-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 PhaseII: geater than 2 years of age and less than or equal to 18 years of age.
BSA greater than or equal to 0.55 m2, 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 substantialmorbidity due to encasement
of, or close proximity to, vital structures, invasiveness, or high vascularity of the
PN. The PN has to cause significant morbidity, such as (but not limited to) head and
neck lesions that could compromise the airway or great vessels, 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 significant cosmetic
problems, 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:
- 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 as per criteria above.
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, or if a patient
with a surgical option refuses surgery.
- 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 AZD6244 hyd sulfate 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, or other VEGFR
inhibitors are eligible for enrollment.
- Growth factors that support platelet or white cell number or function must not
have been administered within the past 7 days.
- Patients who received prior medical therapy for their PN must have recovered
from the toxic effects of all prior therapy before entering this study.
- At least 6 weeks must have elapsed prior to enrollment since the patient
received any prior radiation therapy.
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%.
6. Hematologic Function: Patients must have an absolute neutrophil count greater than or
equal to 1000/(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 ALT within less than or
equal to 1.5 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 5 and/or less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL
Age 10 and/or 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) greater than or equal to 55% (if a
range is given then the upper limit of the range will be used)
10. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine
eligibility for this trial must only be done after obtaining written informed consent
from all patients 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.
11. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of
age will be offered the opportunity to assign DPA so that another person can make
decisions about their medical care if they become incapacitated or cognitively
impaired.
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 on this study in girls, age 9 or older. 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. 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.
12. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath
tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
13. Supplementation with vitamin E greater than 100% of the daily recommended dose.
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 controlled glaucoma and
increased IOP who do not have meaningful vision (light perception only or no light
perception) may be eligible after discussion with the study chair.
4. Subjects with any other significant abnormality on ophthalmic examination (performed
by an ophthalmologist) 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.
Minimum Eligible Age: 2 Years
Maximum Eligible Age: 18 Years
Eligible Gender: Both
