofibroma biopsy:  
• baseline, and as in Appendix III and 
Appendix VI  
Kinome analysis: 
Gary Johnson, University of 
North Carolina 
Multiplexed 
kinase 
inhibitor beads and 
mass 
spectrometry 
(MIB/MS) 
 
Cutaneous neurofibroma biopsy:  
• baseline, and as in Appendix III and 
VI 
Whole genome analysis: 
Ashley 
Cannon, 
UAB/HudsonAlpha 
Whole 
genome 
sequencing 
Cutaneous neurofibroma biopsy:  
Baseline and 12 months on treatment 
Transcriptome analysis: 
Ashley 
Cannon, 
UAB/HudsonAlpha 
RNA sequencing 
Cutaneous neurofibroma biopsy:  
Baseline and 12 months on treatment 


58 
 
DNA methylation studies: 
Ashley 
Cannon, 
UAB/HudsonAlpha 
Genome-wide 
methylation testing 
Cutaneous neurofibroma biopsy:  
Baseline and 12 months on treatment 
9.1.1 Biopsies (See Appendix VI) 
The primary analyses for target inhibition to be performed in cutaneous neurofibroma excisional 
biopsies will be surgical pathology and quantitative analysis of pERK and pAKT. If feasible, the tumor 
kinome will be analyzed in collaboration with Gary Johnson and Wade Clapp(72).  
Biopsies obtained will be processed and analyzed following the priorities outlined below: 
1) Flash frozen for pERK and pAKT determination (to be analyzed by Bob Kinders from ½ core) 
2) Surgical pathology formalin fixed and paraffin embedding 
3) Flash frozen for tumor kinome 
Optional biopsies obtained for whole genome sequencing, transcriptome analysis, and DNA methylation 
studies will be performed by Ashley Cannon at UAB and HudsonAlpha.  
9.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Tissue collected during the course of this study will follow NIH guidelines for the research use of human 
samples and OHRP Issues to Consider in the Research Use of Stored Data or Tissues. Samples will be 
ordered and tracked through the Institution’s ordering system.   
9.2.1 Tumor Collection 
Tumor samples for PD studies will be collected as outlined in Appendix VI. Tumor samples for optional 
genomic studies will be collected as outlined in Appendix VI. Samples will be labeled with the study Id 
number, but no information that could identify the patient.  
9.2.2 Sample Storage and Destruction 
Samples will be stored until shipment. It is the responsibility of the institutional Principal Investigator 
to ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to these 
samples will only be granted following IRB approval of an additional protocol, granting the rights to 
use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to be 
utilized, the individual must provide a written request. Following receipt of this request, the samples 
will be destroyed (or returned to the patient, if so requested), and reported as such to the IRB. Any 
samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity (i.e. broken 
freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB. 
Sample with patient ID are linked to patient demographics and clinical information. This information 
will only be provided to investigators listed on this protocol. It is critical that the sample remains linked 
to patient information such as race, age, dates of diagnosis and death, and histological information about 
the tumor, in order to correlate genotype with these variables. 


59 
 
The study will remain open and status reported to the IRB until all samples have been analyzed, reported 
or destroyed.  Any use of these samples for purposes not described in this protocol will require 
prospective IRB review and approval.   
The amount of blood drawn from adults (those 18 years of age) for research purposes shall not exceed 
10.5 mL/kg or 550 mL, whichever is smaller, in an 8 week period.   
Samples distributed to the testing site at Indiana University for bone marrow progenitor cells and 
cytokine analysis (Dr. W. Clapp’s Laboratory), and for kinome analysis (Dr. Johnson’s laboratory) will 
be sent with only sample identifiers.  No personal information will be linked to patient samples.  The 
record of personal information and sample identifiers will be stored in a secure computer 
database/locked PI or AI file.  Samples will not be sent outside NIH or UAB to non-AI investigators 
without IRB notification and an executed MTA.  
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below. The study 
will remain open so long as sample or data analysis continues.  Samples from consenting subjects will 
be stored until they are no longer of scientific value or if a subject withdraws consent for their continued 
use, at which time they will be destroyed. The PI will report any loss or destruction of samples to the 
NCI or UAB IRB as soon as he is made aware of such loss. 
If the patient withdraws consent, the participant’s data will be excluded from future distributions, but 
data that have already been distributed for approved research use will not be able to be retrieved. 
The PI will report destroyed samples to the local IRB if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities or 
misplaced by a researcher.  Freezer problems, lost samples or other problems associated with samples 
will also be reported to the institutional IRB.  
10 STUDY CALENDAR 
10.1 ON-STUDY EVALUATIONS (SEE APPENDIX III) 
Evaluations performed during screening may also be used as baseline assessment where applicable.  
1. History and Physical Examination: History and physical examination with vital signs, will be 
performed every other week during cycle 1, and then according to the schedule in Appendix III 
and when the patient comes off treatment regardless of the reason. Weight will be recorded at 
the time of response evaluations.    
2. Performance status:  ECOG Performance status will be recorded as described in Appendix III.  
3. Hematology:  Complete blood count, differential and platelets will be performed as described in 
Appendix III and when the patient comes off treatment regardless of the reason. 
4. Chemistries: Electrolytes (including sodium, potassium, chloride, CO2), calcium, phosphorus, 
magnesium, creatinine, BUN, glucose, ALT, bilirubin, total protein and albumin, and CPK will 
be performed as indicated in Appendix III, and when the patient comes off treatment regardless 
of the reason.  Urinalysis will be performed at the time of response evaluations (cutaneous 
neurofibroma measurements) 


60 
 
5. Urine or serum pregnancy test to female subjects of childbearing potential at the time of 
response evaluations (cutaneous neurofibroma measurements). 
6. Ophthalmology evaluation for corneal and lens opacifications and retinal changes prior to 
starting treatment with selumetinib and according to Appendix III. 
7. EKG will be performed at baseline and if clinically indicated. An ECHO will be performed at 
baseline and according to Appendix III. Upon recovery from toxicity (to a LVEF of ≥ 53%), 
patients should be monitored with an ECHO every 2 – 3 cycles or as directed by the 
cardiologist (see algorithm in Section 6.3.) 
8. Response evaluation:  Target cutaneous neurofibromas will be measured as described in 
Section 17.9, Appendix VIII according to the schedule in Appendix III. 
9. Patient reported outcomes: This study will assess changes in skin related morbidity and pain 
using both the Skindex and the Global Impression of Change Scale along with the Numeric 
Rating Scale. Patients will complete the Skindex as described in Appendix IV, the Global 
Impression of Change Scale as described in Appendix X and the Numeric Rating Scale as 
described in Appendix XI. 
10. Patient diary (Section 17.7, Appendix VII) will be completed by all patients daily to monitor 
drug intake and adverse events; medication adherence should be reviewed per Section 17.8, 
Appendix VIIA. If diary review OR capsule count indicates that the administered dose deviates 
by ≥ 20 % from the prescribed dose, the study staff will review adherence with the patient and 
initiate interventions to improve adherence. The adherence intervention session will try to 
identify any barriers to medication adherence and engage the patient in collaborative problem-
solving to minimize problems with taking the study medication.   
11. Excisional biopsy of cutaneous neurofibromas:  Patients who have cutaneous neurofibromas that 
can be excised with minimal morbidity will have mandatory biopsies of ≥ 1 cutaneous 
neurofibroma at baseline, prior to staring treatment with selumetinib, prior to cycles 2 or 5 and 
if progression or dose reduction. A voluntary biopsy will be obtained by cycle 12 if a decrease 
in the cutaneous neurofibroma is observed.  
1) In order to correlate the measured response of cutaneous neurofibromas with target 
inhibition in cutaneous neurofibromas, the percent change in pERK and pAKT will be 
evaluated comparing pretreatment and on treatment levels. The timing of the on-
treatment biopsy will be approximately 4-6 hours after administration of the preceding 
selumetinib dose, which correlates with the expected peak selumetinib concentrations. 
Only percutaneous biopsies will be performed.   
2) At time of Progression: In addition, a voluntary biopsy will be obtained at the time of 
progression (Cutaneous neurofibroma volume increase ≥20%).   
3) After dose reduction: In addition, a voluntary biopsy will be obtained following dose 
reduction and will be performed after 1-2 cycles at the lower dose. 
12. Excisional biopsy of cutaneous neurofibromas (OPTIONAL): Patients who have cutaneous 
neurofibromas that can be excised with minimal morbidity will be asked to allow a biopsy of a 
cutaneous neurofibroma at baseline, prior to staring treatment with selumetinib according to 
Section 9.1.1. 


61 
 
1) If a decrease in cNF size is observed by cycle 12 of selumetinib treatment, two types of 
tissue will be collected from patients: at least 1 cNF with no change in size and at least 1 
cNF with a substantial size decrease. 
10.2 OFF THERAPY EVALUATIONS 
The following tests and procedures should be performed, if possible, at the time a patient comes off 
treatment regardless of the reason for coming off treatment, unless the test or procedure has been 
performed in the past 2 weeks or within a time period described below. 
1. History and physical examination, vital sign including blood pressure, and performance status. 
2. Laboratory:  Complete blood count, differential, and platelet count, electrolytes (including 
sodium, potassium, chloride, CO2), calcium, phosphorus, magnesium, creatinine, BUN, glucose, 
ALT, bilirubin, urinalysis, total protein, and albumin. 
3. Measurement of cutaneous neurofibromas unless performed within the last 4 weeks within the 
past 4 weeks. 
4. Skindex should be done.  
5. Global Impression of Change should be done. 
6. Numeric Rating Scale should be done. 
10.3 STUDY CALENDAR 
See Appendix III 
11 MEASUREMENT OF EFFECT 
There are no validated response criteria for cutaneous neurofibroma, and the primary goal of this study 
will be to determine if selumetinib is able to result in a measurable degree of tumor shrinkage of NF1 
cutaneous neurofibromas. 
Cutaneous neurofibromas will be measured as described in Section 17.9, VIII.  
For the purpose of determining the duration of treatment with selumetinib, responsive disease will be 
defined as a ≥20% decrease in the average volume of the smaller or larger cutaneous neurofibromas 
compared to the baseline volume. Progressive disease will be defined as a ≥ 20% increase in the average 
volume of smaller or larger cutaneous neurofibromas compared to the baseline volume. Stable disease 
will be defined as measurements not meeting criteria for responsive or progressive disease. 
As a secondary endpoint this study aims to evaluate changes in PRO and outcomes (Skindex, Global 
Impression of Change Scale and Numeric Rating Scale) during treatment with selumetinib. Changes 
will be recorded and documented, but as there are, at present, no validated response criteria for the 
evaluations to be performed, no response criteria have been defined a priori and the analysis will be 
descriptive (see statistical section).     


62 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS  
12.1 DATA COLLECTION 
All data will be kept secure. The PI will be responsible for overseeing entry of data into an in-house 
password protected electronic system and ensuring data accuracy, consistency and timeliness. The 
principal investigator, associate investigators/research nurses and/or a contracted data manager will 
assist with the data management efforts. All human subjects personally identifiable information (PII) as 
defined in accordance to the Health Insurance Portability and Accountability Act, eligibility and consent 
verification will be recorded. Primary data obtained during the conduct of the protocol will be kept in 
secure network drives or in approved alternative sites that comply with NIH security standards. Primary 
and final analyzed data will have identifiers so that research data can be attributed to an individual 
human subject participant. Clinical and toxicity data will be entered into the electronic OnCore Trial 
Management System. 
End of study procedures: Data will be stored according to HHS and FDA regulations as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect subject 
confidentiality and trial data has occurred, the IRB will be notified.  
12.2 DATA SHARING PLANS 
12.2.1 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance 
with the NIH Genomic Data Sharing Policy. 
12.3 
CTEP MULTICENTER GUIDELINES 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  The 
specific responsibilities of the Principal Investigator and the Coordinating Center (Study Coordinator) 
and the procedures for auditing are presented in Section 17.10, Appendix IX. 
The Principal Investigator/Coordinating Center is responsible for distributing all IND Action Letters or 
Safety Reports received from CTEP to all participating institutions for submission to their individual 
IRBs for action as required. 
Except in very unusual circumstances, each participating institution will order DCTD-supplied agents 
directly from CTEP.  Agents may be ordered by a participating site only after the initial IRB approval 
for the site has been forwarded by the Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov) 
except for Group studies. 
12.4 
COLLABORATIVE AGREEMENTS LANGUAGE 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis.  
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms 
of award, apply to the use of the Agent(s) in this study: 


63 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators.  The protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a copy of this protocol 
is requested by a patient or patient’s family member participating on the study, the individual should 
sign a confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by 
each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NCI, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, 
obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, 
all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all 
applicable federal statutes and regulations for the protection of human subjects, including, if 
applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 
C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines 
and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this 
clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an additional 30 
days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be provided to 


64 
 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at 
least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also be forwarded 
to CTEP prior to release.  Copies of any manuscript, abstract and/or press release/ media presentation 
should be sent to: 
Email:  ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, manuscript 
or other form of public disclosure shall contain any of Collaborator’s confidential/ proprietary 
information. 
 
13 STATISTICAL CONSIDERATIONS   
This limited site, open label pilot study will be conducted at the University of Alabama and the NCI as 
a collaboration between Bruce Korf (UAB) and Brigitte Widemann (NCI).   
The primary objective of this pilot study is to determine if selumetinib is able to result in a measurable 
degree of tumor shrinkage of NF1 cutaneous neurofibromas.  
Patients with NF1 and measurable cutaneous neurofibromas as defined in Section 3.1 will be eligible to 
enroll.  
Patients will undergo standardized documentation and counting of cutaneous neurofibromas. In brief: 
Patients with NF1 and measurable cutaneous neurofibromas will undergo standardized documentation 
and counting of cutaneous neurofibromas (Section 17.9, Appendix VIII). In brief: Digital photography 
will be performed in all patients prior to treatment with selumetinib, and after every 4 cycles. A 10 x 10 
cm picture frame is placed on predefined areas, which will be chosen for each patient to represent areas 
of cutaneous neurofibroma burden. In all patients, when possible ≥3 areas will be chosen, but only one 
area for a patient is required minimally because of the difficulty in obtaining patients with multiple 
areas. A fourth area may be used to monitor cNFs that will be biopsied so not to disrupt the areas being 
used for cNF size and number response outcomes. Digital photographs will be transferred to a computer, 
and all cutaneous neurofibromas in the frame ≥4 mm in diameter will be marked and counted as 
described by Cunha et al (31).  Within each picture frame target cutaneous neurofibromas will be 
measured with calipers as previously described by Korf et al (unpublished data). The width, length, and 
height will be measured, and the volume of each of the neurofibromas measured will be calculated. The 
effect of selumetinib will be separately evaluated in up to 3-5 smaller (longest neurofibroma diameter 
4-7 mm) and 3-5 larger (longest neurofibroma diameter ≥8 mm) neurofibromas in each of the 3 regions. 
Any patient with at least two lesions classified as smaller and/or 2 classified as larger in a single area 
will be considered evaluable and included in the appropriate analyses. The analyses will be 
supplemented by a description of the numbers of tumors of each type and number of areas evaluated per 
patient, which will be used to further interpret the findings. Sub-analyses, which may largely be 
descriptive, and based on the numbers of areas included may also be done to further interpret the results. 
 
At the time of each response evaluation the number of neurofibromas will be counted in the picture 
frames, and the volume of the target neurofibromas will be measured. The sum of the on-treatment 
volumes for the smaller tumors will be subtracted from the pre-treatment volumes of the same tumors 


65 
 
to arrive at an overall percentage change in tumor size for each patient. This will be repeated for the 
larger tumors. Then, the average percentage change for each size category will be reported along with 
its 95% confidence interval, and other associated statistics.  
With 16  evaluable patients with measurements available at  per cycle 13 who have continued to receive 
selumetinib for the same duration, this would provide 90% power to detect a 1.0 effect size (1 SD of the 
difference in volume from pre to post treatment), using a 0.025 two-sided paired t-test in order to allow 
for a Bonferroni adjustment for two tests to hold the overall significance level to 0.05.  In practice, the 
two comparisons(one for smaller and one for larger tumors) may be reported using a less overly 
conservative Hochberg adjustment. As well, if the paired differences are not normally distributed 
(p<0.05 by a Shapiro-Wilks test), then a Wilcoxon signed rank test may be used instead of a paired t-
test. In order to allow for some patients who may not complete all evaluations, an additional 8 patients 
may be enrolled to ensure there will be 16 fully evaluable patients. Plans are to enroll adults of different 
ages so that changes in neurofibroma size can be evaluated in different age groups.  
Exploratory analyses may also be performed restricted to just the patients who have both small and large 
tumors measured, if appropriate. In addition, the resulting changes in average volume for tumors of a 
given size per patient may be compared against other measures related to qualitative assessment such as 
changes in the Skindex to determine if a potentially valid level of response/non-response can be 
developed in at least a preliminary fashion on the basis of the interpretation of the qualitative 
consequences of a volume decline of an observed magnitude. 
Toxicities will be summarized descriptively and tabulations on the type, severity, and relationship to 
study treatment will be performed. Changes in both the Skindex and Global Impression of Change Scale 
along with the Numeric Rating Scale evaluations, will be exploratory and summarized using descriptive 
statistics and when feasible compared using Wilcoxon rank test or pairwise t-test.  
Tumor biopsies: In all patients for whom paired cutaneous neurofibroma biopsies can be obtained 
mechanisms of response and resistance will be assessed by analyzing pathways in addition to pERK: 
pAKT, and kinome analysis will be performed.  
The changes from baseline for both tumor volume and pathway biomarkers will be determined and 
tested for statistical significance using a Wilcoxon signed rank test. The correlation of tumor volume 
changes and levels and changes of levels of pERK in PNs will be determined using Spearman rank 
correlation. The inhibition of pERK and levels of pAKT will be compared between patients with a tumor 
response and those without a response using a Wilcoxon rank sum test, although it is understood that 
such a comparison is exploratory and does not establish causality. 
13.1 SAMPLE SIZE ACCRUAL 
A maximum of 24 patients will be enrolled, and 16 evaluable patients will be required to have 90% 
power to detect a 1.0 effect size. Approximately 2 patients will be enrolled per month. Thus enrollment 
should be complete within 1 year. 
 
PLANNED ENROLLMENT REPORT 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 


66 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
American 
Indian/ 
Alaska Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Native Hawaiian or 
Other 
Pacific 
Islander 
 
 
 
 
 
Black 
or 
African 
American 
3 
2 
 
 
5 
White 
10 
9 
 
 
19 
More 
Than 
One 
Race 
 
 
 
 
 
Total 
13 
11 
 
 
24 
 
14 HUMAN SUBJECTS PROTECTIONS  
14.1 RATIONALE FOR SUBJECT SELECTION 
Neurofibromatosis type 1 is a genetic disorder with a worldwide incidence of 1:3500 individuals. No 
groups, in regards to gender, and racial and ethnic groups, are being excluded from participation in the 
trial.  Females who are pregnant or breastfeeding will not be eligible for the trial due to risks of fetal and 
teratogenic adverse events as seen animal studies.   
14.2 PARTICIPATION OF CHILDREN 
This trial is designed to if selumetinib is able to result in a measurable degree of tumor shrinkage of NF1 
cutaneous neurofibromas in adults. As cutaneous neurofibromas are predominantly a clinically problem 
in adults, this trial will not enroll children. However, a separate trial with selumetinib for children with 
plexiform neurofibromas will be ongoing and provide a mechanism for children to receive treatment.  
14.3 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
14.3.1 Risks of Selumetinib 
The primary risk to patients participating in this research study is from toxicity of selumetinib, an 
investigational agent, and from the uncommon risks of tumor biopsies.  The protocol provides for 
detailed and careful monitoring of all patients to assess for toxicity.  Selumetinib will be administered 
at the recommended phase II dose and therefore toxicity data from this dose level has been established 
without severe (dose-limiting) toxicities.  Also, in order to minimize potential risk due to long-term and 
cumulative toxicity, treatment will be limited according to Section 6.  All patients entered on the trial 
will have NF1 and substantial cutaneous neurofibroma burden causing distress to the patient, which is 
a manifestation that this agent is hypothesized to benefit.  Selumetinib offers a potential for direct benefit 
although the likelihood of this may be small.  The potential benefits from this therapy are disease 
stabilization or shrinkage of cutaneous neurofibromas, prevention of development of new 
neurofibromas, and a reduction in symptoms caused by the cutaneous neurofibromas.  Furthermore, by 
just entering the study, patients will be followed very carefully, in an organized coherent manner, which 
may also benefit their overall healthcare.   
Patients of Asian descent may experience a higher exposure of selumetinib than the majority of subjects 
of non-Asian descent receiving an equivalent dose of selumetinib. These patients will receive standard 
dosing but will be counselled regarding this higher drug exposure and urged to contact investigators if 


67 
 
they are experiencing any side effects. If, during the course of the selumetinib development program the 
dosing regimen being evaluated in this study is found not to be tolerated in a specific ethnic group, this 
ethnic group may later be excluded from this study. Investigators will be notified, and the protocol will 
be amended to reflect such findings. The data so far do not suggest a safety concern in any specific 
population. 
14.3.2 Risk of cutaneous neurofibroma biopsy 
The rare risks of the cutaneous neurofibroma biopsies include risk of pain, bleeding, bruising or 
infection.  Every effort will be made to ensure the patient’s comfort during biopsy, minimize risk of 
bleeding and infection.  Patients will be monitored after biopsy for the occurrence of any of these side 
effects, and clinically indicated interventions initiated as needed. 
Therefore, overall this study involves greater than minimal risk but presents the prospect of direct benefit 
to individual subjects. 
14.4 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The investigational nature and research objectives of this trial, the procedures and treatments involved 
and their attendant risks and discomforts and benefits, and potential alternative therapies will be 
carefully explained to the patient, and a signed informed consent document will be obtained prior to 
entry onto the study. The PI or an associate investigator of the trial will obtain consent.   
15 MULTI-INSTITUTIONAL GUIDELINES 
Please also refer to Section 17.10, Appendix IX.  The PI of the Coordinating Center for a trial is 
responsible to ascertain that no patients are entered on the trial at a participating institution without full 
IRB approval.   Thus, the UAB IRB must approve the addition of each participating institution to the 
protocol and will require a copy of the local IRB approval from each participating institution before 
UAB IRB approval will be granted. 
In addition, this protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  
15.1 IRB APPROVALS  
The PI will provide the UAB IRB a copy of the participating institution’s approved yearly continuing 
review.  Registration will be halted at any participating institution in which a current continuing approval 
is not on file at the UAB IRB. 
15.2 AMENDMENTS AND CONSENTS 
The PI will provide the UAB IRB with copies of all amendments, consents and local IRB approvals 
from each participating institution. 
15.3 IND ACTION LETTERS OR SAFETY REPORTS 
The PI is responsible for distributing all IND Action Letters or Safety Reports received from CTEP to 
all participating institutions for submission to their individual IRBs for action as required. 


68 
 
15.4 DRUG ORDERING 
Each participating institution will order DCTD-supplied agents directly from CTEP.  Agents may be 
ordered by a participating site only after the initial IRB approval for the site has been forwarded by the 
Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov). 
 


69 
 
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39. 
Jakacki R, Dombi E, Steinberg S, Goldman S, Kieran M, Ullrich N, et al. Preliminary results of 
a phase II trial of pegylated interferon-alfa-2B (PI) in pediatric patients with documented progression of 
neurofibromatosis type 1-related unresectable plexiform neurofibromas (PNF). Neuro-Oncology. 
2012;14. 
40. 
Jakacki RI, Dombi E, Potter DM, Goldman S, Allen JC, Pollack IF, et al. Phase I trial of 
pegylated interferon-alpha-2b in young patients with plexiform neurofibromas. Neurology. 
2011;76(3):265-72. 
41. 
Robertson KA, Nalepa G, Yang FC, Bowers DC, Ho CY, Hutchins GD, et al. Imatinib mesylate 
for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol. 
2012;13(12):1218-24. 
42. 
Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein 
kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008;14(2):342-6. 
43. 
O'Neill E, Kolch W. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br 
J Cancer. 2004;90(2):283-8. 
44. 
Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell 
Biol. 2004;5(11):875-85. 
45. 
Janssen EM, Droin NM, Lemmens EE, Pinkoski MJ, Bensinger SJ, Ehst BD, et al. CD4+ T-cell 
help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature. 
2005;434(7029):88-93. 
46. 
Ahn JH, Park SM, Cho HS, Lee MS, Yoon JB, Vilcek J, et al. Non-apoptotic signaling pathways 
activated by soluble Fas ligand in serum-starved human fibroblasts. Mitogen-activated protein kinases 
and NF-kappaB-dependent gene expression. J Biol Chem. 2001;276(50):47100-6. 


72 
 
47. 
Khokhlatchev AV, Canagarajah B, Wilsbacher J, Robinson M, Atkinson M, Goldsmith E, et al. 
Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. 
Cell. 1998;93(4):605-15. 
48. 
Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, et al. Constitutive activation of 
the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 
1999;18(3):813-22. 
49. 
Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Chauhan D, et al. Targeting MEK1/2 
blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma. Br J Haematol. 
2007;139(1):55-63. 
50. 
Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, et al. AZD6244 (ARRY-142886), 
a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 
kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential 
for combination in preclinical models. Mol Cancer Ther. 2007;6(8):2209-19. 
51. 
Huynh H, Chow PK, Soo KC. AZD6244 and doxorubicin induce growth suppression and 
apoptosis in mouse models of hepatocellular carcinoma. Mol Cancer Ther. 2007;6(9):2468-76. 
52. 
Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, et al. Targeting MEK induces 
myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood. 2007;110(5):1656-63. 
53. 
Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, et al. Selective growth inhibition 
in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. 
J Clin Endocrinol Metab. 2007;92(12):4712-8. 
54. 
Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus 
docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-
controlled, phase 2 study. Lancet Oncol. 2013;14(1):38-47. 
55. 
Robert C, Dummer R, Gutzmer R, Lorigan P, Kim KB, Nyakas M, et al. Selumetinib plus 
dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic 
melanoma: a phase 2 double-blind randomised study. Lancet Oncol. 2013;14(8):733-40. 
56. 
Carvajal RD, Sosman JA, Quevedo JF, Milhem MM, Joshua AM, Kudchadkar RR, et al. Effect 
of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical 
trial. JAMA. 2014;311(23):2397-405. 
57. 
Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-
enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368(7):623-32. 
58. 
Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, et al. Phase I 
pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein 
kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 
2008;26(13):2139-46. 
59. 
Banerjee A, Jakacki R, Onar-Thomas A, Wu S, Nicolaides T, Turner D, et al. A phase 1 study 
of AZD6244 in children with recurrent or refractory low-grade gliomas: A Pediatric Brain Tumor 
Consortium report. J Clin Oncol 32:5s (supp; abstr 10065. 2014. 
60. 
Jessen WJ, Miller SJ, Jousma E, Wu J, Rizvi TA, Brundage ME, et al. MEK inhibition exhibits 
efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013;123(1):340-7. 


73 
 
61. 
Widemann B, Marcus L, Fisher M, Weiss B, Kim A, Dombi E, et al. Phase I study of the MEK1/2 
inhibitor selumetinib (AZD6244) hydrogen sulfate in children and young adults with neurofibromatosis 
type 1 (NF1) and inoperable plexiform neurofibromas (PNs). J Clin Oncol 32:5s, 2014 (suppl; abstr 
10018). 2014. 
62. 
Chren MM, Lasek RJ, Quinn LM, Mostow EN, Zyzanski SJ. Skindex, a quality-of-life measure 
for patients with skin disease: reliability, validity, and responsiveness. J Invest Dermatol. 
1996;107(5):707-13. 
63. 
Chren MM. The Skindex instruments to measure the effects of skin disease on quality of life. 
Dermatol Clin. 2012;30(2):231-6, xiii. 
64. 
Page PZ, Page GP, Ecosse E, Korf BR, Leplege A, Wolkenstein P. Impact of neurofibromatosis 
1 on Quality of Life: a cross-sectional study of 176 American cases. Am J Med Genet A. 
2006;140(18):1893-8. 
65. 
National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. 
Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988;1(3):172-8. 
66. 
Balagula Y, Barth Huston K, Busam KJ, Lacouture ME, Chapman PB, Myskowski PL. 
Dermatologic side effects associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-
142886). Invest New Drugs. 2011;29(5):1114-21. 
67. 
This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the 
agent should be included in the e-mail. 
68. 
Febrile neutropenia/neutropenic infection has been observed primarily in trials combining 
AZD6244 (selumetinib) and docetaxel. 
69. 
SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools 
and/or diarrhea in rats and dogs; however, it is possible that some of these findings might be related to 
exacerbation of the vehicle effect by AZD6244 (selumetinib). 
70. 
Spurlock G, Knight SJ, Thomas N, Kiehl TR, Guha A, Upadhyaya M. Molecular evolution of a 
neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation 
between histopathological, clinical and molecular findings. J Cancer Res Clin Oncol. 
2010;136(12):1869-80. 
71. 
Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
72. 
Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, et al. Dynamic 
reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. 
Cell. 2012;149(2):307-21. 
 
 
 
 


74 
 
17 APPENDICES 
Appendix I: Medications to Avoid 
Patient Drug Information Handout and Wallet Card 
Appendix II: New York Heart Association Classifications 
Appendix III: Required Study Evaluations 
Appendix IV: Skindex 
Appendix V: Safety Management Algorithm for Dyspnea 
Appendix VI: Biopsy Collection and Transport for Analysis 
Appendix VII: Patient Daily Medication Diary for Selumetinib 
Appendix VIIA: Adherence 
Appendix VIII: Measurement and Counting of Cutaneous Neurofibromas 
Appendix IX: CTEP Multicenter Guidelines 
Appendix X: Global Impression of Change Scale 
Appendix XI: Numeric Rating Scale 
 
 
 


75 
 
17.1 APPENDIX I:  
MEDICATIONS TO AVOID 
 
17.1.1 PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD  
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug, selumetinib (AZD6244 hydrogen sulfate).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Selumetinib (AZD6244 hydrogen sulfate) interacts with certain specific enzymes in the liver and 
certain transport proteins that help move drugs in and out of cells. 
 
• The enzymes in question are CYP 1A2, 2C8, 2C9, 2C19, 3A4/5 and UGT 1A1 and 1A3. 
Selumetinib (AZD6244 hydrogen sulfate) is metabolized by these enzymes and may be 
affected by other drugs that inhibit or induce these enzymes.  
• The proteins in question are P-gp and BCRP. Selumetinib (AZD6244 hydrogen sulfate) is a 
substrate of BCRP and P-gp transporters and may be affected by other drugs that inhibit or 
induce these transporters.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
     March 2016 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Selumetinib (AZD6244 hydrogen sulfate) interacts with many drugs which can cause side effects. 
Because of this, it is very important to tell your study doctors about all of your medicines before you 
enroll on this clinical trial.  It is also very important to tell them if you stop taking any regular medicines, 
or if you start taking a new medicine while you take part in this study.  When you talk about your 
medications with your doctors, include medicine you buy without a prescription (over-the-counter 
remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles 
or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  


76 
 
 
These are the things that you and they need to know: 
 
Selumetinib (AZD6244 hydrogen sulfate) must be used very carefully with other medicines that need 
certain liver enzymes and transport proteins to be effective or to be cleared from your system.  Before 
you enroll onto the clinical trial, your study doctor will work with your regular health care providers to 
review any medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP 
1A2, 2C8, 2C9, 2C19, 3A/5, UGT 1A1 and 1A3, P-gp and BCRP.” 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctor or pharmacist to 
determine if there could be any side effects.  
• Avoid taking extra vitamin E found in vitamins or supplements.  
• Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine.  Your 
study doctor’s name is  
__________________________________________                and he or she can be contacted at  
 
_____________________________________. 
 
 
  
                   March 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
selumetinib (AZD6244 hydrogen sulfate).  This clinical trial is 
sponsored by the NCI.  AZD6244 hydrogen sulfate (selumetinib) 
interacts with drugs that are processed by your liver, or use certain 
transport proteins in your body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
 
➢ Selumetinib (AZD6244 hydrogen sulfate) interacts with CYP 1A2, 
2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp, and BCRP, and 
must be used very carefully with other medicines that interact with 
these enzymes and proteins.  
➢ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered “strong inducers/inhibitors of CYP 
1A2, 2C8, 2C9, 2C19, 3A4/5, UGT 1A1 and 1A3, P-gp and 
BCRP.” 
➢ You should avoid taking extra vitamin E found in vitamins or 
supplements. 
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


77 
 
17.2 APPENDIX II: NEW YORK HEART ASSOCIATION CLASSIFICATIONS  
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for Additional 
Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity increases 
discomfort 
Extreme 
Marked 
Unable to work 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
** 
At accustomed occupation or usual tasks. 
 
Reference: Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  (Modified from New York Heart Association, 
1953). 
 
 


78 
 
17.3 APPENDIX III: REQUIRED STUDY EVALUATIONS 
Studies to be obtained 
Pre study 
Prior to Subsequent Cycles3 
End of Therapy 
Evaluation 
History1 
X 
2, 5,9,13, etc 
X 
Physical Exam, vital signs2  
X 
2, 5,9,13, etc 
X 
Height, weight 
X 
2, 5,9,13, etc 
X 
Performance Status 
X 
2, 5,9,13, etc 
X 
EKG 
X 
As clinically indicated 
As clinically 
indicated 
Echocardiogram3 
X 
5, 9, then every 4 cycles 
As clinically 
indicated 
CBC, differential, platelets 
X5 
2, 5,9,13, etc 
X 
Urinalysis 
X 
5,9,13, etc 
X 
Electrolytes including Ca++, PO4, Mg++, 
BUN, creatinine, glucose, ALT, bilirubin, 
Total protein/albumin, amylase, lipase, 
CPK 
X5 
2, 5,9,13, etc 
X 
Ophthalmology toxicity evaluation 
X 
5, 13, then yearly 
As clinically 
indicated 
Pregnancy Test 
X 
5,9,13, etc 
X 
Patient diary and capsule count 
Appendix VIII 
 
2, 5,9,13, etc 
X 
Adherence Questionnaire 
Appendix VIIIA 
 
Only if pill count discrepancy 
>20% 
- 
Cutaneous 
neurofibroma 
disease 
evaluation 
with 
caliper 
and 
photography, Appendix VIII 
X 
5,9,13, etc 
X 
Skindex, 
Appendix IV 
X 
2, 5, 9, 13, etc 
X 
Global Impression of Change Scale, 
Appendix X 
 
2, 5, 9, 13, etc 
X 
Numeric Rating Scale, 
Appendix XI 
X 
2,5,9,13, etc 
X 
Cutaneous neurofibroma biopsy 
For kinome and pERK Appendix VI 
X 
2 or 5 and if progression or 
dose reduction 
- 
Cutaneous 
neurofibroma 
biopsy 
(OPTIONAL): For whole genome 
sequencing, transcriptome analysis, and 
DNA methylation 
X 
By cycle 126 
 


79 
 
1Baseline history includes prior treatment for PN with dates. Interval history includes events and changes since 
last visit, review of all medications and allergies 
2A complete standard physical examination will be performed at baseline, subsequent physical exams will be 
targeted based on signs and symptoms of presenting patient. Vital signs: Heart rate, temperature, blood pressure, 
respiratory rate, O2 saturation by pulse oximetry at baseline and then as indicated. 
3Patients who stop selumetinib for cardiac toxicity should be monitored by ECHO every 3 to 6 weeks.  Upon 
recovery from toxicity, patients should be monitored with an ECHO every 2-3 cycles as directed by the 
cardiologist 
4Study evaluation frequency with “etc.” denotes every subsequent 4 cycles 
5 If greater than 7 days elapses between eligibility blood tests and starting therapy, blood tests should be repeated.  
If test results are outside the window of eligibility, they must be corrected prior to started therapy. 
6 If a decrease in cNF size is observed by cycle 12 of selumetinib treatment, two types of tissue will be collected 
from patients: at least 1 cNF with no change in size and at least 1 cNF with a substantial size decrease. 


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81 
 
These questions concern your feelings over the past 4 weeks about the cutaneous 
neurofibromas that have bothered you the most. Check the answer that comes closest to the 
way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST FOUR WEEKS  
DO THESE STATEMENTS DESCRIBE YOU? 
___________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN          ALL THE   
 
TIME 
___________________________________________ 
 
  1. My cutaneous neurofibromas hurt    .    .    .   .    .    .   .    .    
.    
 
   1              2              3               4              5 
 
  2. My cutaneous neurofibromas affect how well I sleep    .    .    
.     
 
   1              2              3               4              5 
 
  3. I worry that my cutaneous neurofibromas may be serious    .   
 
   1              2              3               4              5 
 
  4. My cutaneous neurofibromas make it hard to work or do 
hobbies    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
  5. My cutaneous neurofibromas affect my social life   .    .    .    .  
 
   1              2              3               4              5 
 
  6. My cutaneous neurofibromas make me feel depressed    .    
.     
 
   1              2              3               4              5 
 
  7. My cutaneous neurofibromas burn or sting    .    .    .    .    .    
.     
 
   1              2              3               4              5 
 
  8. I tend to stay at home because of my cutaneous 
neurofibromas.    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
  9. I worry about getting scars from my cutaneous 
neurofibromas.     
 
   1              2              3               4              5 
 
10. My cutaneous neurofibromas itch    .    .    .    .    .    .    .    .    
.     
 
   1              2              3               4              5 
 
11. My cutaneous neurofibromas affect how close I can be with 
those I love .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
12. I am ashamed of my cutaneous neurofibromas.    .    .    .    .    
 
   1              2              3               4              5 
 
13. I worry that my cutaneous neurofibromas may get worse    .    
 
   1              2              3               4              5 
 
14. I tend to do things by myself because of my cutaneous 
neurofibromas.    .    .    .    .    .    .    .    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
15. I am angry about my cutaneous neurofibromas.    .    .    .    .    
 
   1              2              3               4              5 


82 
 
 
16. Water bothers my cutaneous neurofibromas (bathing, 
washing hands)    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    
.    .    .    
 
   1              2              3               4              5 
 
17. My cutaneous neurofibromas makes showing affection 
difficult     
 
   1              2              3               4              5 
 
 
 
Please turn to next page 
 
These questions concern your feelings over the past 4 week about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST 4 WEEK  
DO THESE STATEMENTS DESCRIBE YOU? 
_____________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN         ALL THE  
                                                                                             TIME 
_____________________________________________ 
 
 
18. I worry about side-effects from cutaneous neurofibromas 
medications / treatments  .    .    .    .    .    .    .    .    .    .    .    
.    .    
 
   1              2              3               4              5 
 
19. My cutaneous neurofibromas are irritated    .    .    .    .    .   
.     
 
   1              2              3               4              5 
 
20. My cutaneous neurofibromas affect my interactions with 
others     
 
   1              2              3               4              5 
 
23. I am frustrated by my cutaneous neurofibromas.    .    .    
.    .     
 
   1              2              3               4              5 
 
24. My cutaneous neurofibromas are sensitive    .    .    .    .    
.    .     
 
   1              2              3               4              5 
 
25. My cutaneous neurofibromas affect my desire to be with 
people    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .    .  
.     
 
   1              2              3               4              5 
 
26. I am humiliated by my cutaneous neurofibromas.    .    .    
.    .     
 
   1              2              3               4              5 
 
27. My cutaneous neurofibromas bleed    .    .    .    .    .    .    
.    .     
 
   1              2              3               4              5 
 
28. I am annoyed by my cutaneous neurofibromas.    .    .    .   
.     
 
   1              2              3               4              5 


83 
 
 
29. My cutaneous neurofibromas interfere with my sex life    
.    .     
 
   1              2              3               4              5 
 
30. My cutaneous neurofibromas make me tired    .    .    .    .   
.     
 
   1              2              3               4              5 
 


 
84
17.5 APPENDIX V: SAFETY MANAGEMENT ALGORITHM FOR DYSPNEA 
 
 
 
AstraZeneca Guidance for selumetinib studies (March 2015) 
 
 
 
 
New AE of  dyspnoea*  or  
worsening of pre - existing  
dyspnoea*  > 1 CTC Grade 
The following should be considered based on clinical  
examination: 
Chest X - ray, PA and lateral view. Consider Echo, ECG, BNP,  
Troponin, sputum, blood, urine culture (bacterial antigens and  
PCR), WBC,  Hb and urea 
If test results indicate diagnosis other  
than ILD/ pneumonitis treat according to  
local practices 
Consider  study drug
† dose interruption  
and/or discontinuation if AE considered  
related to  study drug
† by investigator  
Treatment ineffective 
No obvious underlying cause of  
dyspnoea or suspected ILD 
Perform HRCT scan 
Consider respiratory  
consultation 
HRCT  does not  show  
interstitial lung  
disease/ pneumonitis 
Dyspnoea AE  
resolved 
Continue  study drug
† 
Dyspnoea AE not  
resolved 
Seek cardiology and/or  
respiratory consult if not  
already performed.  
Consider  study drug
† dose  
interruption/reduction 
ILD/ pneumonitis 
diagnosed by HRCT 
Consider  study drug
† 
dose interruption and/or  
discontinuation if AE is 
considered as related to 
study drug  by 
investigator 
Treat according to local  
practices 
BNP: Brain Natriuretic 
P
tid
CTC: National Cancer Institute common toxicology 
it
i
Echo: Echocardiography 
Hb: Haemoglobin 
HRCT: High resolution computerised 
t
h
ILD: Interstitial Lung 
Di
PA: posteroanterior  
PCR: Polymerase chain 
ti
WBC: White blood cells 
Version: Final 3.0   23-Jul-2013 
Guidance for management 
of patients with  
dyspnoea*
† Includes selumetinib/placebo 
or combination treatment, 
as appropriate
* Not considered related to 
disease under study 


 
85
Participant’s ID:  
 
 
 
Date:   
 
 
 
17.6 APPENDIX VI:  BIOPSY COLLECTION AND TRANSPORT FOR ANALYSIS 
17.6.1 Biopsies for pAKT/pERK analysis, pathologic analysis, and kinome analysis. 
A. Samples will be obtained by excisional biopsy.  
B. Order of priority for biopsy specimens after removal of sample for pathology:  
1) pERK/pAKT (frozen)  
2) Pathology (formalin) 
3) Kinome analysis (frozen)   
Samples for pERK/pAKT (Priority #1) 
Description: 
The optimal level of inhibition of pERK/pAKT required for antitumor activity is not known.  In 
this study pERK, pAKT, total ERK and AKT by Quantitative ELISA will be assessed in Dr. Robert 
Kinders’ Laboratory (NCI Frederick) in cutaneous neurofibroma biopsies obtained prior to cycle 
2 compared to baseline, and percent inhibition will be correlated with response as evaluated by 
volumetric cutaneous neurofibroma measurement. Additional biopsies may be obtained at time of 
progression or after dose reduction. 
Handling: 
Part of a specimen (5 mg) will be snap frozen immediately (see below).   
Biopsies will be maintained frozen in designated monitored freezers (-70°C). Samples will be 
batched for analysis upon completion of sample collection.   
Labeling: 
Samples for pERK/pAKT will be labeled with CTEP protocol number, patient study number, 
sample ID, and collection point (pre-dose, etc).  Samples will be documented on a Chain of 
Custody Form for each patient.   
Shipment of Batched Samples: 
Contact Dr. Kinders lab and arrange for shipment.  Samples will be transported on dry ice. 
Samples must be accompanied with this appendix and full Standard Operating Procedure 
guidelines, which provides more details regarding the samples. 
 
Contact information for Dr. Robert Kinders (pERK/pAKT analysis)  
Dr. Bob Kinders (PADIS/LHTP/FNLCR) 
Bldg. 431, Rm. 129  
Frederick, MD 21702-1201  
Phone: 301-846-6410  
kindersr@mail.nih.gov 


 
86
Pathology, Formalin Fixed Specimens (Priority #2) 
 
Specimen Collection Guidelines: Recommendations for processing of formalin fixed specimens:  
1) Place the specimens into the cell safe biopsy capsule and immerse immediately into 10% 
neutral buffered formalin pot for fixation. 
2)  Leave sample(s) for exactly 24 hours in formalin at room temperature, to allow for 
adequate fixation of the samples. 
 Remove the cell safe biopsy capsule (containing the biopsy) from the formalin. 
3) Place the fixed biopsy sample/s inside the block cassette and immediately process to 
paraffin using the preferred Routine Biopsy Paraffin Processing Schedule identified in 
Table 1: (NOTE, if multiple core biopsies are collected then they should be placed into the 
same cassette block and processed together). 
4) Pathology: Samples for pathology will be placed in formalin and delivered to pathology as 
per standard clinical procedure.  
 
Kinome Analyses (Priority #3) 
Samples for Kinome Analysis (Wade Clapp, Indiana University) 
Description: 
Cutaneous neurofibroma kinome analysis will be performed using multiplexed kinase inhibitor 
beads and mass spectrometry (MIB/MS) at baseline, prior to cycle 2, and if available, at time of 
progression or dose reduction 
Handling: 
From a biopsy specimen, sample will be snap frozen immediately.   
Biopsies will be maintained frozen in designated monitored freezers (-70°C). Samples will be 
batched for analysis upon completion of sample collection. 
Labeling: 
Samples will be labeled with CTEP protocol number, patient study number, sample ID, and 
collection point (pre-dose, etc).  Samples will be documented on a Chain of Custody Form for each 
patient.   
Transport of samples to Indiana University 
Contact Dr. Clapp’s lab and arrange for shipment.  Samples will be transported on dry ice. 
 
 


 
87
17.6.2 Optional biopsies for whole genome sequencing, transcriptome analysis, and DNA 
methylation studies (To be performed by Ashley Cannon at UAB and HudsonAlpha). 
A. Samples will be obtained by excisional biopsy.  
B. These biopsies will be optional. 
 
Samples for genomic analyses of cNFs 
For this exploratory objective, genomic analyses of cNFs will be performed under the direction of 
Dr. Ashley Cannon to identify somatic mutations that are driving tumorigenesis as well as 
mutations that may be influencing tumor response to selumetinib. These are pilot genomic studies 
that may not have sufficient statistical power and will likely warrant more comprehensive analyses 
and larger sample sizes in future studies.  
1. Collection time points and procedures: 
a. Prior to selumetinib treatment, ≥1 cNF will be biopsied from each patient.  
b. If a decrease in cNF size is observed by cycle 12 of selumetinib treatment, two types 
of tissue will be collected from consenting patients: at least 1 cNF with no change in 
size and at least 1 cNF with a substantial size decrease. 
2. Procedures: 
At the time of tissue collection, samples will be divided in half, with one half being placed in 
media and the other half will be flash frozen.  
The media samples will be sent to the UAB Molecular Genetics Laboratory (MGL) for Schwann 
cell culture and detection of the somatic NF1 mutation. Schwann cell cultures from each biopsied 
cNF will reduce variability due to cellular heterogeneity.  
All frozen samples as well as a portion of the cultured Schwann cells will be sent to the 
HudsonAlpha Genomic Services Lab for DNA extraction, whole genome sequencing, RNA-seq, 
and genome-wide methylation testing.  
Whole genome sequencing will be performed using the Illumina HiSeq X Ten System. The WGS 
alignment and initial analysis will be accomplished with HudsonAlpha’s established pipeline. 
Genomic variant analysis will be performed with Cartagenia software to confirm the germline 
mutation (control tissue) and identify acquired mutations that correlate with cNF response to 
selumetinib, if a decrease is observed. Candidate genes for the variant analysis will include those 
involved in cell cycle, apoptosis, and DNA repair (e.g. MMR genes, TP53, CDKN2A, and RB1) 
but the entire genome will still be included in the analysis. 
RNA sequencing will be performed by an rRNA reduction process followed by 50M paired reads 
at PE75 on the HiSeq 4000 System. Transciptome analysis will be performed at HudsonAlpha to 
determine whether transcripts are differentially expressed in tumors that respond to selumetinib 
versus those that are unchanged. 
 


 
88
17.7 APPENDIX VII: PATIENT DAILY MEDICATION DIARY FOR SELUMETINIB  
NF1 Patient Diary for Selumetinib NCI CTEP Protocol # ___ 
 
ID #: 
 
Institution: 
 
Cycle Number: 
 
Dose: 
Twice a Day 
Cycle Start Date: 
 
 
 
 
 
 
Time  
(M = missed) 
Number of Capsules Taken 
Comments 
(Please note reason if dose is 
missed) 
Day 
Date 
AM 
PM 
10 mg (am/pm) 
25mg (am/pm) 
 
1 
 
 
 
# taken: ____/____ # taken: ____/____ 
 
2 
 
 
 
# taken: ____/_____ # taken: ____/_____  
3 
 
 
 
# taken: ____/_____ # taken: ____/_____  
4 
 
 
 
# taken: ____/_____ # taken: ____/_____  
5 
 
 
 
# taken: ____/_____ # taken: ____/_____  
6 
 
 
 
# taken: ____/_____ # taken: ____/_____  
7 
 
 
 
# taken: ____/_____ # taken: ____/_____  
8 
 
 
 
# taken: ____/_____ # taken: ____/_____  
9 
 
 
 
# taken: ____/_____ # taken: ____/_____  
10 
 
 
 
# taken: ____/_____ # taken: ____/_____  
11 
 
 
 
# taken: ____/_____ # taken: ____/_____  
12 
 
 
 
# taken: ____/_____ # taken: ____/_____  
13 
 
 
 
# taken: ____/_____ # taken: ____/_____  
14 
 
 
 
# taken: ____/_____ # taken: ____/_____  
15 
 
 
 
# taken: ____/_____ # taken: ____/_____  
16 
 
 
 
# taken: ____/_____ # taken: ____/_____  
17 
 
 
 
# taken: ____/_____ # taken: ____/_____  
18 
 
 
 
# taken: ____/_____ # taken: ____/_____  
19 
 
 
 
# taken: ____/_____ # taken: ____/_____  
20 
 
 
 
# taken: ____/_____ # taken: ____/_____  
21 
 
 
 
# taken: ____/_____ # taken: ____/_____  
22 
 
 
 
# taken: ____/_____ # taken: ____/_____  
23 
 
 
 
# taken: ____/_____ # taken: ____/_____  
24 
 
 
 
# taken: ____/_____ # taken: ____/_____  
25 
 
 
 
# taken: ____/_____ # taken: ____/_____  
26 
 
 
 
# taken: ____/_____ # taken: ____/_____  
27 
 
 
 
# taken: ____/_____ # taken: ____/_____  
28 
 
 
 
# taken: ____/_____ # taken: ____/_____  
Number of Pills Returned:  10 mg:  
25mg:  
 
Patient Signature:  
  Date:  
 
 


 
89
NF1 Patient Diary for Selumetinib NCI CTEP Protocol # ____  
ID #: 
 
Institution: 
 
SIDE EFFECTS:  (Please describe in detail to 
include location of rash, # of stools, # of times 
vomited in 24 hrs, highest temperature etc) 
Start Date 
Stop Date 
Medication 
 
Taken 
(please include dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severity:  1=mild    2=moderate     3=severe 
 
Patient Signature:  
  Date:  
 
 


 
90
 
17.8 APPENDIX VIIA:  ADHERENCE 
Selumetinib Capsule Count Form:  Complete one form for each cycle at the time Selumetinib is prescribed/dispensed and then when 
capsules/bottles are returned. 
Study ID #:_________  
 
Cycle number:  ___________ 
 
Cycle start date:___________ 
 
Current dose (mg/dose): _________  
Number doses per day:__________  
 
 
If there is a discrepancy >20% between total mg returned (actual) and total mg that should have been returned  (expected) the Adherence 
Intervention will be implemented. For questions please contact Staci Martin at 301-435-3964. 
Date 
No. 
of 
capsules 
prescribed 
10 mg           25 mg  
No. of capsules returned 
  10 mg           25 mg  
Total mg returned 
Total mg should have 
been returned 
% Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Comments: 
 
 
 
Signature:   
 
 
 
 
 
 
Date: _____________ 


 
91
 
17.9 APPENDIX VIII:  MEASUREMENT AND COUNTING OF CUTANEOUS NEUROFIBROMAS 
A) Measurement of cutaneous neurofibromas 
Cutaneous neurofibromas will be measured as described below at the following time points: 
Select One: 
   Baseline 
Prior to:    
   Cycle 5  
 
  
   Cycle 9  
 
   Cycle 13  
 
 
     
   Other (Please specify): __________________________________________ 
 
Date/Time counting performed: ____________________________________ 
 
For response evaluation, the average volume of 3-5 small (longest neurofibroma diameter 4-7 mm) 
and 3-5 larger (longest neurofibroma diameter ≥8 mm) target cutaneous neurofibromas in 3 
different body regions will be calculated at each response evaluation (baseline, and then after every 
4 cycles). Cutaneous neurofibromas will be measured with calipers as developed by Dr. Korf, and 
volumes will be calculated by multiplying length, width, and height of each target neurofibroma. 
At each response evaluation the sum of the on-treatment volumes for the smaller tumors will be 
subtracted from the pre-treatment volumes of the same tumors to arrive at an overall percentage 
change in tumor size for each patient. This will be repeated for the larger tumors. Then, the average 
percentage change for each size category will be reported 
Area 1: Location 
Area 1 
Length (mm) 
Width  (mm) 
Height (mm) 
Volume (mm3) 
1 large 
 
 
 
 
2 large 
 
 
 
 
3 large 
 
 
 
 
4 large 
 
 
 
 
5 large 
 
 
 
 
1 small 
 
 
 
 
2 small 
 
 
 
 
3 small 
 
 
 
 
4 small 
 
 
 
 
5 small 
 
 
 
 
Area 2: Location 
Area 2 
Length (mm) 
Width  (mm) 
Height (mm) 
Volume (mm3) 
1 large 
 
 
 
 
2 large 
 
 
 
 
3 large 
 
 
 
 
4 large 
 
 
 
 
5 large 
 
 
 
 
1 small 
 
 
 
 
2 small 
 
 
 
 


 
92
3 small 
 
 
 
 
4 small 
 
 
 
 
5 small 
 
 
 
 
Area 3: Location 
Area 3 
Length (mm) 
Width  (mm) 
Height (mm) 
Volume (mm3) 
1 large 
 
 
 
 
2 large 
 
 
 
 
3 large 
 
 
 
 
4 large 
 
 
 
 
5 large 
 
 
 
 
1 small 
 
 
 
 
2 small 
 
 
 
 
3 small 
 
 
 
 
4 small 
 
 
 
 
5 small 
 
 
 
 
Area 4: Location 
Area 4 
Length (mm) 
Width  (mm) 
Height (mm) 
Volume (mm3) 
1 large 
 
 
 
 
2 large 
 
 
 
 
3 large 
 
 
 
 
4 large 
 
 
 
 
5 large 
 
 
 
 
1 small 
 
 
 
 
2 small 
 
 
 
 
3 small 
 
 
 
 
4 small 
 
 
 
 
5 small 
 
 
 
 
 
B) Counting of cutaneous neurofibromas 
Photography of cutaneous will be performed in all patients to count the cutaneous neurofibromas 
as described below: 
Photograph Timing:  
Select One: 
   Baseline 
Prior to:    
   Cycle 5  
 
  
   Cycle 9  
 
   Cycle 13  
 
 
     
   Other (Please specify): __________________________________________ 
 
Date/Time photography performed: ____________________________________ 
 
Digital photography will be performed in all patients with cutaneous neurofibromas at the time 
points noted.  
• Digital photography/ Paper frames: A 10 x 10 cm picture frame is placed on predefined 


 
93
areas, which will be chosen for each patient to represent areas of cutaneous neurofibroma 
burden. Three areas will be chosen.  All cutaneous neurofibromas in the frame ≥4 mm in 
diameter are marked. Multiple digital photographs of the area in the frame are obtained 
before and after marking; in addition, photographs with a larger view which demonstrate 
the location of the lesions on the body will be taken. These photographs will be used to 
ensure that the same areas are photographed longitudinally. This method will determine 
the number of lesions in a prescribed area, but not their volume. The photographs can be 
taken in the clinic and take about 15 minutes to complete. The cutaneous neurofibromas 
will be then be counted; only cutaneous and not subcutaneous lesions will be counted for 
the purposes of this analysis.  
 
• Number of Cutaneous Neurofibromas counted area 1: __________________________ 
• Number of Cutaneous Neurofibromas counted area 2: __________________________ 
• Number of Cutaneous Neurofibromas counted area 3: __________________________ 
• Number of Cutaneous Neurofibromas counted area 4: __________________________ 
 
 
Signature:  
  Date:  
 
 
 
 
 
  
 
 


 
94
17.10 APPENDIX IX: CTEP MULTICENTER GUIDELINES 
If an institution wishes to collaborate with other participating institutions in performing a CTEP-
sponsored research protocol, then the guidelines below must be followed. 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 


 
95
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
96
17.11 APPENDIX X: GLOBAL IMPRESSION OF CHANGE SCALE 
 
The Global Impression of Change Scale will be completed prior to cycles 2, 5, 9, 13, etc. 
 
Select One: 
Prior to:    
   Cycle 2 
 
   Cycle 5   
  
   Cycle 9  
 
   Cycle 13  
 
     
   Other (Please specify): __________________________________________ 
 
Global Impression of Change Scale - cNF 
  
1. Think about your cutaneous neurofibromas.  Compared to before you started taking the 
medicine for this study, would you say the size of your cutaneous neurofibromas are:  
 
 1 Very Much Improved   
 2 Much Improved  
 3 Minimally Improved  
 4 No Change  
 5 Minimally Worse  
 6 Much Worse  
 7 Very Much Worse  
(Please check only one box) 
 
2. Think about how your cutaneous neurofibromas affect you physically (for example, itching, 
pain, appearance).  Compared to before you started taking the medicine for this study, would you 
say the physical effects of your cutaneous neurofibromas are:  
 
 1 Very Much Improved   
 2 Much Improved  
 3 Minimally Improved  
 4 No Change  
 5 Minimally Worse  
 6 Much Worse  
 7 Very Much Worse  


 
97
(Please check only one box) 
 
3. Think about how your cutaneous neurofibromas affect you emotionally (for example, worry, 
embarrassed, depressed).  Compared to before you started taking the medicine for this study, 
would you say the emotional effects of your cutaneous neurofibromas are:  
 
 1 Very Much Improved   
 2 Much Improved  
 3 Minimally Improved  
 4 No Change  
 5 Minimally Worse  
 6 Much Worse  
 7 Very Much Worse 
(Please check only one box) 
 
4. Think about how your cutaneous neurofibromas affect your daily life (for example, work or 
school, social life, sleep).  Compared to before you started taking the medicine for this study, 
would you say the effects of your cutaneous neurofibromas on you daily life are:  
 
 1 Very Much Improved   
 2 Much Improved  
 3 Minimally Improved  
 4 No Change  
 5 Minimally Worse  
 6 Much Worse  
 7 Very Much Worse 
(Please check only one box) 
 
Please describe any changes you have noticed in your cutaneous neurofibromas or changes in 
how these tumors affect you since you started taking the study drug:_______ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 


 
98
17.12 APPENDIX XI: NUMERIC RATING SCALE 
 
The Numeric Rating Scale (NRS-11) will be completed prior to treatment with selumetinib, and 
prior to cycles 2, 5, 9, 13, etc. 
 
Select One: 
   Baseline 
Prior to:    
   Cycle 2 
 
   Cycle 5   
  
   Cycle 9  
 
   Cycle 13  
 
     
   Other (Please specify): __________________________________________ 
 
Numeric Rating Scale (NRS-11) 
 
Below is a line with numbers from 0 to 10 where 0 means no pain and 10 means the worst 
pain you can imagine.  
 
Please circle the one number that best describes your pain at its worst during the past 
week. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 0 
1 
2 
 3 
 4 
5 
6 
7 
8 
 9 
10 
No  
 
 
 
 
Worst pain 
pain 
 
 
 
 
you can imagine