Clinical trial NCT03095248
Conditions: Neurofibromatosis 2 Vestibular Schwannoma Meningioma Ependymoma Glioma
Sponsor: Children's Hospital Medical Center, Cincinnati
Start date: 2017-05-08; Completion date: 2024-05-21
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this research study the researchers want to learn more about the effects (both good and bad) the study drug selumetinib has on participants with neurofibromatosis type II (NF2) related tumor.

The researchers are asking patients with NF2 related tumors to be in the study, because their hearing has decreased and/or their NF2 related tumor has started to grow.

The goals of this study are:

* Determine if selumetinib will stop NF2 related tumors from growing
* Measure the changes in hearing after receiving selumetinib for 6 months.
* Determine if selumetinib improves how participants feel (physically and emotionally) and how participants can perform daily activities.
* Examine tumor tissue, if available, in a laboratory to see if NF2 related tumors have targets of selumetinib.

Detailed description:
This is a Phase 2 trial to assess the hearing response rate and radiographic response of VS in children and young adults with NF2 who are treated with selumetinib. Dosing will be based on BSA calculated at the beginning of each course.

Selumetinib is taken orally twice a day continuously. One course is equivalent to 28 days. Therapy may continue for up to two years (26 courses) in the absence of disease progression or unacceptable toxicity. Dose modifications will be based on Body Surface Area (BSA).

In December, 2022 the investigator closed the Stratum 1 arm. Stratum 2 is reserved for patients who exhibit growth of a tumor(s) besides vestibular schwannoma.

Arms: arm 1: Stratum 1 included patients with NF2 with vestibular schwannomas who exhibit hearing loss. Participants received continuous twice daily dosing of selumetinib. Dosing was based on BSA calculated at the beginning of each course. One course is equivalent to 28 days. Therapy continued for up to two years (26 courses) in the absence of disease progression or unacceptable toxicity. arm 2: Stratum 2 will include patients who have progressive lesions other than VS (including non-vestibular schwannomas, meningiomas, and spinal cord lesions). Participants will receive continuous twice daily dosing of selumentinib. Dosing is based on BSA calculated at the beginning of each course. One course is equivalent to 28 days. Therapy may continue for up to two years (26 courses) in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Selumetinib
Intervention descriptions: intervention 1: Continuous twice daily dosing; oral agent

Protocol documents:
Prot_SAP_000.pdf: 
CCHMC Protocol SEL-TH-1601 
Version Date: v4_August 26, 2019 
 
1
 
 
 
TITLE:  Phase 2 trial of selumetinib in patients with Neurofibromatosis type II related 
tumors 
 
Coordinating Center: CCHMC 
 
Sponsor Investigator/Study Chair : 
Trent R. Hummel, MD 
 
 
 
Cancer and Blood Diseases Institute 
 
 
 
Cincinnati Children’s Hospital Medical Center 
 
 
 
3333 Burnet Ave 
 
 
 
MLC 7018 
 
 
 
Cincinnati, OH 45229 
 
 
 
Telephone: (513) 803-1140 
 
 
 
Fax: (513) 636-3549 
 
 
 
Email: trent.hummel@cchmc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol is for research purposes only, and should not be copied, redistributed or used for any 
other purpose.  The procedures in this protocol are intended only for use by clinical oncologists in 
carefully structured settings, and may not prove to be more effective than standard treatment.  A 
responsible investigator associated with this clinical trial should be consulted before using or 
attempting any procedure in this protocol. Contents of this document may not be extracted without 
permission from the Study Chair. 
 
 


CCHMC Protocol SEL-TH-1601 
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2
 
Other Agent Name(s), NSC# and Supplier: Selumetinib (AZD6244) (AstraZeneca), NSC# 
772256  
 
IND Sponsor: Trent R. Hummel, MD, Cincinnati Children’s Hospital Medical Center/IND# TBD 
 
Protocol Type/ Version#/ Version Date: Original / Version #2.0 / Version Date: 14 December 
2016 
 
 


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3
 
SCHEMA 
 
Description 
This is a single institution, Phase 2 trial for patients with neurofibromatosis type 2 (NF2) with 
vestibular schwannomas (VS) who exhibit hearing loss. Bilateral vestibular schwannomas (VS) 
are the hallmark of NF2. As these tumors enlarge, they cause sensorineural hearing loss and, 
ultimately, complete hearing loss. 
Selumetinib (AZD6244) is a highly selective, orally bioavailable, non-ATP competitive small 
molecule inhibitor of the mitogen-activated protein (MAP) kinase MEK-1/2.  MAPK activation 
in NF2 has been most thoroughly described in schwannomas and elevated MEK1/2 and ERK1/2 
have been demonstrated in human schwannoma tissue at both the mRNA and protein levels. 
 
Schema 
This is a Phase 2 trial to assess the hearing response rate and radiographic response of VS in 
children and young adults with NF2 who are treated with selumetinib. Dosing is based on BSA 
calculated at the beginning of each course.  
 
Selumetinib is taken orally twice a day continuously. One course is equivalent to 28 days. Therapy 
may continue for up to two years (26 courses) in the absence of disease progression or unacceptable 
toxicity.   
 
Dose modifications will be based on Body Surface Area (BSA) dose reduction guidelines in 
Appendix D.  
There will be two treatment strata.  Stratum 1 is for those patients who have a target vestibular 
schwannoma which is causing hearing loss.  Stratum 2 will be reserved for patients who exhibit 
growth of a tumor(s) besides vestibular schwannoma and are therefore not eligible for stratum 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
OBJECTIVES .......................................................................................................................... 6 
1.1 
Primary Objectives ........................................................................................................... 6 
1.2 
Secondary Objectives ....................................................................................................... 6 
2 
BACKGROUND ..................................................................................................................... 6 
2.1 
Neurofibromatosis Type 2 ................................................................................................ 6 
2.2 
SELUMETINIB ............................................................................................................... 9 
3 
PATIENT SELECTION ........................................................................................................ 17 
3.1 
Inclusion Criteria: ........................................................................................................... 17 
3.2 
Exclusion Criteria ........................................................................................................... 20 
3.3 
Treatment at Primary Institution .................................................................................... 22 
3.4 
Criteria to Start Treatment.............................................................................................. 22 
4 
REGISTRATION PROCEDURES ....................................................................................... 22 
4.1 
IRB Approval ................................................................................................................. 22 
4.2 
Informed Consent for treatment ..................................................................................... 22 
4.3 
Patient Registration ........................................................................................................ 22 
5 
TREATMENT PLAN............................................................................................................ 23 
5.1 
Drug Administration ...................................................................................................... 23 
5.2 
Dose Modifying Toxicities (DMT) ................................................................................ 24 
5.3 
Criteria for starting subsequent courses ......................................................................... 25 
5.4 
Concomitant Medications and Supportive Care Guidelines .......................................... 25 
5.5 
Duration of Therapy ....................................................................................................... 32 
5.6 
Duration of Follow Up ................................................................................................... 33 
5.7 
Criteria for Removal from Study ................................................................................... 34 
6 
DOSING DELAYS/ DOSE MODIFICATION .................................................................... 35 
6.1 
Notification of Study Chair ............................................................................................ 35 
6.2 
Hematologic and Non-Hematologic Adverse Events and Management ........................ 35 
7 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ................................. 38 
7.1 
Adverse Event Characteristics ....................................................................................... 39 
7.2 
Definitions ...................................................................................................................... 40 
7.3 
Documentation and Reporting of non-serious AEs or SARs ......................................... 41 
7.4 
SAEs or Serious SARs ................................................................................................... 41 
7.5 
Other Malignancy ........................................................................................................... 42 
7.6 
Reporting ........................................................................................................................ 43 
8 
AGENT INFORMATION ..................................................................................................... 43 
Selumetinib (AZD6244) ........................................................................................................... 43 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................ 45 
9.1 
Correlative Studies ......................................................................................................... 45 
10 
STUDY CALENDAR ....................................................................................................... 47 
11 
MEASUREMENT OF EFFECT........................................................................................ 48 
11.1 
Hearing Response Criteria (Stratum 1 only) .............................................................. 48 
11.2 
Radiographic Tumor Response Criteria ..................................................................... 49 
12 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING ..................... 51 
12.1 
Regulatory and Compliance Monitoring .................................................................... 51 
12.2 
Responsibility for Data Submission ........................................................................... 52 
12.3 
Data and Safety Monitoring Plan ............................................................................... 52 
12.4 
Oversight by the Sponsor Investigator/Study Chair ................................................... 52 


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12.5 
Privacy and Confidentiality ........................................................................................ 53 
12.6 
Record Retention ........................................................................................................ 53 
13 
STATISTICAL CONSIDERATIONS............................................................................... 53 
13.1 
Evaluability ................................................................................................................. 53 
13.2 
Study Design/Endpoints ............................................................................................. 53 
14 
REFERENCES .................................................................................................................. 55 
APPENDIX A 
 Performance Scales ......................................................................................... 58 
APPENDIX B 
 Medications that may cause QTc Prolongation .............................................. 59 
APPENDIX C 
 Potential Drug Interactions With Selumetinib ................................................ 61 
APPENDIX D: Dose Reduction Guide for Selumetinib .............................................................. 63 
APPENDIX E Hearing Response Guidelines ............................................................................... 64 
APPENDIX F – Participant Diary ................................................................................................ 66 
APPENDIX G: NFTI-QOL (Neurofibromatosis 2 impact on quality of life) .............................. 67 
APPENDIX H Canadian Cardiovascular Society grading of angina pectoris .............................. 69 
APPENDIX I New York Heart Association (NYHA) classification of heart disease .................. 70 
 
 
 


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1 
OBJECTIVES 
1.1 
Primary Objectives  
 
 To assess the hearing response rate at 24 weeks using word recognition scores in children 
and young adults with NF2 who are treated with selumetinib on stratum 1 
 
 To determine the radiographic response rate of other NF2 related tumors (meningiomas 
and ependymomas) in patients treated with selumetinib on stratum 2. 
 
1.2 
Secondary Objectives 
 To determine the radiographic response rate of VS (defined as an decrease in VS volume 
by ≥ 20% compared to baseline) during selumetinib treatment 
 To describe MRI characteristics of the tumors before and after treatment 
 
1.2.3 To evaluate the feasibility of collecting pre-trial tumor samples in NF2 patients 
 
1.2.4  To determine if pre-trial tumor samples indicate activation of the MAPK pathway:  
 
1.2.5 To evaluate the effect of selumetinib on quality of life using the NFTI-QOL scale for 
patients ≥ 16 years of age 
 
 
2 
BACKGROUND 
2.1 
Neurofibromatosis Type 2 
 
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder associated with development 
of multiple types of central nervous system (CNS) and peripheral nervous system (PNS) tumors. 
The causative genetic event in NF2 is loss of tumor suppressor protein merlin as a consequence 
of mutations in the NF2 gene located at chromosome 22q12.2.  Merlin is a member of the ezrin, 
radixin, and moesin (ERM) family of membrane-cytoskeletal linker proteins.1-3 Although merlin 
is important in many cellular processes and functionally overlaps with ERM proteins, it is 
distinguished by its tumor suppressor activity, which inhibits several important cancer signaling 
pathways, including Ras/Raf/MEK/ERK (also called the mitogen-activated protein kinase or 
MAPK pathway), Rac, and phosphoinositide 3-kinase (PI3K)/Akt.1,4-6 The incidence of NF2 is 
approximately 1 in 25,000 individuals.7 CNS and PNS manifestations of NF2 most commonly 
include vestibular schwannoma (VS) (previously called “acoustic neuroma”), meningioma, and 
less commonly, ependymoma and low-grade glioma (LGG) also occur.8 NF2 represents 2.5% of 
all newly diagnosed intramedullary spinal tumors.9 The clinical presentation of patients with 
NF2 and VS classically includes hearing loss, tinnitus, and ataxia, though patients may present 
with symptoms related to other CNS tumors before developing VS.10 A positive family history is 
present in approximately 50% of cases.  Initial screening tests for NF2 include MRI and 


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audiometry, and genetic testing is available.  Due to relative slow growth, standard 
chemotherapy is generally ineffective in NF2, necessitating the use of surgical resection and 
radiation therapy, both of which increase morbidity in this patient population.  While emphasis is 
placed on minimizing intervention, those who require therapy are at high risk of functional 
disability, most commonly hearing loss in the context of VS.  
 
MEK Activation in NF2-Related Tumors 
The biology of NF2 has been intensively studied, and the MAPK signaling pathway has been 
strongly implicated in merlin-deficient tumorigenesis.4,11-13 MAPK proteins play a key role in the 
regulation of many cellular processes, including proliferation, survival, differentiation, apoptosis, 
motility, and metabolism.14 Activated RAS triggers phosphorylation and activation of the RAF 
kinase, which in turn phosphorylates MEK1 and MEK2 on two serine residues.15 Activated 
MEK phosphorylates its only known substrates, ERK1 and ERK2.  Phosphorylated ERK 
dimerizes and translocates to the nucleus, where it is involved in several important cellular 
functions, including cell proliferation.  Overexpression of growth factors and/or receptors 
involved in the MAPK pathway activation or activating mutations of genes encoding the 
signaling proteins may lead to uncontrolled proliferation and tumor formation. In fact, RAS 
genes are the most frequently mutated oncogenes detected in human tumors.16 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. 
 
MAPK activation in NF2 has been most thoroughly described in schwannoma, the prototypical 
NF2 tumor.  Several groups have demonstrated elevated MEK1/2 and ERK1/2 in human 
schwannoma tissue at both the mRNA and protein levels.12,17 ERK1/2 signaling in rat models has 
been shown to enhance Schwann cell de-differentiation18, adhesion19, and proliferation20, and 
MEK inhibition in human schwannoma cell lines has been shown to decrease proliferation and 
increase apoptosis.12 Mechanisms underlying MAPK activation in human NF2-driven tumors are 
multifaceted and largely dependent on activation of growth factors and/or growth factor 
receptors, including platelet-derived growth factor receptor (PDGFR)11,21, insulin-like growth 
factor receptor (IGFR)22, fibroblasts growth factor (FGF)13, and ErbB2/B3.23 Integrin signaling, 
specifically the focal adhesion kinase (FAK)/Src/Ras pathway, has also been implicated in 
ERK1/2 activation11,24, as has p21-activated kinase (PAK), which normally inhibits merlin via a 
negative feedback loop25 and cross-talks with the ERK1/2 signaling pathway.11  
 
Though much less studied, MAPK activation in other merlin-deficient tumor types may be 
driven by similar inciting factors to those in schwannoma.  MAPK over-activity has been 
frequently observed in meningioma26,27, of which 50-60% result from NF2 mutation.28 MAPK 
activation in NF1-driven LGG, however, appears to be mediated by a similar mechanism to that 
seen in NF2 schwannomas, whereby loss of tumor suppressor proteins neurofibromin or merlin 
stabilizes GTP-bound RAS, leading to constitutive activation. 29 
 
Evidence of Selumetinib Activity in NF2 schwannomas 
Ammoun and colleagues initially revealed a long-lasting activation of ERK1/2 in primary human 
schwannoma cells basally and with stimulation with PDGF-DD, a relevant mitogen for 
schwannomas.  They then performed the first in vitro study of selumetinib in a human 


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schwannoma cell line and demonstrated complete inhibition of PDGF-mediated ERK1/2 
activation and cell proliferation at 1 μM (458 ng/mL)42.   
 
 
Figure 1 above shows serum-starved cells selumetinib completely inhibited the PDGF-DD-
mediated ERK1/2 activation. Additionally, a significant decrease in the level of basal ERK1/2 
activity was also observed (Fig. 1A). The effect of selumetinib seems specific as PDGF-DD-
mediated AKT activation was not inhibited (Fig. 1B).  


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Figure 2 above shows selumetinib strongly reduces PDGF-DD-mediated schwannoma 
proliferation in a concentration-dependent manner, with full significant inhibition at 1.0 μM (458 
ng/ml) (Fig. 2A). These results were confirmed using a BrdUrd incorporation assay; Fig. 2B. 
Selumetinib does not seem to be toxic in vitro, as it did not influence cell viability at the 
concentrations tested (Fig. 2C).  They also verified that MEK1/2 is a target for schwannomas by 
staining sections of schwannomas for expression of activated (i.e., phosphorylated) MEK1/2 and 
its downstream kinase phosphorylated ERK1/2. They found increased levels of both kinases in 
their active form in schwannoma tissue, thus supporting their current in vitro data.  
The concentration used above is well below the maximum serum concentration achieved in an 
early phase 1 clinical trial of selumetinib in adults with advanced cancer.33 Ammoun et al. also 
showed in vitro efficacy of selumetinib in combination with PDGFR/c-KIT inhibitor nilotinib in 
human schwannoma cells.43 Nilotinib alone was effective at inhibiting PDGF-mediated and basal 
schwannoma cell proliferation at a low concentration of 0.5 μM, though the anti-proliferative 
effect was even greater with a combination of PDGFR inhibition (0.25 μM nilotinib) and MEK 
inhibition (0.5 μM selumetinib).  
 
 
2.2 
SELUMETINIB 
 
Selumetinib is a highly selective, orally bioavailable, non-ATP competitive small molecule 
inhibitor of the mitogen-activated protein (MAP) kinase MEK-1/2.30 Selumetinib inhibited the 


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activity of purified MEK enzyme with an IC50 of 10-14 nM, and was found to be inactive or 
only minimally active at 10 μM against a panel of other kinases, including epidermal growth 
factor receptor (EGFR), ERBB2, p38α, ERK2, and MKK6 kinases.  Because ERK is the only 
known substrate of MEK, the inhibition of MEK will target only the ERK signal transduction 
pathway; other signal transduction pathways will not be blocked. In vitro, in vivo, and 
preliminary clinical trial results suggest that selumetinib exhibits a favorable pharmacologic and 
toxicologic profile. 
 
 Pre-clinical Studies of Selumetinib 
 
Nonclinical Studies 
Efficacy 
In vitro studies have shown that selumetinib and its N-desmethyl metabolite are potent and 
selective inhibitors of MEK.30 However, significant biochemical activity was not detected when 
the two compounds were tested against a diverse panel of 305 other molecules, including 
enzymes, receptors, kinases, transporters, and ion channels.  The effects of selumetinib on ERK 
phosphorylation and cell viability were determined in a panel of cell lines in which the 
mutational status of RAF and RAS were known.  Selumetinib inhibited ERK1 and ERK2 
phosphorylation with IC50s ranging from 0.0018 to 0.041 uM.  Selumetinib was particularly 
potent in inhibiting the viability of cell lines with V600E BRAF gene mutation and some with 
KRAS mutations.  The N-desmethyl metabolite was found to be 3-fold more active than the 
parent compound at inhibiting ERK phosphorylation and 5-fold more potent at inhibiting cell 
viability.  Significant suppression of tumor growth in response to selumetinib treatment was 
observed in several xenograft mouse models derived from a range of tumor types including 
melanoma, breast, pancreatic, lung, colon, and hepatocellular carcinomas.30,31 In the Calu-6 lung 
cancer xenograft model, selumetinib suppressed tumor growth at doses of 10, 25, or 100 mg/kg 
given twice daily, and the minimal effective dose was identified as 0.75 mg/kg administered 
twice daily (BID).  In this model, MEK activity was inhibited as assessed by the level of 
phosphorylated ERK (pERK) in the tumor.  Studies using human colorectal xenograft models 
(SW620, Colo205) demonstrate that selumetinib inhibits tumor growth by inhibition of cell 
proliferation and by induction of apoptosis. 
 
Pharmacokinetic/Pharmacodynamic Xenograft Studies 
Oral bioavailability of selumetinib was favorable in rats (37% at 10 mg/kg) and monkeys (86% 
at 1 mg/kg), but bioavailability decreased with increasing dose.30 The declining bioavailability at 
higher doses may be due to the low aqueous solubility of selumetinib.  No accumulation of 
selumetinib was observed following multiple dosing in rats or monkeys.  Studies in rats indicate 
that selumetinib is widely distributed, although tissue concentrations were lower than blood 
concentrations.  High levels of protein binding (93.7-99.7%) were observed in all preclinical 
species tested and in humans (98.4%).  Selumetinib was excreted rapidly within 48 hours via the 
feces, mostly as metabolites. 
 
The value of pERK as a biomarker of selumetinib efficacy has been explored in non-clinical 
studies.  In the Calu-6 human lung cancer xenograft model, levels of pERK were determined by 
both immunohistochemical (IHC) staining of formalin-fixed tissue sections and by Western blot 
analysis of tumor protein lysates.30 Following an acute tumor-suppressive dose of 25 mg/kg of 


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selumetinib, immunostaining for pERK in the cytoplasm was reduced by approximately 90% at 
1, 2 and 4 hours post-dose and recovered to >50% of the control by 24 hours.  The increase in 
tumor pERK content by 24 hours correlated with the decrease in plasma concentration of 
selumetinib.  The same trend was observed by Western blot analysis.  These data showed that the 
level of pERK in the tumor is a potential biomarker for selumetinib activity in vivo. 
 
A whole blood fluorescence-activated cell sorting (FACS) assay was developed to monitor 
pERK levels in peripheral blood mononuclear cells (PBMCs) to allow assessment of selumetinib 
activity without tissue biopsy.32 Whole blood samples from cynomolgus monkeys at pre-dose 
and 1, 2, 4, 8, 12 hours post-dose were analyzed for pERK levels.  Plasma concentrations of 
selumetinib correlated with inhibition of TPA-induced ERK phosphorylation.  Similarly, the ex 
vivo addition of selumetinib to human whole blood from volunteers resulted in the inhibition of 
ERK phosphorylation in isolated PBMCs.  Data from an ongoing phase 1 study in cancer 
patients also indicate a strong correlation between plasma drug concentration and inhibition of 
ERK phosphorylation in blood from these patients, demonstrating the effectiveness of pERK as a 
mechanistic biomarker for MEK inhibition in the clinical setting. 
 
Toxicologic Studies 
The toxicologic effects of selumetinib were evaluated in acute dose (one or two doses on a single 
day) and at 1-month repeat-dose studies in Sprague-Dawley rats and cynomolgus monkeys.30 
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.  Diarrhea, dehydration, electrolyte imbalance, and secondary renal changes 
were observed in monkeys.  The vehicle, Captisol® (SBE-CD), used in the formulation is known 
to cause gastrointestinal disturbances in preclinical studies.  A reduction in the volume of 
Captisol® administration to monkeys was associated with a reduced incidence of diarrhea; 
however, it is likely that selumetinib exacerbated the vehicle effects.  The no observable adverse 
effect levels (NOAEL) in rats and monkeys in the 1-month studies were identified as 10 
mg/kg/day and 20 mg/kg/day (administered twice daily), respectively. Selumetinib and its active 
metabolite showed no evidence of mutagenic potential, but selumetinib produced an increase in 
micronucleated immature erythrocytes in mice, predominantly via an aneugenic mode of action. 
 
Safety pharmacology studies were performed to assess the effects of selumetinib and its active 
metabolite on key organ systems.30 The agents did not produce any toxicologically significant 
effect.  Evidence of gastric mucosal lesions and minor increases in airway resistance were 
observed in some rats following a 100 mg/kg dose; however, these effects were not apparent in 
the 1-month study. 
 
2.1.2 Clinical Studies 
As of 31 October 2015, approximately 2880 patients with cancer have received treatment with 
selumetinib, including 1388 patients in AZ-sponsored studies, 57 patients in the Array-sponsored 
Study ARRY-0401, 62 patients in the Merck-sponsored Study D1532C00028, and approximately 
1375 patients in investigator- or collaborative group-sponsored studies. Of the investigator-
sponsored studies, 2 are being conducted in a paediatric population (Studies 8799 (11C0161 
[NCT01362803; Phase 1] and PBTC-029 [NCT01089101; Phase 1/2]). In addition, 354 subjects 
(healthy volunteers or subjects with renal or hepatic impairment) have been exposed to 


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selumetinib Hyd-Sulfate in clinical pharmacology studies. 
 
Selumetinib was initially dosed as a free-base suspension formulation for the First Time in Man 
Phase 1 study.  An MTD of 100 mg BID was established by this study, and subsequent phase 2 
studies were carried out at this dose level using this formulation.  A subsequently developed 
selumetinib Hydrogen-Sulfate salt capsule formulation was found to have an MTD of 75 mg BID 
in a phase 1 study.  Further development of selumetinib will be with the selumetinib Hyd-Sulfate 
capsule formulation.30 
 
Pharmacokinetics 
The single dose pharmacokinetics of selumetinib and its active metabolite N-desmethyl were 
characterized following dosing of the free-base suspension and the Hyd-Sulfate capsule 
formulation.  Selumetinib was rapidly absorbed across all dose levels with a median tmax of 1.5 
hrs.  Following the peak, selumetinib concentrations declined multi-exponentially, with a mean 
t1/2 ranging from 5 to 7 hours, consistent across dose levels. Plasma N-desmethyl selumetinib 
concentrations followed a similar pharmacokinetic profile to selumetinib, although exposure was 
much lower with Cmax and AUC values generally <10% of parent. 
 
AUC following dosing with the free-base suspension formulation increased with increasing dose 
in a less than dose proportional manner, although there was a high degree of inter-patient 
variability.  In contrast, following dosing with the Hyd Sulfate capsule formulation there was 
more of a trend towards increases in exposure (AUC and Cmax) in proportion to increases in 
dose.  In a relative bioavailability study, the Hyd-Sulfate formulation showed significantly 
improved bioavailability over the free-base suspension. Pharmacokinetic data from a food effect 
study indicated that both low fat and high fat food decreases the exposure of selumetinib. 
 
Selumetinib plasma pharmacokinetic parameters were similar after single and multiple dosing 
(days 8, 15 and 22) suggesting minimal accumulation over time after twice daily dosing, 
consistent with the terminal half-life observed.30 
 
Pharmacodynamics 
The effect of selumetinib on ERK phosphorylation in peripheral blood mononuclear cells was 
evaluated in Part A of study ARRY-0401.  Using FACS analysis, the magnitude of pERK 
relative to baseline was determined in TPA-stimulated pre- and post-treatment blood samples.  
Selumetinib inhibited TPA-induced ERK phosphorylation at an IC50 of approximately 134 
ng/mL (total concentration in plasma).  The magnitude of inhibition was found to correlate with 
plasma selumetinib concentrations.  Inhibition of pERK as an indirect measure of MEK 
inhibition by selumetinib was assessed in PBMCs from each patient at 4 time points post single 
dose administration across dose levels.  Inhibition of ERK phosphorylation was observed at all 
doses, with greatest inhibition generally occurring at the first time point; 73% inhibition seen at 1 
hour. 
 
Phase 1 
 
Accrual to the Pediatric Brain Tumor Consortium’s (PBTC) Phase 1 study completed in April, 
2013, and the maximum tolerated dose in all age groups was 25 mg/m2/dose, BID. 39 patients 


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13
were accrued; one was found to be ineligible. Initially, only patients >12 and ≤ 21 years were 
eligible. Dose levels 1 and 2 (33 and 43 mg/m2/dose, BID) were deemed intolerable with dose 
limiting toxicities (DLTs) of headache, rash and mucositis. Following de-escalation to dose level 
0 (25mg/m2/dose BID), eligibility was extended to patients <12 years. Among the 24 patients 
treated at dose level 0, no patient <12 years and 3 of 12 patients ≥12 years experienced DLTs of 
elevated amylase/lipase, rash, and mucositis.  There were 8 sustained responses (1 complete and 
7 partial) and the phase 2 study through the PBTC is ongoing.   
 
There is also an ongoing trial for patients with neurofibromatosis type 1 who have plexiform 
neurofibromas (PN).  PN are benign nerve sheath tumors that have no standard treatment options 
other than surgery, which is often difficult due to proximity to vital structures.  In this trial, 
selumetinib will be administered orally BID on a continuous dosing schedule.  Limited dose 
escalations will be performed to define the MTD based on tolerability of selumetinib during the 
first three treatment cycles. Disease status will be evaluated using volumetric MRI analysis at 
regular intervals. A phase 2 registration study has started and is ongoing based on the phase 1 
data. 
 
Phase 2 –Adult studies 
In a phase 2 randomized trial of temozolomide versus selumetinib for high-stage malignant 
melanoma, 200 patients were randomized.  There was no statistically significant difference 
between the groups for the primary endpoint of PFS.  Six of 104 patients treated with 
selumetinib had a partial response compared with 11 of 96 patients with PR+CR on the 
temozolomide arm. 
 
In a separate randomized phase 2 study, 70 subjects with previously treated, advanced, or 
metastatic pancreatic cancer were randomized to receive selumetinib or capecitebine.  There was 
no statistically significant difference between the two treatment groups in the primary endpoint 
of time to death.  Another phase 2 randomized study of selumetinib versus capecitebine for 
subjects with recurrent/progressive colon cancer also showed no significant difference between 
treatments in the primary endpoint of time to progression.  Overall, the best response reported 
was stable disease in 11 patients (10 treated with selumetinib and 1 treated with capecitebine).  
In a phase 2 randomized study of selumetinib versus pemetrexed, 84 subjects with recurrent 
progressive NSCLC were recruited.  No significant difference was seen in the primary endpoint 
of PFS.  Four patients achieved a best overall response of CR (1 pemetrexed treated) or PR (2 
selumetinib, 1 pemetrexed treated).30 
 
More recently, a phase 2 trial of selumetinib in patients with Iodine-131- resistant papillary 
thyroid cancer showed 1/32 evaluable subjects with a PR, 21/32 with SD, and 11/32 with PD.  
Median PFS was 32 weeks, and the most common toxicities were rash, fatigue, diarrhea, and 
peripheral edema.34 In a separate pilot study in patients with RAI-refractory differentiated 
thyroid cancer (DTC), Ho et al. demonstrated that iodine avidity could be returned to patients 
with previously RAI-refractory disease, resulting in a response in a subset of these patients 
treated with RAI after selumetinib.  This effect may, in part, be a function of BRAF/RAS 
mutation status.35 
 
Two trials have examined the activity of selumetinib in “biologically enriched” cohorts. Patel 


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and colleagues analyzed 18 subjects with metastatic melanoma, treated on a phase 2 study.  Nine 
of 18 had BRAF mutations, and 4 had NRAS mutations. Five of 9 patients with BRAF mutations 
had a PR, and the remaining 4 of 9 had SD for at least 6 weeks.  No responses were seen in the 
BRAF WT group, and responses did not correlate in the NRAS mutated group.36 A recently 
published, randomized phase 2 trial examined the use of selumetinib in combination with 
docetaxel versus docetaxel with placebo for patients with KRAS mutant, advanced NSCLC.  The 
investigators reported a statistically significant improvement in progression free survival in the 
selumetinib treated group (5.3 months versus 2.1 months (95% CI 1.4-3.7); HR for progression 
0.58, (80% CI 0.42-0.79; one-sided p=0.014).37 
 
 Safety Data 
 
AZD6244 Hydrogen-Sulfate Capsule 
Safety data from a phase 1 study of the Hyd-Sulfate capsule formulation are available at dose 
levels of 25 mg BID (n=6), 50 mg BID (n=7), 75 mg BID (n=7), and 100 mg BID (n=8).  One 
DLT was reported in the first 22 days of dosing in the 75 mg BID cohort (CTCAE grade 3 
fatigue that resolved with discontinuation of drug).  Two DLTs (pleural effusion and rash, both 
CTCAE grade 3) were reported in the first 22 days of dosing in the 100 mg BID cohort.  The 
MTD of selumetinib Hyd-Sulfate capsule was determined to be 75 mg BID.  
 
The most frequently reported adverse events were fatigue, dermatitis acneiform, nausea, 
diarrhea, and peripheral edema.  All AEs of dermatitis and fatigue for patients treated in the 75 
mg BID cohort were considered treatment-related.  The majority of AEs were CTCAE grade 1 or 
2 in intensity.  However, 33/56 of patients experienced at least one CTCAE grade 3 event during 
the study, of which 18/56 experienced at least one treatment-related AE > Grade 3.  The majority 
of grade 3 events were reported by only one patient.  Events that were reported in more than one 
patient include left ventricular dysfunction, nausea, vomiting, fatigue, febrile infection, lower 
respiratory tract infection, increased blood alkaline phosphate, GGT increased, hypoxia, 
dermatitis acneiform, and hypertension.  Fatigue was the most commonly reported CTCAE grade 
3 or higher AE. The only grade 4 event in the study was a single episode of hypoglycemia. 
 
Eighteen patients had permanent discontinuation of study treatment due to at least one adverse 
event.  Five patients had AEs of fatigue reported as contributing to discontinuation of treatment.  
Two patients each had AEs of anorexia, vomiting, nausea and LV dysfunction, also reported as 
being at least partly contributing to discontinuation of study treatment.  Seven patients had at 
least one SAE that was considered treatment-related, with hypertension being the only SAE 
reported more than once.30 
 
LVEF 
Scheduled on-treatment assessments (Week 4 or 8) of LVEF were included in two studies of 
selumetinib monotherapy to evaluate a possible cardiac etiology for peripheral edema.  Small 
median reductions (<10 percentage points) from baseline were recorded during selumetinib 
treatment in both studies, although individual patient changes were highly variable (–25 to +19 
percentage points).  No comparative data are available from these studies.  Clinically meaningful 
reductions in LVEF (≥10 percentage points and to below 55%) in patients receiving selumetinib 
in combination with chemotherapy have been recorded in two randomized double-blind placebo-


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controlled Phase 2 studies with scheduled Week 6 echocardiography assessments (D1532C00006 
and D1532C00016). These asymptomatic reductions occurred in 13.6% vs. 7.1% of patients with 
NSCLC receiving selumetinib or placebo in combination with docetaxel and in 20.5% vs. 11.4% 
of patients with advanced melanoma receiving selumetinib or placebo in combination with 
dacarbazine.  Evidence of reversibility of LVEF changes on continuing selumetinib (often 
without therapeutic treatment) has been demonstrated in patients with follow-up assessments 
available. 
 
Increase in Creatinine Phosphokinase Levels 
Increased CPK levels have been reported with MEK inhibitors38-40, which may suggest a class 
effect.  Scheduled measurement of CPK levels has not been included in studies of selumetinib.  
However, AEs of increased CPK levels have been reported in a small number of patients.  In 
study D1532C00006, CPK levels were measured at a single investigational site in patients with 
melanoma believed by the investigator to be receiving selumetinib + dacarbazine.  AEs of 
increased CPK levels were reported in 7 patients (15.9% of the overall selumetinib + dacarbazine 
group).  CPK levels were not measured in the 3 patients at the same site who received placebo + 
dacarbazine.  A causal relationship between selumetinib and increased CPK levels has not been 
established. 
 
Muscle Weakness 
Neck extensor muscle weakness (with mild increase in CPK levels), reversible on selumetinib 
interruption, has been reported in 3 patients with uveal melanoma treated with selumetinib in a 
non-AZ-sponsored study.41 A relationship between selumetinib and muscle weakness has not 
been established. 
 
Potential Drug Interactions 
In vitro metabolic studies of selumetinib using hepatocytes from humans and animals found that 
the biologically active N-desmethyl derivative was detected in mouse and human hepatocytes, 
detected minimally in monkeys, and was not detected in rats.30 CYP3A4 is the predominant 
isoform responsible for selumetinib oxidative metabolism with CYP2C19, CYP1A2, CYP2C9, 
CYP2E1 and CYP3A5 involved to a lesser extent. In vitro studies indicate that selumetinib also 
undergoes direct Phase 2 metabolic reactions to form glucuronide conjugates principally involving 
the enzymes UGT1A1 and UGT1A3. Cytochrome P450 (CYP)1A2 was the enzyme primarily 
responsible for the formation of the N-desmethyl derivative.  CYP2C19 and CYP3A4 were also 
minimally involved in the transformation to N-desmethyl metabolite.  Neither selumetinib, nor its 
active metabolite, were found to be inhibitors of CYP isoforms 1A2, 2C8, 2C19, 2D6, or 3A4.  At 
the systemic selumetinib concentrations observed following 100 mg selumetinib capsule 
formulation in man, no significant cytochrome P450 interactions would be expected.  Since the 
formation of N-desmethyl AZD6244 from selumetinib may occur through the CYP1A2 pathway 
and smoking induces this pathway, the smoking status of the subjects should to be recorded in all 
studies (i.e., smoker or non-smoker) to investigate whether smoking status influences systemic 
drug exposures of N-desmethyl selumetinib. 
 


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Selumetinib exposure in subjects of Asian ethnicity  
Selumetinib exposure appears to be higher in Japanese, non-Japanese-Asian and Indian healthy 
adult volunteers compared to Western adult volunteers. However, there is considerable overlap 
with Western subjects when corrected for body weight or BSA. No specific adjustment to the 
starting dose is recommended for paediatric Asian patients, however these patients should be 
closely monitored for adverse events.  
Vision Changes  
Visual disturbances symptoms, including blurred vision have been reported in 10% of patients 
during treatment with selumetinib. Adverse events of central serous retinopathy/retinal pigment 
epithelial detachment have been reported in a small number of patients receiving selumetinib. 
Rare adverse event of retinal vein occlusion have been reported, however a relationship between 
selumetinib and retinal vein occlusion has not been established.  
Rationale 
 
The preclinical work described above, demonstrating the important role of MAPK pathway 
activation in NF2-driven tumorigenesis, provides strong rationale for targeting the MAPK 
signaling pathway through selective therapeutic inhibition of MEK1/2 with selumetinib. 
Therefore, we are initiating a single institution, Phase 2 trial for patients with neurofibromatosis 
type 2 (NF2).  There will be two strata in this clinical trial.  Stratum 1 will include patients with 
NF2 with VS who exhibit hearing loss.  Stratum 2 will include for patients who have progressive 
lesions other than VS (including non-vestibular schwannomas, meningiomas, and spinal cord 
lesions).  Our hypotheses are: 1) selumetinib given orally twice daily will improve hearing in 
NF2 patients with VS in stratum 1 and 2) selumetinib given orally twice a day will decrease the 
size of NF2-associated tumors in stratum 2. 
 
 
 


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3 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria: 
 
 Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National 
Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative 
mutation in the NF2 gene.  
The NIH criteria includes presence of:  
 Bilateral vestibular schwannomas, OR  
 First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two 
of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile 
posterior subcapsular lenticular opacity.  
 
The Manchester criteria includes presence of:  
 Bilateral vestibular schwannomas, OR  
 First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two 
of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile 
posterior subcapsular lenticular opacity, OR  
 Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, 
glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR  
 Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR 
any two of: schwannoma, glioma, neurofibroma, cataract.  
 
 Patients do not need to have a histologic diagnosis in order to start therapy but must have 
measurable disease (in 2 dimensions) on MRI scan to be eligible. 
 
 
3.1.2.1 For Stratum 1: Patients must have a target VS with the following qualities: 
Associated with a word recognition score of < 85% and > 0% 
AND 
Documented progression defined as:  Either progressive hearing loss or progressive 
tumor growth in last 18 months defined as ≥ 20% increase in volume. 
3.1.2.2.  For Stratum 2:  Patients must not meet the eligibility criteria as stated for 
Stratum 1 and have a target lesion that has exhibited progression.  Progression is 
defined as: ≥ 25% increase in sum of the products of perpendicular diameters of 
lesions in the preceding 18 months; any new lesion; or clinical deterioration related 
to disease. 


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 Patients must be able to swallow capsules 
 Age:   
Patients must be ≥ 3 years to ≤ 45 years of age at start of treatment 
 Prior Therapy  
Since there is no standard effective chemotherapy for patients with NF2 and vestibular 
schwannomas, meningiomas, or ependymomas patients may be treated on this trial 
without having received prior medical therapy directed at their VS, meningiomas, or 
ependymomas. 
 
Since selumetinib is not expected to cause substantial myelosuppression, there will be no 
limit to number of prior myelosuppressive regimen for these NF2 patients. 
 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, biologic therapy or radiotherapy prior to entering this study except for 
alopecia.  
 
Myelosuppressive chemotherapy: Patients must have received their last dose of known 
myelosuppressive anticancer chemotherapy at least three weeks prior to study registration 
or at least six weeks if nitrosourea.  
 
Biologic agent: Patient must have received their last dose of the biologic agent ≥ 7 days 
prior to study registration.  For biologic agents that have a prolonged half-life, at least 
three half-lives must have elapsed prior to registration  
 
Monoclonal antibody treatment: At least three half-lives must have elapsed prior to 
registration 
 
 Corticosteroids:  
Patients who are receiving dexamethasone or other corticosteroids must be on a stable or 
decreasing dose for at least 1 week prior to registration. It is recommended that patients 
be off all steroid therapy or receive the least dose that will control their neurologic 
symptoms 
 
 Prior radiotherapy  
XRT: ≥ 6 months must have elapsed if prior XRT to vestibular schwannoma or other 
tumor. 
 
 Stem Cell Transplant or Rescue without TBI:  
No evidence of active graft vs. host disease and ≥ 3 months must have elapsed since 
transplant. 
 


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 Performance Status: 
Karnofsky ≥ 60% for patients > 16 years of age 
Lansky ≥ 60 for patients ≤ 16 years of age.   
 Organ Function Requirements 
3.1.10.1    Adequate Bone Marrow Function Defined as: 
- Peripheral absolute neutrophil count (ANC) ≥ 1500/μL 
- Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving 
platelet transfusions within a 7 day period prior to registration) 
- Hemoglobin ≥ 9 g/dL (may receive RBC transfusions) 
 
3.1.10.2    Adequate Renal Function Defined as: 
- Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or 
- A serum creatinine ≤1.5×ULN for age and sex  
 
3.1.10.3    Adequate Liver Function Defined as: 
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of 
normal (ULN) for age 
- AST(SGOT)/ALT(SGPT) ≤2.5×ULN institutional upper limit of normal for age 
 
3.1.10.4    Central Nervous System Function: 
- Patients with seizure disorder may be enrolled if they are receiving non-enzyme 
inducing anticonvulsants and the seizures are well controlled. 
 
3.1.10.5   Cardiac Function  
Adequate cardiac function defined as:  
 LVEF ≥55% by ECHO 
 QTc interval ≤450 msecs by EKG 
 
3.1.10.6   Hypertension  
 Patients, 3 to < 18 years of age must have a blood pressure that is ≤ 95th 
percentile for age, height and gender at the time of registration.   
 Patients who are ≥18 years of age must have a blood pressure that is <140/90 mm 
of Hg at the time of registration. 
 
Patients may be on blood pressure medication provided that it is not on the 
contraindicated list and that the medication has not been adjusted in the previous 
3 months. 
 
 Growth factors:  
All colony forming growth factor(s) have been discontinued for at least one week prior to 
registration (filgrastim, sargramostim, and erythropoietin). For patients on long acting growth 
factors, the interval should be two weeks.  
 


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 Inclusion of Women and Minorities 
Both males and females of all races and ethnic groups are eligible for this study. 
 
 Informed Consent:  
All patients and/or their parents or legal guardians must sign a written informed consent. 
Assent, when appropriate, will be obtained according to institutional guidelines. 
 
3.2 
Exclusion Criteria 
 Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and 
teratogenic adverse events as seen in animal/human studies. The effects of selumetinib on 
the developing human fetus are unknown. For this reason, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for the duration of study participation, 
and for four weeks after dosing with selumetinib ceases.  The selumetinib manufacturer 
recommends that adequate contraception for male patients should be used for 16 weeks 
post-last dose due to sperm life cycle. Women of child-bearing potential must have a 
negative pregnancy test prior to study registration. Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.    
Note:  Female subjects are considered “of child-bearing potential” if they are 
anatomically and physiologically capable of becoming pregnant.  For girls of normal 
reproductive potential, the possibility of becoming pregnant requires ovulatory menstrual 
cycles and heterosexual intercourse. Although the timing of ovulation relative to 
menarche is variable, there is consistent evidence that some girls may have ovulatory 
cycles prior to menarche, and that, in healthy populations, regular ovulation may begin 
within a few months of menarche. Therefore, menarche is the most feasible clinical 
indicator of the biological potential for pregnancy. 
 
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. 
 Patients with any clinically significant unrelated systemic illness (serious infections or 
significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely to interfere 
with the study procedures or results 
 Patients who are currently receiving another investigational drug within 4 weeks prior to 
the first dose of study treatment, or within a period during which the investigational drug 
or systemic anticancer treatment has not been cleared from the body (e.g. a period of 5 
‘half-lives’), whichever is the most appropriate and as judged by the investigator are not 
eligible.  


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21
 Patients who have taken another BRAF inhibitor such as Vemurafenib or Dabrafenib prior 
to study registration are not eligible.  Prior treatment with selumetinib or another MEK 
inhibitor is not allowed. 
 Patients with QTc interval of > 450 msec  
 Patients who require enzyme inducing anti-convulsants to control seizures.  
 Anticoagulation: Patients receiving coumadin are eligible but must have their PT and 
INR monitored prior to each 4 week course.  
 Patients who in the opinion of the investigator may not be able to comply with the safety 
monitoring requirements of the study are not eligible.  
 Patients with the following cardiac conditions: 
a. Uncontrolled hypertension in adults (BP ≥ 140/90 mmHg despite medical 
therapy) 
b. Acute coronary syndrome within 6 months prior to starting treatment 
c. Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite 
medical therapy (Appendix H) 
d. Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or 
severe valvular heart disease (Appendix I) 
e. Prior or current cardiomyopathy including but not limited to the following: 
i. Known hypertrophic cardiomyopathy 
ii. Known arrhythmogenic right ventricular cardiomyopathy 
f. Previous moderate or severe impairment of left ventricular systolic function 
(LVEF <45% on echocardiography or equivalent on MuGA) if known even if full 
recovery has occurred. 
g. Severe valvular heart disease 
h. Baseline Left ventricular ejection fraction (LVEF) below the LLN or <55% 
measured by echocardiography or institution’s LLN for MUGA 
i. Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest  
 Ophthalmological conditions as follows: 
 
a. Current or past history of retinal pigment epithelial detachment (RPED)/central 
serous retinopathy (CSR) or retinal vein occlusion 
b. Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma (irrespective of 
IOP) as defined by ophthalmologist 
 Major surgery within 4 weeks of starting selumetinib.  Portacath insertion, G Tube 
placement, and insertion of ventriculoperitoneal shunt are not considered major surgeries. 
 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to selumetinib or combination medications or any excipient of these 
medicinal products 
 History of a medical or psychiatric illness, that in the investigator's judgment renders the 
patient incapable of further therapy on this protocol 


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22
 Patients with progressive disease associated with significant or disabling clinical  
symptoms requiring immediate intervention with surgery or radiation therapy are not 
eligible. 
 
3.3 
Treatment at Primary Institution 
All investigational agent(s) should be dispensed and all imaging studies obtained at Cincinnati 
Children’s Hospital Medical Center.  
3.4 
Criteria to Start Treatment 
 Subjects must start therapy within fourteen (14) days of registration. 
 Imaging evaluations necessary to establish eligibility for study entry must be done within 
four weeks prior to registration.  
 
All other evaluations necessary to establish eligibility for study entry must be done within 
14 days prior to registration.  
 Laboratory values used to assess eligibility must be no older than seven (7) days prior to 
the start of therapy. Laboratory tests used to determine eligibility need not be repeated if 
therapy starts within seven (7) days. If a test that is repeated post registration and prior to 
the start of therapy is outside the limits for eligibility, it must be rechecked within 48 hours 
prior to the start of therapy. If the recheck is still outside the limits for eligibility, the patient 
may not receive protocol therapy and will be considered off study. 
 
 
4 
REGISTRATION PROCEDURES 
4.1 
IRB Approval 
Local IRB/REB approval of this study must be obtained prior to consenting and registration of 
patients.  
4.2 
Informed Consent for treatment 
Consent should be obtained prior to the initiation of any procedures or assessments performed for 
the purpose of determining protocol eligibility, which would not otherwise be consistent with the 
institution’s standards of clinical practice.  
 
Prior to consent, the protocol’s status should be verified via the CCHMC Phase 1/regulatory 
teams to ensure the study is open to accrual.  
 
4.3 
Patient Registration 
Patients must be registered prior to any protocol treatment.  Patient registration is only available 
to authorized personnel at CCHMC.  Signing off of the eligibility checklist by Investigator or sub-
Investigator completes registration. 
 
 


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5 
TREATMENT PLAN 
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 6.2.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's tumor.  
 
5.1 
Drug Administration 
For stratum 1 and stratum 2 patients with NF2 dosing will be based on BSA. Dosing is based on 
BSA calculated at the beginning of each course. Selumetinib will be supplied as 10 mg and 25 
mg capsules or currently available formulation. Patients will receive selumetinib orally twice 
daily approximately 12 hours apart. Four consecutive weeks will constitute one course and 
subsequent courses will immediately follow, with no scheduled break in the administration of the 
drug.  
 
The recommended dose of selumetinib is 25 mg/m2 of body surface area (BSA), taken orally 
twice daily (approximately every 12 hours).  
 
Dosing is individualised based on BSA (mg/m2) and rounded to the nearest achievable 5 mg or 
10 mg dose (up to a maximum single dose of 50 mg). Different strengths of selumetinib capsules 
can be combined to attain the desired dose (Table 1). selumetinib is not recommended in patients 
with a BSA <0.55 m2. 
Table 1 
Dosing scheme of selumetinib 25 mg/m2 twice daily 
Body Surface Area (BSA) 
Dose in mg (twice daily) 
0.55 – 0.69 m2 
10 
0.70 – 0.89 m2 
20 
0.90 – 1.09 m2 
25 
1.10 – 1.29 m2 
30 
1.30 – 1.49 m2 
35 
1.50 – 1.69 m2 
40 
1.70 – 1.89 m2 
45 
≥1.90 m2 
50 
 
Dosing is based on the BSA calculated at the beginning of each course of therapy for all patients. 
Dosing reduction tables are available in APPENDIX D. Patients will be provided with a 
Medication Diary for selumetinib, instructed in its use, and asked to bring the diary and pill 
bottles with them to each appointment.  


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Selumetinib capsules must be taken whole (do not crush or chew) and should be taken on an 
empty stomach (no food or drink other than water) either 1 hour before or 2 hours after meals. 
Selumetinib capsules should be taken with water only.  
Participants should be advised to drink plenty of water or take rehydration fluids to avoid 
dehydration if diarrhea occurs. Patients who vomit a dose of selumetinib should NOT be re-
dosed, and appropriate anti-emetic therapy should be implemented prior to the next scheduled 
dose. 
Participants should avoid excessive exposure to sunlight.  Patients should use adequate sunscreen 
protection if exposure to sunlight is to be anticipated.   
 
During the studies, participants should avoid consuming large amounts of grapefruits, Seville 
oranges, or any other products that may contain these fruits, e.g., grapefruit juice, as these may 
affect selumetinib metabolism. 
 
Participants should avoid donating blood while taking selumetinib and for at least 12 weeks after 
receiving the last dose of selumetinib.  
 
Unless considered 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 strong inhibitors or moderate/strong inducers  of  CYP3A4 and fluconazole 
(potent CYP2C19 and moderate CYP3A4 inhibitor), as this may interfere with the metabolism of 
selumetinib.  See Appendix C. 
5.2 
Dose Modifying Toxicities (DMT) 
Toxicities will be graded according to CTCAE version 5.0 of the NCI Common Terminology 
Criteria for Adverse Events. CTCAE version 5.00 is identified and located on the CTEP website 
at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate 
treatment areas should have access to a copy of CTCAE version 5.0.  
 
DMT will be defined as any of the events listed in this section that are at least possibly related to 
the investigational agent that occur regardless of expectedness. Please consult Table 7 for 
appropriate dose modifications. 
 The following are Dose-Modifying Toxicities (DMT’s) 
 Any selumetinib-related adverse event that results in a delay of treatment > 7 days 
 Non-hematologic dose modifying toxicity is defined as: 
o Any grade 4 non hematologic toxicity 
o Any grade 3 non-hematologic toxicity with the exception of: 
 Grade 3 nausea and vomiting of < 3 days  
 Grade 3 asymptomatic elevation of transaminases that returns to levels 
meeting eligibility criteria within 7 days of study drug interruption and 
does not recur upon restarting drug 
 Grade 3 fever or infection if fewer than 3 days in duration  
 Grade 3 asymptomatic hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation  


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 Grade 3 asymptomatic elevation of CPK  
o Any grade 2 non-hematological toxicity that persists for more than 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by patients 
as to warrant treatment interruption and/or dose reduction will be considered 
dose-modifying.  
 
 Hematologic dose modifying toxicity is defined as: 
o Any grade 4 hematologic toxicity with the exception of lymphopenia  
o Grade 3 thrombocytopenia with bleeding  
 
5.3 
Criteria for starting subsequent courses 
 
A course may be repeated every 28 days if the patient has at least stable disease and the patient 
meets the following criteria within seven days of the start of each course:   
 ANC ≥ 1,000/μL  
 Platelets ≥ 100,000/μL  
 Non-hematologic dose modifying toxicity related to selumetinib recovered to < 
grade 2 or baseline (for rash or diarrhea: tolerable grade 2 or baseline)  
 No evidence of progressive disease 
5.4 
Concomitant Medications and Supportive Care Guidelines 
Because there is a potential for interaction of selumetinib with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form (CRF) must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. Refer to 
APPENDIX C for a list of medications which should be avoided, if possible. The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes. Data to be recorded for each medication in CRF 
is Indication, Drug Name, Dose, Start and Stop dates  
 
Unless considered 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 strong inhibitors or moderate/strong inducers of CYP3A4 and fluconazole 
(potent CYP2C19 and moderate CYP3A4 inhibitor), as this may interfere with the metabolism of 
selumetinib.   
 
High vitamin E doses may potentiate warfarin’s anticoagulant activity. Monitor PT/INR more 
frequently in patients receiving both warfarin and selumetinib hydrogen sulfate capsules. 
As selumetinib capsules contain vitamin E, patients should not take any supplemental vitamin E 
during treatment with selumetinib. 
 
 Follow up for certain adverse events should be performed to better characterize the 
effects of selumetinib therapy 
 Peripheral Edema - Patients experiencing grade 3 or prolonged grade 2 (> 14 days) 
edema should have cardiac ejection fraction (EF) measurements, serum chemistry 
(including electrolytes and albumin), and routine urinalysis as clinically indicated.  


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26
 Cardiac monitoring - Reversible, asymptomatic reductions in LVEF have been 
recorded in a small number of patients receiving selumetinib in studies with 
scheduled echocardiography assessments. Guidance for the investigation and 
management of decreases of LVEF is described below.  
o ECHO - Patients will have increased monitoring for cardiac function (ECHO) at 
baseline and every 3 months thereafter during treatment. Patients who develop 
symptoms consistent with cardiac impairment (e.g., congestive cardiac failure, 
pulmonary edema, or dyspnea) at any time during treatment should have EF 
measurements (echocardiography) at the time of the event as well as other routine 
investigations. Patients who show a ≥10% change in ejection fraction from 
baseline should be managed according to the recommended management for 
cardiac adverse events described below and in Table 7. Patients who have a drop 
in LVEF of ≥10% from baseline and to below 55% at the discontinuation of 
selumetinib, should have a follow-up ECHO after 30 days to evaluate the 
potential for reversibility.   
 
 
 Muscle weakness - Patients should be monitored for CPK elevation and for 
the development of muscle weakness (refer to management guidelines 
described in Table 7).  
 Respiratory events (including dyspnea or pulmonary edema) should be 
followed up with a chest X-ray (PA and lateral view).  See below algorithm 
for management.  


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27
 
 Oxygen saturation will be measured at baseline and again following any 
respiratory event.  
 Visual disturbances - Patients experiencing visual disturbances should 
undergo a complete ophthalmologic examination which includes the 
following:  
o Visual acuity 
o Visual fields, if feasible 
o Fundoscopic exam  
o See Table 7 and algorithm below 
 
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 
reaction
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 


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 Febrile Neutropenia 
Febrile neutropenia should be managed according to the local institutional guidelines. Measures 
include laboratory testing, blood and urine cultures, and institution of broad spectrum antibiotics.  
 Diarrhea 
Patients should be advised to drink plenty of water or rehydration fluids to avoid dehydration if 
diarrhea occurs. Should diarrhea occur follow the loperamide dosing guidelines in Table 6 
immediately following first dose of diarrhea.  Patients should be given dietary advice in case of 
diarrhoea (e.g. BRAT [bananas, rice, apple sauce, toast, plain pasta] diet; readily digestible food; 
avoidance of lactose-containing products, fried, fatty or spicy food) and increase fluid intake. Refer 
to Table 7, Section 6.2 when modifying the selumetinib dose in response to diarrhea.  
 
Table 6  
Weight Specific Guidelines for Therapeutic Use of Loperamide
Weight 
(kg)
Initial (Loading) Loperamide dose 
(mg)
Subsequent daytime loperamide 
dose
Subsequent nighttime loperamide 
dose
8-10
1
0.5mg q 3h
0.75mg q 4h
10-20
1
1mg q 3h
1mg q 4h
20-30
2
1mg q 3h
2mg q 4h
30-42
2
1mg q 2h
2mg q4h
> 42
4
2mg q 2h
4mg q 4h
  
Please see algorithm below when assessing diarrhea: 


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If Grade 1/2 diarrhea:  Full clinical and laboratory evaluation including ruling out infectious causes 
(Clostridium difficile or viral causes).   
 
If Grade 3/4 diarrhea:  Consider hospitalization if needed, full clinical and laboratory evaluation 
Diarrhea
CTC Grade 1 or 2 
uncomplicated diarrhea 
Loperamide : 4mg initially
then 2mg every 4 hours or 
after each unformed stool
Dietary management
Diarrhoea resolving or
resolved after 12hrs of 
loperamide
treatment
Continue loperamide
for 12 
hours after diarrhea 
resolved
Adjust diet
Persistent diarrhea not 
resolved after 12 hours of 
loperamide
and remains 
uncomplicated CTC Grade 1 
or 2
Patient should: Contact the 
physician and increase to high 
dose loperamide
(2mg every 2 
hours; possibly 4mg every 4hrs 
at night)
Additional treatment may be
considered according to local
practice
Diarrhea resolving or 
resolved after 24 hours of 
high dose loperamide
treatment
Continue loperamide
for 12 
hours after diarrhea 
resolved 
Adjust diet
Persistent diarrhea not
resolved after 24 hours of 
high dose loperamide
 
Full examination.   
Treat as per local practices. 
(Rehydration, electrolytes, 
octreotide, antibiotics, 
hospitalisation). Consider 
selumetinib  
dose interruption  
CTC Grade 1 or 2 
complicated diarrhea* and 
CTC Grade 3 or 4 at any
time
Hospitalization 
Treat as per local practices 
(iv rehydration, electrolytes, octreotide, iv 
antibiotics). 
Selumetinib dose interruption 
Guidance for the management of patients with diarrhea
*Diarrhea becomes complicated by associated vomiting or inability to take oral fluids; marked abdominal distension or 
cramping; bloody stools, fever or symptoms of hypotension  


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including infectious evaluation.  Consider starting octreotide. Hold selumetinib until < tolerable 
grade 2.  Continue loperamide. 
 Dermatology/Skin Toxicities/Paronychia 
 
The use of medications for the supportive care of rash is permitted, provided that compliance 
with Section 5.4 regarding concomitant medications is observed. Early initiation of treatment for 
rashes is strongly recommended to minimize the duration and severity of the adverse event. 
 
On day 1 of treatment with selumetinib:   
 Recommend to use skin moisturizer (alcohol free) at bedtime.   
 Avoid excessive exposure to sunlight.  Use sunglasses and sunscreen.   
 Use of topical retinoids or benzoyl peroxide is not recommended. 
 
For adults with grade 1 rash:  Apply a mild / moderate strength topical steroid and/or topical 
antibiotic. 
For adults with grade 2 rash:  Apply a moderate strength topical steroid and consider an oral 
antibiotic. 
For adults with ≥ grade 3 rash or a grade 2 rash considered to be intolerable:  Hold selumetinib.  
Apply moderate strength topical steroid and consider an oral antibiotic. If an infection is 
suspected, consider other broad-spectrum antibiotic cover.  Also consider referral to a 
dermatologist (and manage rash per recommendation).  If rash improves to grade 2 or less, 
restart selumetinib at reduced dose. 
 
For both adult and pediatric subjects, the following guidelines have been found to be useful:  
 
Acneiform rash:  
Experience with acneiform rash in the pediatric studies to date suggests that topical clindamycin 
gel or lotion applied BID, rather than steroids, is the most helpful for pustular rash (typically 
seen in the older child/adolescent). In severe cases, semisynthetic oral tetracyclines such as 
doxycycline or minocyline may also be useful for older children and adolescents, but should be 
avoided in children younger than 8 years old because of risk to tooth development.  
 
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.  
 


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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. 
 
Oral Care: 
 
Prevention, early diagnosis and management of stomatitis may reduce the need for dose 
interruption and / or reductions of the study medications due to severe stomatitis and so allow the 
patient to continue on the study drugs. It is strongly recommended that patients receive advice 
regarding daily oral health care regimes, both before and during treatment. 
 
Patients with a healthy mouth may use non-alcoholic mouthwash several times (4 to 6 times 
daily, or according to the instructions) daily, e.g. after each meal, during the study.  
Saline mouthwashes (Sodium chloride 0.9%) should be preferred in cases of stomatitis, and 
should be used at a different time to 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. 
 
Smoking should be strongly discouraged; patients should be offered help with smoking cessation 
if necessary in the form of nicotine replacement therapy or referral to smoking cessation 
services.  
 
A high alcohol intake should be discouraged and patients advised to avoid painful stimuli such as 
spicy foods, hot food and drink. 
 
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. 
Toothbrush should be replaced regularly at least every 3 months but patients with stomatitis 
should change their toothbrush every 4 - 6 weeks. 
 
• 
Use of soft toothbrush is recommended 
 
• 
Dental floss should be used once daily (caution in patients with coagulopathies including 
a low platelet count) 
 
In the event of sore mouth or stomatitis: 
 Consider treating stomatitis at an early stage (CTCAE grade 1) or as soon as the patient 
complains of a sore mouth.  
 Consider using oral topical analgesic anaesthesia with or without topical steroids, 


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antiviral and/or antifungal medications depending on the patient’s clinical condition and 
the local standard medical practice. 
 
 Elevated CPK:  To reduce possible consequences associated with CK elevation that may 
be arising from a muscular source, the management guideline described below should be 
followed: 
 
 Pneumocystis jiroveci pneumonia (PJP) prophylaxis 
The use of medication (i.e., Bactrim) for PJP prophylaxis in patients is recommended, but is at 
the investigator’s discretion. 
 Neurosurgical Procedures 
If a neurosurgical procedure is required for a reason other than tumor progression (i.e. the onset of 
hydrocephalus), these procedures should be documented, but will not constitute criteria for 
declaring the patient “off therapy”. Given the potential for the drug to affect wound healing, 
selumetinib should be held until the patient is clinically stable and has recovered from the acute 
effects of surgery.  
 
 Concomitant Therapy 
Other anti-cancer or experimental agents are not permitted.  
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s) or disease progression, treatment may 
continue for 26 courses (approximately two years) or until one of the Off Treatment Criteria found 


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in Section 5.6 applies.  
During the second year of treatment, procedures consistent with good clinical care will continue. 
Patients will be seen monthly for medical history, physical exam (including height, weight, vital 
signs, and performance status), neurologic exam, dates of drug administration, relevant 
laboratory evaluations and routine neuro-imaging assessments. Therapy-related events will be 
recorded per standard assessments, including adverse events, date of disease progression, date of 
last follow up, date patient goes off treatment and date off study. Please review the table in 
Section 10 of the protocol for the required assessments and intervals. All patients must 
discontinue treatment with selumetinib following the completion of 26 courses of treatment.  
5.6 
Duration of Follow Up 
Discontinuation of Treatment 
At the discontinuation of treatment, the “Off Treatment Date” is to be recorded in the CRF and is 
to be consistent with the reason given for going off treatment. The “Last Treatment Date” is 
defined as the last date that the patient received protocol based therapy. Date of “off treatment” 
must be the greatest of the date of last treatment, date of procedure, date of patient assessment, 
notification of patient/family decision, or decision made by the physician that resulted in the 
patient being taken off protocol treatment. The reason for discontinuation of treatment must be 
documented by the attending investigator in the medical record and recorded in the CRF. The 
“Off Treatment Date” and the “Last Treatment Date” should be the same for patients that 
complete all protocol defined treatment. 
Patients will be considered Off Treatment for the following reasons: 
 Development of unacceptable toxicity as outlined in Section 5.2.1 that does not resolve 
within 14 days. 
 Non-compliance with study guidelines 
 Progressive disease, as outlined in section 11.1 and 11.2 
 Development of a medical or psychiatric illness, that in the investigator's judgment 
renders the patient incapable of further therapy on this protocol 
 The patient, parent or legal guardian refuses further treatment on this protocol 
 Pregnancy 
 Completion of maximum number of courses of treatment with selumetinib 
 
Patients will be monitored every 6 months for 2 years after protocol treatment. Ongoing AE’s 
should be monitored as per section 7.4.3. Additionally, patients will be followed for initiation of 
subsequent therapy for NF2, selumetinib related adverse events (including cardiac toxicities), date 
of disease progression, date of last follow up, and date of death. 
 
Patients who are off protocol therapy must be followed until an Off Study Criterion is met.  
Ongoing AE’s should be monitored as per section 7.4.3.  


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5.7 
Criteria for Removal from Study 
The date and reason for the patient coming off study must be documented in the CRF. 
 Patient determined to be ineligible (Treatment with selumetinib was never started).  
 Patient determined to be ineligible (Treatment with selumetinib WAS started). 
These patients must be observed for 30 days following date deemed ineligible.  All AE’s must be 
recorded in that 30-day period. 
 Patient, parent, or guardian withdraws consent for continued participation. 
 Patient death while on study. The IRB, Sponsor, and FDA must be notified as per Section 
7 
 Patients removed from treatment for progressive disease (PD) be observed for 30 days 
following last dose of selumetinib. 
 Commencement of additional anti-cancer therapy 
 Completion of protocol defined follow up  
 
 
 


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6 
DOSING DELAYS/ DOSE MODIFICATION 
6.1 
Notification of Study Chair 
The study chair or co-chair must be notified of any dosage modifications, prior to the 
implementation of the dose modification 
 
6.2 
Hematologic and Non-Hematologic Adverse Events and Management 
 
 Table 7 
Event 
AE Grade or Observation 
Dose Modification 
Dermatology/Skin 
 
Grade 1 or 2
Maintain dose
Intolerable Grade 2; 
Grade 3 or 4 
Hold selumetinib until ≤ tolerable grade 2; 
reduce one dose level and resume 
treatment. Skin care guidelines are located 
in Section 5.4.4. 
Grade 4 
Patients with grade 4 rash (i.e. life 
threatening generalized exfoliative 
ulceration; erythemia multiforme/toxic 
epidermal necrolysis should be removed 
from study. Skin care guidelines are 
located in Section 5.4.4 
Diarrhea (if anti-diarrheal 
treatment is ineffective) 
 
Grade 1 or 2 
See algorithm and guidelines in Section 
5.4.3.  
Grade 3 or 4 
See algorithm and guidelines in Section 
5.4 
Hold selumetinib until </= tolerable grade 
2, on loperamide.  Reduce 1 dose level and 
resume treatment. 
Visual Disturbances - for 
any new or progressive 
vision problem(including 
but not limited to the 
following) 
 Blurred Vision, Flashing 
Lights, Floater, Photophobia 
 
Grade 1 or 2 
Hold selumetinib until Eye exam is 
completed; If the Ophthalmology exam is 
normal and the toxicity resolves within 
24hrs or an alternate cause for the vision 
problem is identified – restart selumetinib 
at the same dose level.  See algorithm in 
5.4.1 
Grade 3 or 4  
Hold selumetinib until Eye exam is 
completed; If alternate etiology for vision 
change is identified, contact study chair to 
discuss restarting of selumetinib.  See 
algorithm in 5.4.1 
Hematologic 
With the exception of 
Grade 1, 2, or 3 
Maintain dose 
Grade 3 thrombocytopenia 
Hold selumetinib until < grade 2, then 


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lymphopenia 
associated with bleeding 
reduce 1 dose level and resume treatment. 
Grade 4 
Hold selumetinib until < grade 2, then 
reduce 1 dose level and resume treatment. 
Liver Function 
 
Serum bilirubin, 
AST, ALT 
Grade 1 or 2 
Maintain dose 
Grade 3 
Hold selumetinib. If returns to levels 
meeting eligibility criteria within 7 days, 
then restart at the same dose. 
Grade 3 that does not return to 
meet eligibility criteria within 7 
days , or Grade 4 
Hold selumetinib until < grade 2, then 
reduce 1 dose level and resume treatment. 
Other non-hematological 
toxicity 
 
 
Grade 1 or 2 
Maintain dose 
Grade 2 of concern (e.g., 
pulmonary, neurotoxicity, or 
intolerable stomatitis) 
Grade 2 that persists for >7 days 
and is considered sufficiently 
medically significant or intolerable 
by patients as to warrant treatment 
interruption and /or dose 
modifying 
 
Hold selumetinib until < grade 2, then 
reduce 1 dose level and resume treatment. 
 
Grade 3 or 4  
Hold selumetinib until < grade 1, then 
reduce 1 dose level and resume treatment. 
 
 
 
 
 
 
 
 


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Elevated CPK:  Please see algorithm below 
 
 
Cardiac Function:  Please see algorithm below 
 


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 Criteria for continued treatment after toxicity 
The study chair or co-chair must be notified of any dosage modification prior to the 
implementation of the dose modification.  
Dose de-escalations to dose level -1 are permitted.  See Appendix D. 
 
All patients who require dose de-escalation from dose level -1 must be taken off treatment. 
7 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting. 
Adverse Events and Potential Risks for Selumetinib are listed below.  Investigators may also 
refer to the most current version of the Selumetinib IB for additional expected AE’s.  
Adverse events will be managed according to local practice.  
Expected Adverse Events  
Likely (≥20% of patients) 
Less Likely (<20% to 3%) 
Rare (<3%) 
 
Rashes (all) 
 
Rashes (acneiform) 
 
Diarrhea 
 
Nausea 
 
Vomiting 
 
Asthenic events 
 
Peripheral edema 
 
Dyspnoea 
 
CK increased
 
Dry skin 
 
Stomatitis 
 
Dry Mouth 
 
Facial edema 
 
Pyrexia 
 
Blurred vision 
 
Increased blood pressure 
 
ALT/AST increased 
 
Paronychia 
 
Hyperphosphatemia 
 
Hypoalbuminaemia 
 
Reduced LVEF 
 
Retinal vein occlusion 
 
Central 
serous 
retinopathy/ 
retinal 
pigment 
epithelial 
detachment 
 


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Physeal dysplasia 
A potential risk of effects on bone was identified from a nonclinical experiment. Based on this, 
pediatric studies of selumetinib should include bone growth assessment at regular intervals 
including clinical examination, growth chart monitoring and imaging (Section 10 for schedule). 
Children who show signs of physeal dysplasia at the time of selumetinib discontinuation should 
have a follow-up assessment after 30 days to evaluate the potential for reversibility. 
7.1 
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. 
 
 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. 


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7.2 
Definitions 
 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal laboratory 
finding, symptom, or disease temporally associated with the use of a drug) in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) need not be considered AEs and should not be recorded as 
an AE.  Disease progression should not be recorded as an AE, unless it is attributable by the 
investigator to the study therapy. 
 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the 
drug is the cause.   Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration of the 
following factors: temporal relationship of the AE to study drug exposure, known mechanism of 
action or side effect profile of study treatment, other recent or concomitant drug exposures, 
normal clinical course of the disease under investigation, and any other underlying or concurrent 
medical conditions.  Other factors to consider in considering drug as the cause of the AE: 
 Single occurrence of an uncommon event known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
 One or more occurrences of an event not commonly associated with drug exposure, 
but otherwise uncommon in the population (e.g., tendon rupture); often more than 
once occurrence from one or multiple studies would be needed before the sponsor 
could determine that there is reasonable possibility that the drug caused the event.   
 An aggregate analysis of specific events observed in a clinical trial that indicates the 
events occur more frequently in the drug treatment group than in a concurrent or 
historical control group 
 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not consistent with 
the applicable product information (e.g., Investigator’s Brochure (IB) for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product).  Unexpected also refers to AEs or SARs that are mentioned in the IB 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.   
 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or sponsor, it results 


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in any of the following outcomes: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
 Requires inpatient hospitalization (>24 hours) or prolongation of existing 
hospitalization;* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 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 the definition.  
For reporting purposes, also consider the occurrences of pregnancy as an event which 
must be reported as an important medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as administration of 
chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
7.3 
Documentation and Reporting of non-serious AEs or SARs 
 For non-serious AEs or SARs, documentation must begin from day 1 of study treatment 
and continue through the 30 day follow-up period after treatment is discontinued.   
 Adverse events grades 1 and 2 if the attribution is at least possibly related to selumetinib.  
Record all adverse events grades 3, 4 or result in death (Grade 5) (while on treatment or 
within 30 days of treatment), regardless of attribution on the case report forms. 
 Baseline abnormalities:  Any baseline (pretreatment) abnormalities observed from the 
time treatment consent is obtained to the start of trial therapy should be recorded on the 
case report form. 
 
Collected information should be recorded in the Case Report Forms (CRF) for that patient.  
Please include a description of the event, its severity or toxicity grade, onset and resolved dates 
(if applicable), and the relationship to the study drug.    Documentation should occur at least 
monthly.  
7.4 
SAEs or Serious SARs  
 Timing  
After informed consent but prior to initiation of study medications, only SAEs caused by a 
protocol-mandated intervention will be collected.  
 


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 Documentation and Sponsor Notification 
For any other experience or condition that meets the definition of an SAE or a serious SAR, 
recording of the event must begin from day 1 of study treatment and continue through the 30 day 
follow-up period after treatment is discontinued.  All SAEs or Serious SAR (including deaths) 
regardless of attribution will be recorded in the CRF.  The Sponsor must be notified of any SAE 
or Serious SAR within 24 hours of learning of the event.  These events (SAEs or Serious SARs) 
must also be documented within the CRF for that participant within 2 business days of 
notification of the Sponsor-Investigator/Study Chair or designee. 
 
 Documentation and Assessment 
Once an AE is detected with a possible causal relationship to selumetinib, it should be followed 
until its resolution to baseline or until it is judged to be permanent and stable.  Assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity, 
changes to the suspected relationship to the study treatment, the interventions required to treat it, 
and the outcome. 
 
 
Progression of malignancy if documented by use of appropriate method (as in section 11.1) 
should not be reported as a serious adverse event unless results in death.    
  
 
Deaths (while on treatment or within 30 days of treatment), regardless of attribution will  be 
recorded on the case report forms and reported as an SAE. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (including cysts and polyps)-Other (Progressive Disease)” under  the system 
organ class (SOC) of the same name.  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.   
 
7.5 
Other Malignancy 
 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) is to be reported as an SAE. A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
Three options are available to describe the event:  
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia)  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
 A Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy) does not need to be reported.   
 


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7.6 
Reporting  
 IRB Reporting Requirements: 
CCHMC IRB Reporting Requirements:  Unexpected and related adverse events will be reported 
to the CCHMC IRB per institutional policies.  The sponsor-investigator will report   any 
unexpected life threatening event or death (grade 4 or 5) adverse event to the CCHMC IRB 
within 7 calendar days after the sponsor is made aware of the event.  
Reporting of Protocol Violations/ Deviations and Unanticipated Problems:  Any protocol 
violations, deviations, or unanticipated problems should be documented and reported according 
to CCHMC policy. 
 FDA Expedited Reporting requirements for studies conducted under an IND: 
If the Sponsor- Investigator deems that an event is both a serious SAR AND unexpected, the 
Sponsor-Investigator is responsible for submitting the event to the IND (FDA) within 15 
calendar days.  If the Sponsor-Investigator is notified of an unexpected fatal or life-threatening 
SAR, the FDA is to be notified as soon as possible but in no case later than 7 calendar days after 
the Sponsor-Investigator’s initial receipt of the information.  A MedWatch Form 3500A will be 
completed and submitted to the IND (FDA) for expedited reporting requirements as outlined in 
21 CFR 312.32.  The MedWatch 3500a form can be accessed at 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.   
 Reporting to Astra-Zeneca: 
The IND Sponsor or designee will report all adverse events or adverse drug reactions subject to 
expedited reporting to Astrazeneca at the same time the report is submitted to the FDA.  Astra-
Zeneca will also be notified of unexpected, suspected serious adverse event to within 15 days.        
 
8 
AGENT INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7 
Selumetinib (AZD6244)  
 Agent Information 
 
Chemical Name: 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5- 
carboxylic acid (2-hydroxy-ethoxy)-amide hydrogen sulfate\ 
Other Names: ARRY-142886; AR00142866; AR-142886-01); Selumetinib Classification: 
Mitogen-activated protein kinase (MEK) inhibitor 
CAS Registry Number: 943332-08-9 
Molecular Formula: C17H15BrClFN4O3 · H2SO4 M.W.:555.7 
Mechanism of Action: The RAS/RAF/MEK/ERK pathway is an important mediator of many 
cellular processes including proliferation, survival, differentiation, apoptosis, motility, and 
metabolism. This pathway is often aberrantly activated in human tumors due to the 
overexpression of activated K-RAS, mutant b-Raf, or other growth factor receptors. Selumetinib 


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is a selective mitogen-activated protein kinase (MEK) inhibitor. By inhibiting MEK, selumetinib 
inhibits ERK phosphorylation. Thus, selumetinib may inhibit oncogenic growth signaling in 
tumor cells by targeting the RAS/RAF/MEK/ERK pathway. 
Formulation: Selumetinib hydrogen sulfate capsules contain 10 and 25 mg of selumetinib 
(expressed as free base) supplied as a series of size 4, plain, hydroxypropylmethylcellulose 
(HPMC) capsules in white high density polyethylene (HDPE) containers with foil-lined, 
induction-sealed, child-resistant closures. Each bottle contains 60 capsules.  May be replaced 
with most current formulations, as determined by Astra-Zeneca. 
Each capsule contains a dispersion of selumetinib hydrogen sulfate in d-α-tocopheryl 
polyethylene glycol 1000 succinate (TPGS; a water soluble form of vitamin E). 
Storage: Store the selumetinib hydrogen sulfate capsules at room temperature (20°C-25°C). 
Brief excursions are permitted between 15°C and 30°C. The temperature of shipments of 10mg 
capsules must also be monitored to ensure the temperature is within the required limits (below 
30C). Data is available to support the 10mg capsule being stored at 30C or less and that 
performance could be reduced if stored at temperatures higher than 30C. 
25mg capsules are stored at room temperature; however temperature monitoring is not necessary 
for 25mg capsules. 
Stability: Stability studies are ongoing. 
Availability: Selumetinib hydrogen sulfate capsules are provided to CCHMC by Astra-Zeneca 
Route of Administration: Oral. Take selumetinib on an empty stomach either 1 hour before or 2 
hours after meals and should be taken with water only. 
Potential Drug Interactions: CYP3A4 is the predominant isoform responsible for selumetinib 
oxidative metabolism with CYP2C19, CYP1A2, CYP2C9, CYP2E1 and CYP3A5 involved to a 
lesser extent. In vitro studies indicate that selumetinib also undergoes direct Phase 2 metabolic 
reactions to form glucuronide conjugates principally involving the enzymes UGT1A1 and 
UGT1A3. Selumetinib is primarily metabolized by CYP1A2 to N-desmethyl AZD6244 which is 
3-5 fold more pharmacologically active than Selumetinib but circulates at ~7% of the parent. 
Based on clinical trials, concomitant medications that are strong inhibitors/inducers of CYP3A4 
or fluconazole (strong CYP2C19 and moderate CYP3A4 inhibitor) should be avoided, if 
possible. A list of medications with the potential for interaction with selumetinib is available in 
APPENDIX C.  
In vitro, selumetinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, CYP3A4 and CYP2E1. In vitro, selumetinib is not an inducer of CYP3A4, 
CYP1A2 and CYP2B6.  
 
In vitro studies suggest that selumetinib does not inhibit the breast cancer resistance protein 
(BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, MATE1 and MATE2K at 
the recommended paediatric dose. A clinically relevant effect on the pharmacokinetics of 
concomitantly administered substrates of OAT3 cannot be excluded.  


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Based on in vitro studies, selumetinib is a substrate for BCRP and P-gp transporters but is 
unlikely to result in clinically relevant drug interactions at the recommended paediatric dose.  
 
Vitamin E intake 
 
Selumetinib capsules contain vitamin E in the form of TPGS, a water-soluble form of 
vitamin E, which acts as a formulation excipient. The maximum daily dose of vitamin E that a 
study subject may receive from selumetinib is approximately 270 mg/day. High doses 
of vitamin E have been reported to potentiate the anticoagulant activity of coumarins such as 
warfarin. Therefore, selumetinib should be administered with caution in patients who 
are also receiving concomitant coumarin anticoagulant medications. These patients should 
have their international normalized ratio [INR] monitored closely/ anticoagulant assessments 
conducted more frequently, and the dose of the anticoagulant should be adjusted accordingly. 
 
In addition, the concomitant intake of supplemental vitamin E should be avoided in all subjects 
receiving selumetinib/placebo. 
 
 Agent Ordering and Agent Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received using the NCI Drug Accountability 
Record Form (DARF).   
 
 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
9.1 
Correlative Studies 
 Required: Assessment for MEK activation in pre-trial tumor material  
10 unstained slides of formalin fixed paraffin embedded tumor tissue will be collected from all 
patients who have pre-trial tumor material available.  No biopsy will be performed for the purpose 
of this correlative study.  This tumor tissue will be used to assess phopho-ERK (Western blot or 
ELISA), Ki-67 markers, blood vessel density, and MAPK activation markers (by whole-exome 
and RNA sequencing).  With participant consent, tissue will be stored for future research. 
 
Samples will be delivered to the Ratner Lab at Cincinnati Children’s Hospital Medical Center.  
 
Ratner Laboratory T7  
240 Albert Sabin Way  
Cincinnati, OH 45229  
Phone: 513-636-3502 
 
 NF-QOL studies  
 
NF-QOL will be mandatory for all patients eligible to complete the questionnaire. See Appendix 
G.  For patients under the age of 16 years of age, the patient will complete the NFTI-QOL in 


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collaboration with the parent proxy. Patients 16 and older will complete the questionnaire 
independently. 
 
 Special Studies - Neuroimaging Studies  
Patients will have MRI brain and spine with and without contrast performed prior to initiation of 
therapy, after courses 3, 6, 9, 12, 16, 20, 26 until progression or end of therapy. MRI spine should 
be performed at the same time when obtaining MRI Brain when clinically indicated. 
 
Stratum 1 patients: Volumetric measurements of VS: Traditionally, VSs have been measured 
using either 1-dimensional measurements (in the long axis) or 2-dimensional measurements 
(calculated by taking the square root of the product of the short axis-long axis measured to the 
plane perpendicular to the face of the temporal bone). However, the irregular shape of VSs, as 
determined by the unique anatomy of the IAC and cerebellopontine angle, makes it difficult for 
linear measurements to accurately and fully represent growth for the entire tumor. As a result, 
VS growth may be underestimated by linear measurement criteria. Semi-automated volumetric 
analysis overcomes these limitations since it uses data from 3 dimensions. The coefficient of 
variation (COV) ranges from 0.6% to 6.8% and is generally below 5% for lesions greater than 1 
cc.12 Volumetric analysis not only better reflects tumor size, but also allows accurate detection of 
smaller changes in tumor size compared to standard solid tumor response criteria (e.g., RECIST 
criteria). This ability to detect small changes in size is critical for tumors with slow growth rates 
such as VS, and, when used in clinical trials, helps limit exposure to potentially toxic and/or 
inactive agents. Trials for NF- related tumors, such as plexiform neurofibromas, are now 
routinely using volumetric changes as the primary endpoint, typically choosing a 20% increase 
for progression and 20% decrease for radiographic response.45 
 
 


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10 STUDY CALENDAR  
 
 
Pre-
therapy 
Courses 
1-12H 
Courses  
13-26H 
Completion/ 
Discontinuation 
 Of Treatment 
PHYSICAL ASSESSMENTS 
 
 
 
 
Medical history  
X 
XA 
 X 
X 
Physical exam /height/weight 
X 
XA 
X 
X 
Vital signs 
X 
XA 
 X 
X 
Performance status 
X 
XA 
 X 
X 
Neurologic exam  
X 
XA 
 X 
X 
Smoking Status 
X 
 
 
 
Hearing evaluation (stratum 1)# 
X 
XC 
XC 
 
LABORATORY EVALUATIONS 
 
 
 
 
CBC - WBC, HgB, Hct, Platelets, ANC, ALC B 
X 
XA 
  XA 
X 
PT and INR for those patients on warfain  
 
X 
X 
 
Serum Chemistry - Sodium, Potassium, 
Bicarbonate, Chloride, Calcium, BUN, 
Creatinine, Glucose, Phosphorous, Magnesium, 
Albumin, Total ProteinB
X 
XA 
  XA 
X 
SGPT (ALT), SGOT(AST), Alkaline 
phosphatase, Total BilirubinB 
X 
XA 
  XA 
X 
CPK ** 
X 
XA 
  XA 
 
Serum or urine pregnancy test (for females of 
childbearing potential)
X 
XA 
  XA 
 
Echocardiogram (ECHO) 
X 
XC 
XC 
 
12-lead EKG  
X 
 
 
 
Ophthalmology evaluation 
X D 
X D 
X D 
X
 
Pulse Oximetry 
X 
 
 
 
Chest X Ray 
XE 
 
 
 
Growth plate assessment 
X 
XC 
XC 
 
IMAGING ASSESSMENTS 
 
 
 
 
Brain MRI  
X 
XC 
XC 
X 
Spine MRI  
X 
XC, F 
XC, F 
X F 
CORRELATIVE STUDIES 
 
 
 
 
NF1-QOL 
X 
Every 3 
courses 
Every 4  
courses 
 
Pre-trial tumor materials (if available) 
X 
 
 
 


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Pre-
therapy 
Courses 
1-12H 
Courses  
13-26H 
Completion/ 
Discontinuation 
 Of Treatment 
A. To be done prior to each course.  See Section 5.3.  Height does not need to be recorded for patients >18 years of age after 
initial measurement.  Childbearing potential are those female patients who have reached menarche. 
# - Audiology will include measurement of pure tone thresholds and determination of word recognition scores 
B. To be done more frequently throughout the duration of treatment if required to monitor toxicities. 
C. To be done prior to initiation of therapy, after courses 3, 6, 9, 12, 16, 20, 26 until progression or end of therapy.    The 
assessment is a tibial x-ray (AP and lateral views) of the right knee.  If abnormalities are detected on routine X-rays, MRI 
scan of both knees should be performed. Growth plate assessments should be done for patients under the age of 18 only, 
unless growth plate closure is documented.   
D. Baseline and following any visual disturbance during treatment.  See section 5.2 
E. To be done if pulse oximetry is < 95% or if clinically indicated during treatment. See section 5.2 
F. MRI Spine should be done at the same time points as the standard MRI brain, if clinically indicated. 
G. Formalin fixed paraffin embedded tumor tissue will be collected from all patients who have pre-trial tumor material available 
H. All evaluations to be completed within 7 days of anticipated start date of the next course. 
** Please note that Grade 3 asymptomatic elevations of CPK do not require a dose reduction 
 
11 MEASUREMENT OF EFFECT 
11.1 Hearing Response Criteria (Stratum 1 only) 
 
Hearing is monitored in clinical practice by measuring pure tone thresholds, word recognition 
scores, brainstem auditory evoked responses (BAERs), and otoacoustic emissions (OAEs). 
Pure tone thresholds measure the minimum sound level that an ear can perceive. Thresholds are 
typically measured at octaves and half-octaves from 250 Hz to 8000 Hz. An average of 
thresholds at 500, 1000, 2000 and 4000 Hz (PTA) is recommended as a standard outcome 
measure by the American Academy of Otolaryngology, Head and Neck Surgery (AAO-HNS) for 
reporting in cases of VS. 
Word recognition scores measure the ability to recognize (as opposed to detect) auditory 
information. Patients are presented a list of 50 words at a fully audible level and the percentage 
identified correctly is the score. This study will use full 50-item monosyllable lists and 
standardized recordings. 
Because tumors associated with NF2 have benign histology, overall survival is not an 
appropriate endpoint for clinical trials in this condition. Instead, the goal of treatment is to 
minimize neurologic morbidity (including hearing loss) and to defer surgical treatments that may 
cause iatrogenic dysfunction. For this reason, hearing function is the most important way to 
monitor the activity of new agents designed to treat VSs. 
Word recognition is the measure most closely associated with daily hearing function since it 
measures the ability to comprehend speech.  If word recognition quality improves, the patient 
can converse successfully, even if a hearing aid is needed to make sounds sufficiently loud. 
Statistical methods have been developed to determine significant changes in this measure. Word 
recognition scores represent summary scores from a collection of binary endpoints 
(correct/incorrect responses) and thus follow a binomial distribution (e.g., non- Gaussian 


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distribution). Although it is tempting to use a set change in word recognition score (e.g., fifteen 
percentage points) as a clinical response, this approach is inappropriate given the binomial model 
of variance. A more rigorous approach involves the use of the 95% (p=0.05) critical difference 
table44. The 95% critical differences for 50-word lists as proposed here have been used in 
previous studies45 and in clinical trials evaluating the effect of drug treatment on hearing. 
 Hearing Response (HR): Improvement in word recognition score above the 95% 
critical difference, taking as reference the baseline word recognition score 
(APPENDIX E) 
 Stable Hearing (SH): Persistence of word recognition score within the 95% critical 
difference, taking as reference the baseline word recognition score (APPENDIX E) 
 Progressive Hearing Loss (PHL): Decline in word recognition score below the 95% 
critical difference, taking as reference the baseline word recognition score 
(APPENDIX E) 
Duration of hearing response: The duration of hearing response (HR) is measured from 
the time that measurement criteria are met for HR until the first date that the word 
recognition score decreases beneath the upper limit of the 95% critical difference of the 
baseline word recognition score. 
Duration of stable hearing: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the word recognition score 
recorded at baseline 
11.2 Radiographic Tumor Response Criteria  
 Stratum 1 
 
Stratum 1: Response and progression for vestibular schwannomas will be evaluated in this study 
using the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria 
proposed by Widemann and colleagues for neurofibromatosis-associated lesions..46  Response 
and progression for stratum 1 will not be evaluated using the Response Evaluation Criteria in 
Solid Tumors (RECIST) or by MacDonald Criteria, since they may underestimate progression in 
these irregularly shaped tumors. However, linear measurements utilizing RECIST will be 
collected as part of the trial for comparison with volumetric measurements.  Linear 
measurements utilizing RECIST will be used for non-target lesions on stratum 1.  
Target lesions. Investigators should identify a single target lesion in all subjects. The target 
lesion in this study is the progressive VS (i.e. the lesion that is enlarging or is associated with 
hearing loss) that led to registration in the protocol. In cases where subjects have a single ear 
with hearing, the target lesion should be the enlarging VS ipsilateral to the hearing ear. In cases 
where subjects have hearing in both ears, the target lesion should be the tumor associated with 
word recognition score < 85% and is growing the fastest or is causing the most rapid hearing 
loss. In cases where both VSs are associated with word recognition < 85% and progressing 
equally rapidly, the target lesion should be the larger of the two tumors on imaging. Target 
lesions should be identified at baseline and measured using volumetric analysis of the baseline 
MRI scan. The baseline volumetric MRI scan will be used as reference for comparison of all 


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future MRI scans to characterize the objective tumor response. 
Non-target lesions. Non-target lesions in this study include VSs contralateral to the target lesion 
(if present).  
Volumetric analysis of MRI scans should be performed on sequences with fine cuts through the 
internal auditory canal  
NOTE: Histologic confirmation of tumor type is not required. 
11.2.1.1 Evaluation of Target Lesion 
Target lesions defined in section 11.2.1 (REiNS criteria) 
Radiographic Response (RR) 
At least a 20% decrease in the volume of the target lesions, taking as reference the 
baseline volume.  
Progressive Disease (PD) 
At least a 20% increase in the volume of the target lesion, taking as reference the 
lower volume during treatment  
Stable Disease (SD) 
Does not meet criteria for radiographic response or for progressive disease. 
11.2.1.2 Evaluation of Non Target Lesions 
Non-Target lesions defined in section 11.2.1 (RECIST criteria) 
 
 Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level 
  
 Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above the normal limits 
  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions  
 
Duration of radiographic response: The duration of radiographic response is measured from 
the time measurement criteria are met for RR until the first date that progressive disease is 
objectively documented (taking as reference for progressive disease the lowest tumor volume 
during treatment). 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the measurements recorded at baseline. 
 Stratum 2 Tumor Response Criteria: 
Stratum 2 Response and progression for non-VS tumor by MacDonald Criteria. 


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11.2.2.1 Complete Response 
Complete disappearance on MR of all enhancing tumor and mass effect, on a stable or 
decreasing dose of corticosteroids (or receiving only adrenal replacement doses), 
accompanied by a stable or improving neurologic examination, and maintained for at 
least 8 weeks.  
 
11.2.2.2 Partial Response 
Partial Response (PR): Greater than or equal to 50% reduction in tumor size by bi-
dimensional measurement, as compared with the baseline measurements, on a stable or 
decreasing dose of corticosteroids, accompanied by a stable or improving neurologic 
examination, and maintained for at least 8 weeks. 
 
11.2.2.3 Stable Disease 
Stable Disease (SD): Neurologic exam is at least stable and maintenance corticosteroid 
dose not increased, and MR/CT imaging meets neither the criteria for PR nor the criteria 
for Progressive Disease. If this category is to be reported as of possible clinical benefit, 
Stable Disease status must be maintained for 6 courses. 
11.2.2.4 Progressive Disease 
Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic 
status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or 
corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater 
than 25% increase in the bi-dimensional measurement, taking as a reference the smallest 
disease measurement recorded since the start of protocol therapy, OR the appearance of a 
new lesion, OR increasing doses of corticosteroids required to maintain stable 
neurological status or imaging AND/OR unequivocal radiological progression of existing 
non-target lesions. 
 
12 RECORDS, REPORTING, AND DATA AND SAFETY MONITORING  
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
the applicable regulatory requirements.   
12.1  Regulatory and Compliance Monitoring 
 
Monitoring of clinical studies is a continuous, ongoing review of the conduct of the trial to 
ensure that it is conducted, documented, and reported in accordance with the IRB-approved 
protocol, Title 21 CFR, the International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines, and applicable regulatory requirements of the sponsor, CCHMC. 
  
Monitoring will include review of central elements defined as: 
 Data related to primary study endpoints; 
 Appropriateness of consent documentation; 
 Protocol eligibility; 
 Protocol compliance; 
 Timeliness of data entry, including the reporting of adverse events (AE/SAR) and serious 


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advent events (SAESSAR) as events are reported; 
 Appropriateness of treatment delivery; 
 Modifications in dose or timing; 
 Investigational Drug Service (IDS) compliance (drug accountability); 
 Documentation of response assessment measures; 
 Essential regulatory documentation; and 
 Site Investigator supervision of overall conduct of the study. 
  
Specifically, source document verification of eligibility for all enrolled study participants 
including verification of appropriate documentation of consent will be performed. 100% Source 
Document Verification (SDV) of case records will be conducted for the first 2 participants 
enrolled on the study, as well as, 4 - 5 randomly selected participants thereafter, by comparing 
data in the source documents to data entered in the Case Report Forms (CRF). In addition, 100% 
SDV may be performed for pivotal clinical parameters related to primary study endpoints. 
  
Regulatory and compliance monitoring will be a combination of on-site visits (scheduled to 
occur at least annually or more frequently based on registration, the degree of risk or severity of 
monitoring findings, and other study management issues) along with off-site continuous (remote) 
efforts. 
 
12.2 Responsibility for Data Submission  
All participant data will be recorded on case report forms by CCHMC study personnel. 
 
12.3 Data and Safety Monitoring Plan 
This study will be reviewed in accordance with the CCHMC Cancer Center Data and Safety 
Monitoring Plan for Phase 1, Pilot, and Phase 2 Studies. In brief, the role of the CCHMC Cancer 
Center Data and Safety Monitoring Board (DSMB) is to protect the interests of participants and 
the scientific integrity of clinical trials. The DSMB consists of individuals with recognized 
expertise in oncology, radiation therapy, conduct of clinical trials, and biostatistics. The DSMB 
meets a minimum of twice per year.   Approximately 4 weeks before each meeting of the DSMB, 
the study chair and/or designee will be responsible for preparing study reports for review by the 
DSMB. The DSMB will provide recommendations to change the study or to continue the study 
unchanged.  
 
12.4 Oversight by the Sponsor Investigator/Study Chair  
The Sponsor Investigator/Study Chair along with the CCHMC coordinating center will review 
trial progress regularly.  
 
This ongoing review by the Sponsor Investigator/Study Chair or designee will include 
verification of trial eligibility and the appropriateness of documentation of the informed consent 
process for all patients to confirm registration into the study prior to the first dose of 
investigational agent.  In the event that the study chair is not available, an appointed designee 
will review eligibility to confirm registration.   
 


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In addition, the Sponsor Investigator/Study Chair and/or designee will review participant trial 
progress in real-time including participant evaluability, dose modifying toxicities, and serious 
adverse events.   
 
12.5 Privacy and Confidentiality 
No information provided from individual patient records may be discussed with anyone other 
than those individuals involved in the research study or clinical care. Data may not be released in 
any form except as stated in the agreement or regulations.  Each participant enrolled will, from 
that point forward, be identified by a unique identifier (study number). This study number will 
also be used for any research specimens collected and shipped to analysts outside CCHMC (if 
applicable).  
 
All research records generated will be stored in a locked office area, only accessible to study 
personnel, and/or on a secure CCHMC network drive and/or the coordinating centers clinical 
trial management system (OnCore). Clinical information will be accessed, according to HIPAA 
requirements, by study personnel to complete study documents, as needed.  
 
12.6 Record Retention 
Study records will be maintained per applicable regulatory requirements and institutional policies 
and procedures.   
 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 Evaluability  
 Evaluability for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with selumetinib. 
 Evaluability for Response  
All patients who receive study drug will be considered evaluable for response. 
Each participant should be assigned one of the following categories: 1) hearing response, 2) 
stable hearing, 3) progressive hearing loss, 4) progressive disease 5) tumor response 6) early 
death from NF2-related condition, 7) early death from toxicity, 8) early death because of other 
cause. 
13.2 Study Design/Endpoints 
 
The primary endpoint for the Stratum 1 is hearing response at 24 weeks, defined as an 
improvement in word recognition score above the 95% critical difference, taking as reference the 
baseline word recognition score (Appendix E). This primary objective of the efficacy of 
selumetinib will be addressed according to a Simon two-stage design.47 The first stage will 
consist of 9 subjects. If 0 of the 9 subjects have an efficacious response the study will terminate 
at the end of the first stage and the drug will be deemed ineffective. If 1 or more subjects have an 


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efficacious response, 8 additional subjects will be enrolled for the second stage. If both stages are 
completed and there are 3 or more efficacious responses then the drug will be considered 
successful, in the case of two or fewer desired responses the drug will be deemed ineffective.  
The primary endpoint for the Stratum 2 is to estimate the sustained objective response rate 
(CR+PR). Stratum 2’s primary objective of the efficacy of selumetinib will be also addressed 
according to a Simon two-stage design.47 The first stage will consist of 9 subjects. If 0 of the 9 
subjects have an efficacious response the study will terminate at the end of the first stage and the 
drug will be deemed ineffective. If 1 or more subjects have an efficacious response, 8 additional 
subjects will be enrolled for the second stage. If both stages are completed and there are 3 or 
more efficacious responses then the drug will be considered successful, in the case of two or 
fewer desired responses the drug will be deemed ineffective.  
 
Using the described design, if the true probability of an efficacy is 0.05, then the probability of 
terminating at the end of the first stage (9 subjects) is 0.63. The total probability of concluding 
the drug is effective is 0.05. Under this low probability of efficacy the expected sample size is 12 
subjects. If the true probability of an efficacy is 0.25, then the probability of terminating at the 
end of the first stage (9 subjects) is 0.075. Under this alternative probability of efficacy the 
power to conclude the drug is effective is 0.81.  We anticipate that this trial will complete accrual 
in two years. 
 
Simon Two-Stage Design  
 
Simon47 proposed a two-stage design primarily for use in phase 2 clinical trials where a single 
treatment arm is compared to a historical control. The stated objective of the design is to 
minimize the expected number of patients treated if the null hypothesis of no treatment effect is 
in true. Under this framework a design is conducted in two stages as follows. The total number 
of subjects that under consideration, N, is equal to the sum of the sample sizes from each stage, 
n1 and n2, respectively. After the first n1 subjects (the first stage) a criteria is set so that if fewer 
than this pre-specified criteria exhibit a response to treatment the trial is terminated and the 
treatment is deemed ineffective; otherwise, the final n2 subjects are enrolled. After the second 
stage a different pre-specified criteria is used such that if fewer than this value exhibit a response 
the treatment is deemed ineffective; if a greater than or equal number of patients exhibit a 
response to treatment the null hypothesis is rejected and the treatment is declared effective. The 
expected sample size = n1 * (the probability of termination after the first stage under the null 
hypothesis) + n2. The selection of the overall sample size, the sample sizes of each stage and the 
two pre-specified rejection/acceptance criteria are selected such that the expected sample size is 
minimized, a minimum power is obtained (usually around 0.8 or 0.90) and a desired level of 
significance (usual α ≤ 0.05) is satisfied. This is considered to be an ethical solution to phase 2 
trial design since it minimized the number of patients administered an ineffective treatment. Lee 
and Feng (2005) reviewed 126 phase II trials where the design was reported and found that 25% 
percent used a Simon two-stage design. 
 
 


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14 REFERENCES 
 
1. 
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Fraenzer J-T, Pan H, Minimo L, et al. Overexpression of the NF2 gene inhibits 
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in merlin-deficient human schwannomas. Glia. 2012;60(11):1721–1733.  
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gene, is an inhibitor of the p21-activated kinase, Pak1. Mol. Cell. 2003;12(4):841–849.  
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Johnson MD, O'Connell M, Vito F, Bakos RS. Increased STAT-3 and synchronous 
activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR 
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Mawrin C, Sasse T, Kirches E, et al. Different activation of mitogen-activated protein 
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Clin. Cancer Res. 2005;11(11):4074–4082.  
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Hanemann CO. Magic but treatable? Tumours due to loss of merlin. Brain. 2008;131(Pt 
3):606–615.  
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Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and 
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Zenteca A. AZD6244 Investigator's Brochure. 2009.  
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Huynh H, Soo KC, Chow PKH, Tran E. Targeted inhibition of the extracellular signal-
regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of 
hepatocellular carcinoma. Mol. Cancer Ther. 2007;6(1):138–146.  
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Doyle M, Yet T, Suzy B. Validation and use of a biomarker for clinical development of 
the MEK1/2 inhibitor ARRY-142886 (AZD6244). Journal of Clinical Oncology : official 
journal of the American Society of Clinical Oncology. 2005;23(16 suppl):210s.  
33. 
Adjei AA, Cohen RB, Franklin W, 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. Journal of Clinical 
Oncology : official journal of the American Society of Clinical Oncology. 
2008;26(13):2139–2146.  
34. 
Hayes DN, Lucas AS, Tanvetyanon T, et al. Phase II efficacy and pharmacogenomic 
study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary 
thyroid carcinoma with or without follicular elements. Clin. Cancer Res. 
2012;18(7):2056–2065.  
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advanced thyroid cancer. N. Engl. J. Med. 2013;368(7):623–632.  
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Patel SP, Lazar AJ, Papadopoulos NE, et al. Clinical responses to selumetinib (AZD6244; 
ARRY-142886)-based combination therapy stratified by gene mutations in patients with 
metastatic melanoma. Cancer. 2013;119(4):799–805.  
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Jänne PA, Shaw AT, Pereira JR, 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.  
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Bendell JC, Rodon J, Burris HA, et al. Phase I, dose-escalation study of BKM120, an oral 
pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Journal of Clinical 
Oncology : official journal of the American Society of Clinical Oncology. 
2012;30(3):282–290.  
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Leijen S, Middleton MR, Tresca P, et al. Phase I dose-escalation study of the safety, 
pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 
(CH4987655) in patients with advanced solid tumors. Clin. Cancer Res. 
2012;18(17):4794–4805.  
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Martinez-Garcia M, Banerji U, Albanell J, et al. First-in-human, phase I dose-escalation 
study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-
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Ammoun S, Ristic N, Matthies C, Hilton DA, Hanemann CO. Targeting ERK1/2 
activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor 
AZD6244. Neurobiol. Dis. 2010;37(1):141–146.  
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Ammoun S, Schmid MC, Triner J, Manley P, Hanemann CO. Nilotinib alone or in 
combination with selumetinib is a drug candidate for neurofibromatosis type 2. Neuro-
Oncology. 2011;13(7):759–766.  
 44.     Thornton AR, Raffin MJ. Speech-discrimination scores modeled as a binomial variable. 
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 45.    Halpin C, Rauch SD. Using audiometric thresholds and word recognition in a treatment 
study. Otol Neurotol 2006;27(1):110-116. 
46.     Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D, et al. Recommendations for  
imaging tumor response in neurofibromatosis clinical trials. Neurology. 2013 Nov 
19;81(21 Suppl 1):S33-40. 
 
47.     Simon R. Optimal two-stage designs for phase II clinical trials.  Controlled Clinical Trials  
1989; 10:1-10). 
  
 
 


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APPENDIX A 
 
Performance Scales 
 
MODIFIED LANSKY SCORE (Score as 0 - 100) 
A.  Normal Range 
100 = Fully active 
90 = Minor restrictions in physically strenuous play 
80 = Restricted in strenuous play, tires more easily, otherwise active 
 
B.  Mild to moderate restriction 
70 = Both greater restrictions of and less time spent in active play 
60 = Ambulatory up to 50% of time, limited active play with 
assistance/supervision 
50 = Considerable assistance required for any active play; full able to 
engage in quiet play 
 
C.  Moderate to severe restriction 
40 = Able to initiate quiet activities 
30 = Needs considerable assistance for quiet activity 
20 = Limited to very passive activity initiated by others e.g. TV) 
10 = Completely disabled, not even passive play 
  0 = Unresponsive, coma 
 
KARNOFSKY SCALE 
100 = Normal; no complaints 
90 = Able to carry on normal activities; minor signs or symptoms of disease 
80 = Normal activity with effort 
70 = Cares for self.  Unable to carry on normal activity or to do active work 
60 = Requires occasional assistance but able to care for most of his/her 
needs 
50 = Requires considerable assistance and frequent medical care 
40 = Disabled; requires special care and assistance 
30 = Severely disabled; hospitalization indicated though death not imminent 
20 = Very sick.  Hospitalization necessary.  Active support treatment 
necessary. 
10 = Moribund 
  0 = Dead 
 
 
 


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APPENDIX B 
 
Medications that may cause QTc Prolongation 
 
The following table presents a list of drugs that may prolong the QTc.  Patients on these 
medications are excluded from the study.   
 
 
Compound 
 
Compound Half Life 
Possible 
Washout 
Period - 
Hours 
Possible 
Washout 
Period - 
Days 
Alfuzocin
~10 hours
7
Amantadine
17 +/- 4 hours (10-25)
4
Amiodarone 
(cordarone)
58 days (15-142) 
36 days (active metabolite)
 
180 
Amitriptyline*
> 24 hours, wide interpatient variability
Arsenic trioxide
Not characterized
Azithromycin
40 hours
Bepridil
42 hr (26-64)
10
Chloral hydrate 
Readily converted to Trichloroethanol (active 
metabolite T1/2=7-10 hour)
48 
 
Chloroquine
Prolonged (days to weeks)
Chlorpromazine
30 +/- 7 hours
7
Cisapride
6 – 12 hour, up to 20 hour
60
Clarithromycin 
 
Non linear PK3-4 hr (250mg Q12) 
5-7 hr (500mg Q12)
36 
 
Cloroquine
6 to 60 days; mean 20 days
Desipramine*
> 24 hours, wide interpatient variability
Disopyramide
6.7 hr (4-10)
36
Dofetilide
10 hr
48
Dolesetron
8.1 hr
Domperidone
7-8 hr
48
Doxepin*
> 24 hours, wide interpatient variability
Droperidol
2.2 hours
10
Erythromycin
* Each salt form has different Half life*
Felbamate
20-23 hr
5
Flecainide
20 hr (12-27)
5
Foscarnet  
87.5+/-41.8 hours 
*distribution and release from bone*
 
20 
Fosphenytoin
12-29 hr
6
Gatifloxacin
7-14 hr
48
Gemifloxacin
7 hours
48
Grepafloxacin
16 hr
3
Halofantrine
6-10 days ( variable among individual)
45
Haloperidol
18 +/-5 hr
5
Ibutilide
6 hours (2-12) * variable among subject*
36
Imipramine*
> 24 hours, wide interpatient variability
Indapamide
14 hours (biphasic elimination)
3
Isradipine
8 hours ( multiple metabolites)
48
Levofloxacin
6-8 hours
48


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Levomethadyl 
Multiple compartment PK with active metabolite 
2.6 day for LAAM, 2 day for nor-LAAM, 4 day 
for dinor-LAAM
 
Compound 
 
Compound Half Life 
Possible 
Washout 
Period - 
Hours
Possible 
Washout 
Period - 
Days
Lithium
24 hour (10-50)
7
Mesoridazine
24-48 hours ( animal study)
10
Methadone
15-30 hours
7
Moexipril/HCTZ 
2-9 hour (include active metabolite) for 
moexipril; 5.6-14.8 hours for HCTZ 
48 
 
Moxifloxacin 
12 +/-1.3 hours 
Naratriptan
6 hours
36
Nicardipine
~ 2 hour post IV infusion
12
Nortriptyline*
> 24 hours, wide interpatient variability
Octreotide
1.7 hours
12
Ofloxacin
5 to 7.5 hours
2
Ondansetron
4 hours (IV/IM); 3 hours (PO)
1 to 3
Pentamidine
6.4+/-1.3 hours
36
Pimozide
55 hours
10
Procainamide
3-4 hour for PA and NAPA (active metabolite)
24
Protiptyline*
> 24 hours, wide interpatient variability
Quetiapine
6 hours
36
Quinidine
6-8 hours in adult; 3-4 hours in children
36
Quinine
4-5 hours
Risperidone 
3-20 hours (extensive to poor metabolizer) 
9-hydroxyrisperidone (active metabolite) T ½ 
=21-30 hours (extensive to poor metabolizer)
 
4 
Salmeterol
5.5 hours ( only one datum)
36
Sotalol
12 hours
72
Sparfloxacin
20 hours (16-30)
4
Sumatriptan
2.5 hours
12
Tacrolimus 
~34 hours in healthy; ~19 hours in Kidney 
transplant
 
7 
Tamoxifen
5-7 days (biphasic)
30
Telithromycin
2-3 hr
24
Thioridazine
20-40 hours (Phenothiazines)
7
Tizanidine
2.5 hours
12
Vardenifil
4 to 5 hours
Venlaflaxine 
5 +/-2 hours for parent comp. 
11+-2 hours for OVD (active metabolite)
60 
 
Voriconizole
6 hours; dose dependent
Ziprasidone
7 hr
36
Zolmitriptan
2.8-3.7 hours (higher in female)
18
 
 
 


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APPENDIX C 
 Potential Drug Interactions With Selumetinib  
 
Changes to, or addition of, the following medications should be avoided, unless clinically indicated: 
 
 
Strong inhibitors of CYP3A4 or fluconazole (strong CYP2C19/ moderate CYP3A4 inhibitor) 
 
CYP3A4 
 
 
Indinavir 
 
 
Nelfinavir 
 
 
Ritonavir 
 
 
Clarithromycin 
 
 
Itraconazole 
 
 
Ketoconazole 
 
 
Nefazodone 
 
 
Saquinavir 
 
 
Suboxone 
 
 
Telithromycin 
 
 
Aprepitant 
 
 
Erythromycin 
 
 
Fluconazole 
 
 
Grapefruit juice 
 
 
Verapamil 
 
 
Diltiazem 
 
Strong / moderate Inducers of CYP3A4 
 
CYP3A4 
 
 
Efavirenz 
 
 
Nevirapine 
 
 
Barbiturates 
 
 
Carbamazepine 
 
 
Glucocorticoids 
 
 
Modafinil 
 
 
Oxcarbazepine 
 
 
Phenobarbital 
 
 
Phenytoin 
 
 
Pioglitazone 
 
 
Rifabutin 
 
 
Rifampin 
 
 
St John's wort 
 


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Strong inhibitors of CYP3A4 or fluconazole (strong CYP2C19/ moderate CYP3A4 inhibitor) 
 
CYP3A4 
 
 
Troglitazone 
 
 
When AZD 6244 is co-administered with compounds classified as inhibitors, increased plasma 
concentration of AZD 6244 is the potential outcome. The co-administration of „inducers‟ would 
potentially lower plasma AZD 6244 concentrations.  
(1) Gorski, et al. (2004). Clin Pharmacol Ther. 75:89-100. 
(2) Saruwatari, et al. (2003). J Pharm Pharmacol. 55:1553-1559.  


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APPENDIX D: Dose Reduction Guide for Selumetinib  
 
 
 
Body Surface  
Area (m2) 
 
0.55 to 0.69
0.7 to 0.89
0.9 to 1.09
1.1 to 1.29
1.3 to 1.49
1.5 to 1.69
1.7 to 1.89
 1.9 to >2.0
Selumetinib dose (mg) 
Dose level 0 
 
am 
10
20
25
30
35
40
45
50
pm 
10
20
25
30
35
40
45
50
 
First dose reduction 
           (mg) 
       Dose level -1 
am
pm
10
Zero
20
10
25
10
25
20
25
25
30
30
35
30
35
35
 
 
 
For all patients, dosing will be based on BSA.  
 
 
Dosing Table for AZD 6244 20 mg/m2 BID 
 
 
 
 


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APPENDIX E Hearing Response Guidelines:  
Clinical criteria for definition of hearing response based on a 50-word hearing test. Upper and 
lower limits for the 95% critical differences for percentage scores are adapted from Thornton.REF


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APPENDIX F – Participant Diary 
 
STUDY : 
DRUG: 
Amount (mL / # of pills):
 
Patient initials/ID number: 
Dose: 
Dose Frequency: 
Cycle Number: 
 
Week #                                       Date 
 
 
Time dose taken* 
Indicate reason for missed doses 
 
 
 
 
 
 
 
AM       PM 
AM       PM 
AM       PM 
AM       PM 
AM       PM 
AM       PM 
AM       PM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIDE EFFECTS 
Nausea (see scale below)† 
 
 
 
 
 
 
 
Vomiting (# of times in 24 hr) 
 
 
 
 
 
 
 
Diarrhea (# of times in 24 hr) 
 
 
 
 
 
 
 
Constipation∞ 
 
 
 
 
 
 
 
OTHER SIDE EFFECTS (list below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATIONS (Name)                                Dose              Frequency             Start Date              Stop Date                         Reason for Use of Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*     If you miss a dose write “M” in the box. 
†        Rate nausea mild if you are able to eat and drink a reasonable amount, moderate if you can eat and drink but the amount is substantially decreased, or severe if you are unable to eat 
and drink. 
∞ Indicate # of bowel movements/day 
 
 
Parent/patient signature                                                                                                   Date 
 


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APPENDIX G: NFTI-QOL (Neurofibromatosis 2 impact on quality of life) 
 
SUBJECT IDENTIFIER: _____________________________________ 
 
 
INSTRUCTIONS FOR COMPLETING THE NFTI-QOL 
 
Please complete the following information: 
 
Age:              years 
 
Gender: Male     1   Female    2           (please tick) 
 
 
For each of the questions on the next page, please tick the one box that 
describes how you feel today 
 
Usual activities include: work; housework; study; sport; social; family or leisure 
activities 
 
 
Guy’s NFTI-QOL 
 
Q1. Do balance or dizziness problems stop you performing your usual activities? 
No balance problems or dizziness                                          □0 
Balance or dizziness problems but no difficulties                 □1 
Balance or dizziness problems cause me some difficulties   □2 
Balance or dizziness problems stop my usual activities        □3 
 
Q2. Do hearing problems stop you performing your usual activities? 
No hearing problems                                                              □0 
Hearing problems but no difficulty                                        □1 
Hearing problems cause me some difficulty                          □2 
Hearing problems stop my usual activities                            □3 
 
 
Q3. Does facial weakness stop you performing your usual activities? 
No facial weakness                                                                □0 
Facial weakness, but no difficulty                                         □1 
Facial weakness causes some difficulty                                 □2 
Facial weakness stops my usual activities                             □3 
 
 
Q4. Do problems with your sight stop you performing your usual activities? 
No problems with sight                                                          □0 


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APPENDIX H Canadian Cardiovascular Society grading of angina pectoris 
 
Grade 
Description 
I 
Ordinary physical activity does not cause angina, such as walking 
and climbing stairs. Angina with strenuous or rapid or prolonged 
exertion at work or recreation
II 
Slight limitation of ordinary activity. Walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, or in 
cold, or in wind, or under emotional stress, or only during the few 
hours after awakening. Walking more than two blocks on the level 
and climbing more than one flight of ordinary stairs at a normal 
pace and in normal conditions
III 
Marked limitation of ordinary physical activity. Walking one or two 
blocks on the level and climbing one flight of stairs in normal 
conditions and at normal pace 
IV 
Inability to carry on any physical activity without discomfort, 
anginal syndrome may be present at rest
 
Campeau Lucien. Grading of angina pectoris Circulation 1976;54:5223  
Available on the Canadian Cardiovascular Society Website at www.ccs.ca 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I New York Heart Association (NYHA) classification of heart disease 
NYHA Class
Symptoms
I 
No symptoms and no limitation in ordinary physical activity, 
e.g. shortness of breath when walking, climbing stairs etc.
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity.
III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest.
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
 
New York Heart Association 1994 
The Criteria Committee of the New York Heart Association: Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th edition. Boston, MA: Little, Brown & 
Co; 1994:253-256.