AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

Background

- Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of
the central and peripheral nervous system, including plexiform neurofibromas (PN), which
are benign nerve sheath tumors that are among the most debilitating complications of
NF1. PN may be congenital and appear to have the fastest growth rate in young children.
Surgery is the only standard treatment option available for PN. However, this is often
difficult due to the encasement of vital structures, and extensive and invasive PN
growth.

- PN are composed of neoplastic Schwann cells that lack NF1 gene expression. This results
in upregulation of Ras, which initiates several signaling cascades regulating cell
proliferation.

- Selumetinib (AZD6244 hyd sulfate), a novel orally bioavailable mitogen activated protein
kinase inhibitor, is a specific inhibitor of MEK 1, which may mediate anti-tumor effects
in PN by inhibition of downstream signaling of Ras. Selumetinib is currently undergoing
evaluation in adult cancers and children with brain tumors.

- In this phase I study of selumetinib directed at NF1 PN, we have observed a degree of

activity which has not been observed previously; therefore a phase II evaluation will be
conducted

Objectives

Phase I:

- To determine the maximum tolerated dose (MTD) of oral selumetinib administered daily to
pediatric patients with NF1 and inoperable PN. Based on the results of the dose
escalation in this study, the current MTD has been determined as 20 mg/m2/dose. To be
consistent in pediatric dosing, an additional dose level of 25 mg/m2/dose was added,
which is the MTD recently determined in a study conducted by the Pediatric Brain Tumor
Consortium (PBTC). Amendment H (November 2014): The MTD has been determined to be 25
mg/m(2)/dose.

- To define the acute and chronic toxicities and pharmacokinetics (PK) of selumetinib.
Completed with amendment H.

Phase II:

-Primary objectives: To evaluate the confirmed partial and complete response rate of
selumetinib using volumetric MRI analysis in children and young adults with NF1 and
inoperable PN with PN related morbidity at the time of enrollment.

Eligibility

Pediatric Patients (greater than or equal to 2 and less than or equal to 18 years) who are
able to swallow intact capsules, with NF1 and inoperable measurable PN that have the
potential to cause significant morbidity.

Design

- Selumetinib will be administered orally BID on a continuous dosing schedule (28 days = 1
treatment cycle). In the phase I portion, limited dose escalations will be performed to
define the MTD based on tolerability of selumetinib during the first three treatment
cycles. In the phase II portion, the recommended phase II dose level (RP2D) will be
administered.

- Phase II: Patients will be enrolled on one of two strata:

- Stratum 1: PN related morbidity present at enrollment

---PN related pain, disfigurement, or difficulty in physical functioning

- Stratum 2: No significant PN related morbidity present at enrollment, but potential
for development of PN morbidity

- Patient reported and functional outcomes will be evaluated at regular intervals.

- Disease status will be evaluated using volumetric MRI analysis at regular intervals.

- The day 1 and steady state plasma PK and PD of selumetinib will be evaluated.

-INCLUSION CRITERIA:

1. Age Phase I: greater than 3 years and less than or equal to 18 years at the time of
study enrollment, if able to swallow whole capsules. The age limits including young
children were chosen because early childhood and puberty are considered to be the
greatest risk for disease progression, and selumetinib may provide the most benefit to
this young group of patients. In addition, an important objective of this study is to
characterize the pharmacokinetics of selumetinib in the pediatric population since it
has been well studied in adults.

Age Phase II: geater than 2 years of age and less than or equal to 18 years of age.
BSA greater than or equal to 0.55 m(2), and able to swallow whole capsules.

2. Diagnosis: Patients with NF1 and inoperable PN, defined as PN that cannot be
surgically completely removed without risk for substantial morbidity due to encasement
of, or close proximity to, vital structures, invasiveness, or high vascularity of the
PN. The PN has to cause (stratum 1) or have the potential to cause (stratum 2)
significant morbidity, such as (but not limited to) head and neck lesions that could
compromise the airway or great vessels, paraspinal lesions that can cause myelopathy
brachial or lumbar plexus lesions that could cause nerve compression and loss of
function, lesions that could result in major deformity (e.g., orbital lesions) or are
significantly disfiguring, lesions of the extremity that cause limb hypertrophy or
loss of function, and painful lesions. Patients will be enrolled into stratum 1 or 2
based on PN related morbidity.

Histiologic confirmation of tumor is not necessary in the presence of consistent
clinical and radiographic findings, but should be considered if malignant degeneration
of a PN is clinically suspected.

A PN is defined as a neurofibroma that has grown along the length of a nerve and may
involve multiple fascicles and branches. A spinal PN involves two or more levels with
connection between the levels or extending laterally along the nerve. In addition to
PN, all study subjects must have either positive genetic testing for NF1 or have at
least one other diagnostic criterion for NF1 listed below: (NIH Consensus conference):

- Six or more caf(SqrRoot)(Copyright)-au-lait macules (greater than or equal to
0.5cm in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal
subjects)

- Freckling in axilla or groin

- Optic glioma

- Two or more Lisch nodules

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or
thinning of long bone cortex)

- A first-degree relative with NF1

3. Measurable disease: Patients must have at least one measurable PN, defined as a lesion
of at least 3 cm measured in one dimension. Patients who underwent surgery for
resection of a PN are eligible provided the PN was incompletely resected and is
measurable.

Phase II: Measurability and suitability for volumetric MRI analysis of the target PN
must be confirmed with the NCI POB prior to enrolling a patient. The target PN will be
defined as the clinically most relevant PN, which has to be amenable to volumetric MRI
analysis. PN will be classified as typical PN versus nodular PN versus solitary
nodular PN prior to enrollment

4. Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is
not considered to be feasible without substantial risk or morbidity.

- Since there is no standard effective chemotherapy for patients with NF1 and PN,
patients may be treated on this trial without having received prior medical
therapy directed at their PN.

- Since selumetinib is not expected to cause substantial myelosuppression, there
will be no limit to number of prior myelosuppressive regimen for PN or other
tumor manifestations associated with NF1 such as optic glioma.

- Patients who have received previous investigational agents or biologic therapy,
such as tipifarnib, pirfenidone, Peg-Intron, sorafenib, imatinib or other
targeted therapies are eligible for enrollment. At least 4 weeks must have
elapsed since receiving medical therapy directed at the PN. Patients who received
prior medical therapy for their PN must have recovered from the acute toxic
effects of all prior therapy to less than or equal to grade 1 before entering
this study.

- Growth factors that support platelet or white cell number or function must not
have been administered within 7 days prior to enrollment.

- At least 6 weeks must have elapsed prior to enrollment since the patient received
any prior radiation therapy.

- At least 4 weeks must have elapsed since any surgeries, with evidence of good
wound healing.

5. Performance status: Patients greater than or equal to 16 years of age must have a
Karnofsky performance level of greater than or equal to70%, and children < 16 years
old must have a Lansky performance of greater than or equal to 70%. Patients who are
wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be
considered ambulatory when they are up in their wheelchair. Similarly, patients with
limited mobility secondary to need for mechanical support (such as an airway PN
requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of
the study.

6. Hematologic Function: Patients must have an absolute neutrophil count greater than or
equal to 1500/(micro)l, hemoglobin greater than or equal to 9g/dl, and platelet
greater than or equal to 100,000/(micro)l.

7. Hepatic Function: Patients must have bilirubin within 1.5 times the upper limit of
normal for age, with the exception of Gilbert syndrome, and AST/ ALT within less than
or equal to 3 times the upper limit of normal.

8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater
than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age
described below.

Age (years)/Maximum Serum Creatinine(mg/dL):

Age less than or equal to 5/Maximum Serum Creatinine 0.8 mg/dL

Age greater than 5 to less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL

Age greater than 10 to less than or equal to 15/ Maximum Serum Creatinine 1.2 mg/dL

Age greater than 15/ Maximum Serum Creatinine 1.5 mg/dL

9. Cardiac Function: Normal ejection fraction (ECHO or cardiac MRI) greater than or equal
to 53% (or the institutional normal; if a range is given then the upper value of the
range will be used); QTcF less than or equal to 450 msec.

10. Adequate Blood Pressure defined as:

A blood pressure (BP) less than or equal to the 95th percentile for age, height, and
gender measured as described in (Appendix IB). Adequate blood pressure can be achieved
using medication for treatment of hypertension.

11. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine
eligibility for this trial must only be done after obtaining written informed consent
from all patients or their legal guardians (if the patient is <18 years old). When
appropriate, pediatric patients will be included in all discussions. This can be
accomplished through one of the following mechanisms: a) the NCI POB screening
protocol, b) an IRB-approved institutional screening protocol, or c) the
study-specific protocol. Documentation of the informed consent for screening will be
maintained in the patient s research chart. Studies or procedures that were performed
for clinical indications (not exclusively to determine eligibility) may be used for
baseline values even if the studies were done before informed consent was obtained.

12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated.

13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other
products containing these fruits, e.g. grapefruit juice or marmalade) during the
study, as these may affect selumetinib metabolism.

EXCLUSION CRITERIA:

1. Pregnant or breast-feeding females are excluded due to potential risks of fetal and
teratogenic adverse events of an investigational agent. Pregnancy tests must be
obtained prior to enrollment for all females of childbearing potential as per
institutional standards (at NIH subjects 9 years and older or those showing pubertal
development). Males or females of reproductive potential may not participate unless
they have agreed to use an effective contraceptive method. Abstinence is an acceptable
method of birth control.

2. Phase I: Patients who anticipate the need for surgical intervention within the first
three cycles (3 months), as surgical intervention during the period of DLT evaluation
may affect analysis of adherence and/or make the subject inevaluable.

3. Use of an investigational agent within the past 30 days.

4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor,
immunotherapy, or biologic therapy.

5. Any evidence of severe or uncontrolled systemic disease, active infection, active
bleeding diatheses, or renal transplant, including any patient known to have hepatitis
C, or human immunodeficiency virus (HIV) will be excluded. Patients with HIV who have
adequate CD4 count, not requiring antiretroviral medication, may be enrolled.

6. Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study.

7. Inability to swallow capsules, since capsules cannot be crushed or broken.

8. Inability to undergo MRI and/or contraindication for MRI examinations following the
MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with
volumetric analysis of target PN on MRI.

9. Refractory nausea and vomiting, chronic grastointestinal disease (e.g., inflammatory
bowel disease), or significant bowel resection that would preclude adequate
absorption.

10. Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the
subject meets criteria for re-treatment.

11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath
tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.

12. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
multivitamin containing vitamin E must be stopped prior to initiation of therapy.

13. Patients not achieving adequate blood pressure in spite of antihypertensive therapy
for control of blood pressure.

14. Cardiac Function: a) known inherited coronary disease, b) Symptomatic heart failure
(NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease),
c) Prior or current cardiomyopathy, d) Sever valvular heart disease, 3) History of
atrial fibrillation

15. Ophthalmologic conditions:

1. Current or past history of central serous retinopathy

2. Current or past history of retinal vein occlusion

3. Known intraocular pression (IOP) greater than 21 mmHg (or ULN adjusted by age) or
uncontrolled glaucoma (irrespective of IOP); Patients with known glaucoma and
increased IOP who do not have meaningful vision (light perception only or no
light perception) and are not experiencing pain related to the glaucoma, may be
eligible after discussion with the study chair.

4. Subjects with any other significant abnormality on ophthalmic examination should
be discussed with the Study Chair for potential eligibility

5. Ophthalmological f ndings secondary to long-standing optic pathway glioma (such
as visual loss, optic nerve pallor or strabismus) or long-standing
orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a
significant abnormality for the purposes of the study

16. Known severe hypersensitivity to selumetinib or any excipient of selumetinib or
history of allergic reactions attributed to compounds of similar chemical or biologic
composition to selumetinib.

17. Recent major surgery within a minimum of 4 weeks prior to starting study treatment,
with the exception of surgical placement for vascular access.

18. Any unresolved chronic toxicity with CTC AE grade greater than or equal to 2 from
anti-NF1 therapy, except for alopecia.

19. Clinical judgement by the investigator that the patient should not participate in the
study.

20. While not an exclusion criterion, 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 known to
either induce or inhibit the activity of hepatic mircrosomal isoenzymes CYP1A2,
CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib.